Structured Knowledge-Gap Register
This register is rendered directly from the knowledge_gaps entries curated in the gene-review and module YAML (see the KnowledgeGap schema class). It is the structured, queryable counterpart to the worked prose entries on the parent project page.
1620 curated gap(s) across genes and modules.
- By status: NARROWING (69), OPEN (1186), RESOLVED (3), — (362)
- By kind: BIOLOGY (1320), CURATION (394), ONTOLOGY (149), — (110)
| Entity | Level | Status | Kind | Aspect | Prov. | Gap statement |
|---|---|---|---|---|---|---|
| 114 | gene | OPEN | ONTOLOGY | — | 1 | GO has no molecular-function term for cleavage of a cyclic oligoadenylate second messenger, so the activity of this enzyme can only be asserted with GO:0004521 RNA endonuclease activity, which omits the substrate that defines it. |
| 114 | gene | RESOLVED | CURATION | — | 2 | The UniProt entry is reviewed Swiss-Prot yet still titled "Uncharacterized protein 114", with no FUNCTION line and zero GO annotations, six years after the protein was characterised enzymatically, structurally and in a living host. |
| 114 | gene | OPEN | BIOLOGY | — | 1 | Whether this gene is required for SIRV1 itself to overcome type III CRISPR immunity in its natural host is undetermined. Sufficiency was shown by expressing it in trans to rescue a different, duf1874-less virus; necessity in the virus of… |
| A0A2G9RZF1 (core function) | core_function | — | BIOLOGY | — | 0 | A0A2G9RZF1 is a gene prediction fragment, not a complete protein. Its true molecular function cannot be determined from this 156-aa fragment. The complete gene product is a tolloid-family metalloprotease (BMP-1 or TLL1) with metalloendop… |
| A0A8B6BFL6 (core function) | core_function | — | BIOLOGY | — | 0 | No direct biochemical assay has confirmed reverse transcriptase activity for this specific protein. |
| A0A8B6BFL6 (core function) | core_function | — | BIOLOGY | — | 0 | The specific DIRS1 family or subfamily assignment has not been determined by phylogenetic analysis of the full-length protein. |
| A0A8B6BFL6 (core function) | core_function | — | BIOLOGY | — | 0 | Cellular localization has not been experimentally determined; nucleus and cytoplasm are inferred by analogy to characterized retrotransposon systems. |
| A3GALT2 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 2 | It is unknown whether an intact endogenous full-length A3GALT2 transcript and protein are expressed in any human cell type or developmental state. |
| A3GALT2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether endogenous human A3GALT2 catalyzes any measurable reaction or contributes causally to physiological iGb3 or iGb4 flux is unresolved. |
| A3GALT2 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | The native subcellular location and membrane topology of endogenous human A3GALT2 protein are unknown. |
| AAD3 | gene | NARROWING | BIOLOGY | MF_DARK | 2 | The aryl-alcohol dehydrogenase activity implied by the gene name has been directly tested on purified Aad3p and refuted, but no positive molecular function has taken its place. What remains unknown is whether Aad3p retains any catalytic … |
| AAD3 | gene | OPEN | BIOLOGY | BP_DARK | 3 | The biological role of AAD3 in S. cerevisiae — the pathway or physiological process (if any) it participates in, and the condition under which it is expressed or required — is undetermined. The aryl-alcohol/lignin context inherited from … |
| AAD3 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 2 | Why the AAD (aryl-alcohol dehydrogenase) gene family expanded to multiple, largely subtelomeric paralogs in Saccharomyces cerevisiae, and why a catalytically dead member such as AAD3 is retained as a full-length ORF across most sequenced… |
| AADAC (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Whether human AADAC directly hydrolyzes diacylglycerol, and which molecular species it prefers, has not been established with purified human enzyme or native human tissue. |
| AADACL2 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 2 | No substrate and no measured activity. AADACL2 has never been assayed - not against an ester, an amide, a lipid or a xenobiotic - so although the catalytic machinery is demonstrably intact, which bond it hydrolyses, on which substrate, a… |
| AADACL2 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 2 | Whether AADACL2 is secreted or membrane-anchored is undetermined, and GOA currently asserts both. The N-terminal hydrophobic segment is annotated as a cleaved signal peptide (SIGNAL 1..18) by UniProt and is the positional homolog of an e… |
| AADACL2 | gene | OPEN | CURATION | MF_DARK | 4 | The mechanistic molecular function of the AADAC family is annotated only at ortholog-specific PANTHER nodes and not at the node the family shares, so three human genes carry no mechanism term they are entitled to. GO:0017171 serine hydro… |
| AADACL4 | gene | OPEN | BIOLOGY | MF_DARK | 2 | No substrate is known for AADACL4 - neither a physiological acyl donor nor an in vitro surrogate ester has been tested - so the activity cannot be refined below the substrate-agnostic parent term. |
| AADACL4 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 2 | Which membrane AADACL4 occupies, and whether its N-terminal hydrophobic segment is an uncleaved type II signal anchor at all rather than a cleaved signal peptide, are both undetermined. |
| AADACL4 | gene | OPEN | BIOLOGY | BP_DARK | 2 | No biological process is known for AADACL4, and it has no protein-level detection: there is no cell or tissue in which the protein has been shown to be present, no loss-of- function phenotype, and no pathway assignment. |
| AAK1 | gene | NARROWING | BIOLOGY | RESIDUAL_SUBGAP | 1 | The cargo- and cell-type-specific division of AP2M1 phosphorylation and clathrin-dependent endocytosis among AAK1, BMP2K, GAK, and other kinases is not resolved. |
| AAK1 | gene | NARROWING | BIOLOGY | RESIDUAL_SUBGAP | 1 | The individual contribution of AAK1 versus BMP2K to endogenous PDLIM5 Thr-290 and talin-1 Thr-2270 phosphorylation in intact cells remains unresolved. |
| AARS1 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | Direct full-length human AARS1 Gly-tRNA(Ala) deacylation, and its kinetic specificity relative to Ser-tRNA(Ala), were not established in the human studies examined here. |
| AARS1 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 3 | The physiological lactate range, cell states, and substrate spectrum in which endogenous AARS1 makes a material contribution to protein lysine lactylation, relative to other enzymatic routes, remain incompletely defined. |
| AARS1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 3 | It is unknown whether the two human AARS1 isoforms differ in aminoacylation, editing, lactate-responsive localization, or lactyltransferase activity, and whether the isoform-2 insertion within C-Ala changes the domain's cellular role. |
| AARS2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The relative in vivo contributions of AARS2 pre-transfer and post-transfer editing to clearance of glycine errors, and the physiological balance between glycine and serine mischarging of mitochondrial tRNA(Ala), remain unresolved in huma… |
| AARS2 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | The physiological lactate range, cell states, tissues, and substrate spectrum in which endogenous AARS2 materially contributes to protein lysine lactylation, relative to class I HDACs and other routes, remain incompletely defined. |
| AARS2 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 1 | Which AARS2 species encounters cGAS, and how its mitochondrial import or trafficking permits that encounter under elevated lactate, remain unresolved. |
| AASDHPPT | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 3 | Endogenous human AASDHPPT has not been directly localized to the mitochondrial matrix, and the size, regulation, and physiological importance of a human matrix pool remain unknown. |
| AASDHPPT | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | It is unknown whether human AASDHPPT isoform 2 produces a stable protein with any phosphopantetheinyl-transferase activity or whether it has a distinct cellular location. |
| AASDHPPT | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 1 | The endogenous AASDHPPT dependence and site occupancy of proposed substrates such as AASDH and DHRS2 have not been established directly in human cells. |
| ABCG5 (core function) | core_function | — | — | — | 1 | The human-transgene absorption experiment does not resolve the relative contributions of intestinal efflux and increased biliary cholesterol delivery. |
| ABCG5 (core function) | core_function | — | — | — | 0 | The individual rat diet, drug, radiation and exercise expression responses were not established as conserved human ABCG5 protein-level functions by the source studies inspected. |
| ABRACL | gene | OPEN | ONTOLOGY | MF_DARK | 2 | GO cannot express what ABRACL does. It binds cofilin and reduces cofilin-stimulated filament disassembly without competing for the filament, which is an inhibitor activity directed at an actin-severing protein. GO carries the activator o… |
| ABRACL | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 2 | The direction in which ABRACL shifts the filamentous/globular actin balance is unresolved. Losing the Dictyostelium ortholog raises cytoskeleton-associated actin; depleting human ABRACL lowers the F-/G-actin ratio; and purified human ABR… |
| ABTB1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | ABTB1-specific CRL3 substrate-adaptor activity remains inferential because no physiological ABTB1 substrate or direct substrate-bridging assay has been established in the reviewed evidence. |
| ABTB1 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 2 | The compartment where ABTB1 performs its putative CRL3/scaffold function is not well resolved. |
| ABTB1 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | ABTB1's anti-proliferative/PTEN-linked role and prostate-cancer expression association remain mechanistically and contextually unresolved. |
| ACAD9 (core function) | core_function | OPEN | — | MF_DARK | 2 | The examined evidence establishes ACAD9-dependent assembly stabilization but does not resolve which precise molecular-function term represents that contribution, including whether ACAD9 itself bridges two macromolecules as GO:0030674 req… |
| ACAP2 / GTPase activator activity | annotation | — | ONTOLOGY + CURATION | — | 0 | GO cannot express which GTPase a GAP acts on. ACAP2's defining specificity - ARF6 in preference to ARF1 and ARF5, and explicitly not RAB35 - is invisible in the annotation. |
| ACAP3 | gene | OPEN | ONTOLOGY | MF_DARK | 1 | GO can no longer express which GTPase a GAP acts on, so the defining fact about ACAP3's molecular function - that its GAP activity is specific to Arf6 - cannot be recorded as a molecular function. |
| ACAP3 | gene | OPEN | CURATION | MF_DARK | 1 | Not one of ACAP3's ten GOA annotations derives from an experiment; every annotation is either a phylogenetic or an electronic inference, although four functional papers exist. |
| ACAP3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | ACAP3's only known physical partner is its own paralogue ACAP2, and neither the architecture of that association nor its purpose is known. |
| ACAP3 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | ACAP3 has no lipid-binding annotation and no lipid-binding data, despite carrying both a PH domain and a BAR domain, and despite the family's GAP activity being phosphoinositide-dependent. |
| ACAP3 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The guanine-nucleotide-exchange factor that ACAP3 pairs with to maintain the Arf6 cycle in neurons is not identified. |
| ACAP3 (core function) | core_function | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | No study has localised human ACAP3 in any cell type, so the compartment in which it acts on EGFR is inferred rather than observed. |
| acn1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | Whether acn1 is a catalytically active acyltransferase, and if so what reaction it catalyzes, is undetermined. No enzymatic assay has been performed on the acn1 protein; the acyltransferase molecular-function annotation is inferred entir… |
| acn1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The physiological substrate(s) of acn1 (its acyl donor and acyl acceptor) are unknown. It is undetermined whether acn1 acts on diacylglycerol (DGAT-type), a fatty alcohol (wax-ester synthase-type), a sterol, a lysophospholipid, or a prot… |
| acn1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biological process and physiological role of acn1 are unknown. No pathway, developmental role, or cellular process has been established; the only curated biological-process annotation is a root-level "no data" placeholder. |
| acn1 | gene | OPEN | BIOLOGY | CC_DARK | 1 | acn1's subcellular compartment is unresolved. The family prior (MBOAT enzymes are typically ER-resident) conflicts with the single experimental datum for acn1, a genome-wide GFP screen that reported mitochondrial localization. |
| ACRBP (core function) | core_function | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | Whether human ACRBP performs the acrosomal-granule packaging step at all is undetermined, and the two available lines of evidence point in opposite directions. The step is established only in mouse and only by transgenic rescue with the … |
| acrIF3 | gene | OPEN | CURATION | — | 1 | The protein is unreviewed in UniProt and named only "Phage protein", a machine-generated placeholder, despite three deposited structures of this very sequence and a mechanism established twice independently. The single GO annotation it c… |
| acrIF3 | gene | OPEN | BIOLOGY | — | 1 | It is undetermined whether AcrF3 can extract Cas2/3 that is already engaged with a licensed R-loop, or whether it can only intercept free Cas2/3 before recruitment. |
| acrIIA2 | gene | OPEN | CURATION + BIOLOGY | — | 1 | No function has been measured on this accession. Every functional claim for A0A059T5F6 is transferred from the 92.7 percent identical Listeria monocytogenes prophage protein AEO04363.1, and GOA holds no annotations for it at all. |
| acrIIA2 | gene | OPEN | BIOLOGY | — | 1 | Whether AcrIIA2 inhibits only target licensing, as pure PAM-site occlusion predicts, or additionally interferes with the cleavage step, is undetermined. |
| acrIIA4 | gene | OPEN | ONTOLOGY | — | 1 | GO has no molecular-function term for mimicry-based competitive inhibition, so the activity that is the whole point of AcrIIA4 cannot be asserted with an existing identifier. |
| acrIIA4 | gene | OPEN | BIOLOGY | — | 1 | Whether AcrIIA4 is expressed from the resident prophage at a level and time that matters during a natural Listeria infection is undetermined; all inhibition data come from induced heterologous expression or from purified protein. |
| acrIIC1 | gene | OPEN | ONTOLOGY | — | 1 | GO can state that AcrIIC1 inhibits a nuclease but cannot state that it occludes one catalytic domain of a multidomain nuclease while the enzyme's other activities, including DNA binding, survive. The diagnostic feature of the mechanism i… |
| acrIIC1 | gene | OPEN | BIOLOGY | — | 1 | Whether the AcrIIC1 redox switch operates in the native Neisseria meningitidis cytoplasm is undetermined; the switch was characterised with reference to eukaryotic cellular environments and gene-editing applications. |
| acrIIC1 | gene | OPEN | CURATION | — | 1 | The protein is unreviewed in UniProt and named only "Anti-CRISPR protein", taken from a PDB deposition rather than asserted by a curator, despite four deposited structures of this sequence and a mechanism published in Cell. |
| ACRV1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | ACRV1 has no assignable molecular function. Neither its own experimental record nor its protein family supplies a candidate activity, and the gap is a genuine absence of biochemistry rather than a curation backlog. |
| ACRV1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | Why an abundant, conserved, testis-specific acrosomal protein is dispensable for mouse fertility is unresolved; whether the null phenotype is masked by redundancy among acrosomal matrix proteins, or whether SP-10's contribution is only m… |
| ACRV1 / fusion of sperm to egg plasma membrane involved in single fertilization | annotation | OPEN | BIOLOGY | MF_DARK | 2 | The oolemmal ligand that SP-10 engages is unidentified; beta-1 integrins have been excluded but no positive candidate has been proposed or tested. |
| ACRV1 / protein binding | annotation | OPEN | BIOLOGY | MF_DARK | 1 | No physiological binding partner of SP-10 inside the acrosome has been identified; the acrosomal-matrix anchor that retains it against detergent extraction is an inferred, uncharacterised entity. |
| acrVA1 | gene | OPEN | BIOLOGY | MF_DARK | 0 | Which entity bears the catalytic centre for the crRNA cleavage that AcrVA1 causes is unestablished. AcrVA1 alone has no detectable ribonuclease activity, the primary work states that its data do not identify the component carrying the ca… |
| acrVA1 | gene | OPEN | CURATION | — | 1 | The protein is unreviewed in UniProt, named only "AcrVA1" from a PDB deposition, and carries no GO annotations at all, despite a published mechanism the discovering authors called a mode of inhibition not previously observed for any anti… |
| acrVA1 | gene | OPEN | BIOLOGY | — | 1 | The natural host-element pairing is unestablished. Which mobile element carries acrVA1, and which Cas12a system it evolved against, are not determined, so the biological setting in which this counter-defence operates is unknown. |
| acrVA1 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 2 | Which entity bears the catalytic centre for the crRNA cleavage is undetermined. The activity requires AcrVA1 and the Cas12a-crRNA complex together, and AcrVA1 alone has no detectable ribonuclease activity, so the alternative that AcrVA1 … |
| ACTA1 (core function) | core_function | — | — | — | 0 | The audited biochemical source measures phosphate release from pig skeletal alpha-actin; it does not supply a direct human ACTA1 ATP-cleavage rate. |
| ACTA1 (core function) | core_function | — | — | — | 0 | The reported affinity change was measured on patient actin containing 28% mutant protein, and the accessible report does not identify the ACTN isoform. |
| ACTA2 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | A human ACTA2-specific intrinsic ATP-hydrolysis rate was not established from the sources assessed here. Actin-activated myosin ATPase measurements should be distinguished from hydrolysis by ACTA2 itself. |
| ACTL7A (core function) | core_function | — | BIOLOGY | MF_DARK | 2 | It is not known whether ACTL7A is itself the filament-forming subunit of the subacrosomal actin network or instead nucleates, stabilises or anchors filaments built from conventional actin. |
| ACTL7A (core function) | core_function | — | BIOLOGY | MF_DARK | 1 | The mechanism linking ACTL7A to phospholipase C zeta is undetermined: it is not known whether ACTL7A binds the phospholipase directly, whether it retains it indirectly by holding the postacrosomal sheath together, or whether the loss is … |
| ACTL7B | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 0 | Every functional statement about ACTL7B comes from mouse. There is no human loss-of-function evidence, no human localisation study, and no biochemical assay on the human protein; the only human-specific data are transcript and protein de… |
| ACTL7B | gene | OPEN | BIOLOGY | MF_DARK | 0 | Whether ACTL7B binds a nucleotide is unknown. The pocket is intermediate: 13 of 20 nucleotide contacts computed from the F-actin structure are conserved, including the P-loop serine and lysine and the catalytic Gln137, but G15, D157, R21… |
| ACTL7B | gene | NARROWING | BIOLOGY | MF_DARK | 0 | The nuclear pool of ACTL7B has a localisation but no activity. Intranuclear ACTL7B is documented in spermatocytes and round spermatids, a conserved putative nuclear localisation sequence has been described, HDAC1 and HDAC3 lose intranucl… |
| ACTL7B (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 0 | What ACTL7B physically does to hold spermatid architecture together is unknown. No binding partner in the acrosome, acroplaxome or head-tail coupling region has been identified, no oligomeric state has been determined, and it is not know… |
| ACTL7B (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The direction of the relationship is unresolved. It is not known whether ACTL7B is a cargo adaptor that dynein light chains dock onto, a scaffold that sequesters them, or a substrate whose own positioning depends on them; the authors' ow… |
| ACTMAP | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Nothing is known about how ACTMAP itself is regulated, and no function has been attached to its one mapped post-translational modification. |
| ACTMAP | gene | OPEN | BIOLOGY | BP_DARK | 2 | Why loss of ACTMAP produces a functional defect only in skeletal muscle, when immature actin accumulates in every tissue, is unexplained. |
| ACTMAP | gene | OPEN | BIOLOGY | MF_DARK | 1 | There is no experimental structure of ACTMAP; the fold assignment and the identity of the catalytic nucleophile rest on AlphaFold models combined with mutagenesis, and no enzyme-substrate complex exists. |
| ACTMAP | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | How covalent liganding of Cys132 triggers proteasomal degradation of ACTMAP, and which ligase does it, is unknown. |
| ACTMAP | gene | OPEN | CURATION | WHOLLY_DARK | 2 | The model organism database record for the orthologue is empty, so the in vivo phenotype cannot be reached through GO at all. |
| ACTMAP (core function) | core_function | OPEN | ONTOLOGY | RESIDUAL_SUBGAP | 1 | No GO term expresses the actual chemistry, namely release of an N-alpha-acetylated N-terminal residue giving a substituted amino acid as product, so the molecular function has to be recorded with a term that is silent about the substrate. |
| ACTMAP (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | Whether profilin binding is functionally required for cleavage of immature actin, or is incidental to it, is undetermined. |
| ACTMAP (core function) | core_function | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 1 | Whether the human enzyme cleaves the acetylated cysteine of muscle alpha-actins has not been shown; the human demonstration covers beta- and gamma-actin only. |
| ACTMAP / initiator methionyl aminopeptidase activity | annotation | OPEN | ONTOLOGY | RESIDUAL_SUBGAP | 1 | GO has no term for hydrolytic release of an N-alpha-acetylated N-terminal residue from a protein, which is the reaction ACTMAP catalyses, so every term currently available to it is either wrong about the substrate or silent about it. |
| ACTR10 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The molecular link between ACTR10 and the mitochondrial outer membrane is unidentified: no ACTR10-binding protein or lipid on mitochondria has been reported, so it is unknown whether ACTR10 contacts the organelle directly or through an i… |
| ACTR10 (core function) | core_function | OPEN | BIOLOGY | BP_DARK | 1 | No aspect of ACTR10's mitochondrial cargo-coupling function has been assayed in a human system; the evidence is entirely zebrafish genetics plus shRNA in cultured rodent neurons. |
| ACTR1A (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | ACTR1A's own contribution to dynein-driven transport has never been tested by loss of ACTR1A at endogenous expression levels in human cells; the field's standard perturbation, p50/dynamitin overexpression, disperses the entire complex an… |
| ACTR1A (core function) | core_function | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | It is not known whether ACTR1A binds ATP and hydrolyses it as actin does, nor what the bound nucleotide is for: no nucleotide-binding, exchange or hydrolysis measurement has ever been reported for Arp1 from any organism. |
| ACTR1B (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | No experiment has isolated beta-centractin's own contribution to dynactin. There is no beta-selective depletion, no dynactin reconstituted with a defined beta content, and no reported phenotype for loss of ACTR1B alone; ACTR1B scores as … |
| ACTR5 | gene | OPEN | BIOLOGY | MF_DARK | 2 | The surface by which human ARP5 binds H2A-H2B, and whether that binding occurs at physiological concentrations, are undetermined. |
| ACTR5 | gene | OPEN | BIOLOGY | MF_DARK | 2 | Whether the nucleotide in ACTR5's actin cleft exchanges, is hydrolysed, or is structural is untested. |
| ACTR5 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 2 | Whether ACTR5 and IES6 have a function outside the INO80 complex is unresolved, and the published claim that they do is not adopted here. |
| ACTR5 | gene | OPEN | BIOLOGY | MF_DARK | 1 | No human ARP5 point mutant has been tested for nucleosome sliding, so ARP5's DNA-contact residues are structurally identified but functionally untested in human INO80. |
| ACTR5 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 1 | Whether ARP5 acts in double-strand break repair itself, or in the damage signalling that precedes it, is not separated by the existing data. |
| ACTR8 (core function) | core_function | — | BIOLOGY | MF_DARK | 3 | Whether human ARP8 binds extranucleosomal linker DNA as a length sensor, as the yeast ARP8 module does, is untested - and the two human measurements of ARP8 DNA affinity that exist disagree in emphasis without being reconciled. |
| ACTR8 (core function) | core_function | — | BIOLOGY | MF_DARK | 2 | The molecular activity by which ARP8 supports mitotic chromosome alignment is unknown, and so is what ARP8 is bound to on a mitotic chromosome, where nucleosomes are compacted and INO80 is apparently not assembled with it. |
| ACTRT2 (core function) | core_function | — | — | — | 0 | It is not known what ACTRT2 itself contributes to the perinuclear theca, as distinct from what the complex contributes. No Actrt2 knockout has been examined for perinuclear-theca architecture, acrosome attachment or sperm-head shape, the… |
| ACTRT2 (core function) | core_function | — | — | — | 0 | Whether ACTRT2 binds a nucleotide, and in what state, is untested. The phosphate-binding, cation and sensor positions are retained while the hydrolysis trigger is not, which predicts a nucleotide-bound but non-cycling fold, but no struct… |
| ACTRT2 (core function) | core_function | — | — | — | 0 | How the reported protection of spermatogonia from ferroptosis relates to the structural role is unresolved. Reducing ACTRT2 in a spermatogonial line increases busulfan-induced death with reactive-oxygen accumulation and mitochondrial cha… |
| ACTRT3 (core function) | core_function | — | BIOLOGY | MF_DARK | 0 | It is not known what ACTRT3 does within the perinuclear theca beyond being present in it: whether it is a load-bearing element of the scaffold, an adaptor that recruits other theca proteins, or a nucleotide-dependent switch that changes … |
| ACTRT3 (core function) | core_function | — | BIOLOGY | MF_DARK | 0 | Whether the PFN3-ARPM1 interaction is direct, and whether it uses the surface of ACTRT3 that corresponds to profilin's binding site on beta-actin. |
| ADAM5 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 1 | Whether the human ADAM5 locus produces any polypeptide at all is undetermined. The only direct test is a single 1999 Western blot with a heterologous (macaque) antiserum, which was negative; no targeted assay with a human-sequence-specif… |
| ADAM5 | gene | OPEN | BIOLOGY | BP_DARK | 1 | Whether the ADAM5 pseudogene transcript has a function of its own as a regulatory RNA is unknown. The proposed competing-endogenous-RNA mechanism rests on a predicted miRNA binding site and a copy-number association, with no direct demon… |
| ADAM5 | gene | OPEN | BIOLOGY | BP_DARK | 2 | It is not known how the human sperm ADAM adhesion complex is constituted, given that five of its rodent components - ADAM1A, ADAM1B, ADAM3A, ADAM3B and ADAM5 - are pseudogenes in humans. Whether a reduced ADAM2-based complex forms, wheth… |
| ADAMTSL1 | gene | OPEN | BIOLOGY | MF_DARK | 3 | No molecular function is known for ADAMTSL1: no ligand, no binding partner, no activity and no structural role has been demonstrated, and the gene carries no molecular-function annotation of any evidence code in GOA. |
| ADAMTSL1 / extracellular matrix organization | annotation | OPEN | BIOLOGY | BP_DARK | 3 | Whether ADAMTSL1 itself participates in organising the extracellular matrix, as opposed to merely residing in it and being turned over within it, has never been tested. |
| ADAMTSL3 / elastic fiber | annotation | OPEN | BIOLOGY | CC_DARK | 1 | ADAMTSL3 has never been localised in tissue. There is no published immunolocalisation of the endogenous protein to microfibrils, elastic fibres, or any other defined matrix structure. |
| ADAMTSL3 / extracellular matrix | annotation | OPEN | CURATION | — | 1 | UniProt records ADAMTSL3's extracellular matrix localisation with ECO:0000269|PubMed:14667842, but no corresponding IDA row exists in GOA, so the only localisation annotation this gene carries for its best-established compartment is a ph… |
| ADAMTSL3 / synapse organization | annotation | OPEN | BIOLOGY | MF_DARK | 1 | No molecular activity is known for ADAMTSL3 in the nervous system. How a secreted matrix glycoprotein raises DCC protein levels, and whether it does so by binding DCC, by binding something that presents DCC, or by altering the matrix in … |
| ADCK1 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether ADCK1 acts on YME1L1 directly is unknown. The ADCK1-YME1L1 relationship rests entirely on genetic epistasis in flies and in human cells; no physical interaction between the two has been reported, although ADCK1's contacts with th… |
| ADCK1 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 2 | No molecular function is known for ADCK1: neither a substrate nor a reaction has been identified, and no purified ADCK1 has ever been assayed in vitro. The published mutagenesis does not close the gap, because A164G, K183I, D315A and D33… |
| ADCK1 (core function) | core_function | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | The identity of the nucleotide ADCK1 binds is unknown. Its ATP-ligand BINDING sites at 161..169 and 183 are ProRule transfers (ECO:0000255), not measurements, while the closest characterised relative carrying the same alanine-rich loop, … |
| ADCK5 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 3 | ADCK5 has never been assayed. Its catalytic activity, its substrate and its physiological process are all undetermined: whether it transfers a phosphate to a protein, to a small molecule, or hydrolyses ATP without transferring anything a… |
| ADCK5 | gene | OPEN | ONTOLOGY | MF_DARK | 3 | GO cannot express what is actually known about this protein's molecular architecture: a protein-kinase-like fold whose conventional peptide-substrate pocket is occluded by its own N-terminal KxGQ domain and whose glycine-rich nucleotide … |
| adg2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular function of Adg2 is undetermined. No catalytic activity, ligand, adhesion target, or binding partner has been identified, and the protein has no recognizable enzymatic domain. |
| adg2 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The direct biological role of Adg2 is not experimentally established. Its assignment to cell separation rests on transcriptional co-regulation with characterized separation genes, not on any measured adg2 loss-of-function phenotype. |
| adg2 | gene | OPEN | BIOLOGY | CC_DARK | 1 | Whether Adg2 is actually GPI-anchored, and whether it resides at the plasma membrane or is cross-linked into the cell wall, has not been experimentally verified; the C-terminal omega (GPI-attachment) site has not been mapped. |
| ADGRA1 | gene | — | BIOLOGY | — | 3 | Whether ADGRA1 sits on the presynaptic or the postsynaptic side of the inhibitory synapse is unresolved. Two distinct questions are involved and the evidence bears on them unequally. On LOCALISATION, the only positive statements are that… |
| ADGRA1 | gene | — | BIOLOGY | — | 2 | No agonist is known for ADGRA1, and unlike every other adhesion GPCR it cannot use the tethered-agonist mechanism, because it has no GAIN domain and only a 19-residue extracellular N-terminus. The one experiment that tested whether that … |
| ADGRA1 | gene | — | BIOLOGY | — | 1 | The C-terminal PDZ-binding motif binds at least 21 scaffold proteins with measurable affinity, yet its cellular job is unidentified: deleting it changes neither synaptic localisation nor co-localisation with Galpha13. Which of the PDZ pa… |
| ADGRA1 | gene | — | BIOLOGY + CURATION | — | 1 | Almost every functional fact about ADGRA1 comes from mouse. The only experiments on the human protein are an RNAi study in pluripotent stem cells, whose readouts are pleiotropic and isolate no molecular function, and two in vitro PDZ-dom… |
| ADGRA1 | gene | — | CURATION | — | 1 | PAINT gives ADGRA1 no molecular function and no functional biological process. Node PTN002914505, whose human reach is exactly ADGRA1, carries only two cellular-component terms, both traceable to a 2017 sub-cellular proteomics survey. Th… |
| ADGRA1 | gene | — | ONTOLOGY | — | 1 | GO:0004930 and GO:0007186 both presuppose a ligand in their definitions ('combining with an extracellular signal'; 'initiated by a ligand binding to its receptor'), and GO offers no ligand-free sibling. Orphan and constitutively active r… |
| ADGRA2 | gene | OPEN | BIOLOGY | MF_DARK | 0 | No agonist and no transducer are known for ADGRA2: neither a ligand that binds the receptor itself nor any coupling to a heterotrimeric G protein has been demonstrated, so it is unknown whether the intact seven-transmembrane bundle signa… |
| ADGRA2 | gene | OPEN | BIOLOGY | MF_DARK | 0 | It is unknown whether ADGRA2's GAIN-B/GPS region undergoes the autoproteolysis that defines adhesion GPCRs, and whether a tethered-agonist (Stachel) sequence is generated and used. |
| ADGRA2 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 0 | The physiological role of the human ADGRA2 intracellular domain is unresolved: its class-I PDZ-binding motif (...LWKSETTV) binds at least 19 PDZ proteins in quantitative assays, yet the mammalian receptor appears not to need its intracel… |
| ADGRA3 | gene | NARROWING | BIOLOGY | MF_DARK | 3 | ADGRA3 has no known ligand. Every signalling result to date is constitutive activity of the receptor or of its cleaved C-terminal fragment; nothing extracellular has been shown to bind the receptor and change its output. The large ectodo… |
| ADGRA3 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 6 | Whether the Wnt/planar-cell-polarity role established for zebrafish adgra3 holds for the human protein is unresolved, and the available human evidence points in two directions at once. Zebrafish Gpr125 recruits Dishevelled to the membran… |
| ADGRA3 | gene | OPEN | CURATION | RESIDUAL_SUBGAP | 4 | None of the seven papers that experimentally characterised ADGRA3 has produced a single GO annotation. QuickGO returns zero annotations, for any species and any gene, for each of PMID:36089063 (autoproteolysis, DLG1, basolateral targetin… |
| ADGRA3 | gene | OPEN | BIOLOGY | BP_DARK | 4 | The mouse knockout phenotypes have no mechanistic link to any measured ADGRA3 activity. Adgra3-null males are infertile with a blockage between ejaculatory duct and urethra despite normal spermatogenesis, and Adgra3-null females develop … |
| ADGRV1 (core function) | core_function | — | — | — | 1 | Which receptor isoforms, activation states and G proteins mediate ADGRV1 signaling in native human hair cells and photoreceptors? |
| ADIPOQ | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | No structure of adiponectin bound to any of its three receptors exists. The three deposited structures (4DOU, 6U66, 6U6N) all cover only the globular C1q domain, residues 104-244, so neither the collagen-like domain nor any receptor comp… |
| ADIPOQ | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether the globular fragment of adiponectin, which is far more potent than the full-length protein in many assays, is actually generated in vivo in humans remains unresolved. It can be released from full-length adiponectin by neutrophil… |
| ADIPOQ | gene | OPEN | BIOLOGY + ONTOLOGY | RESIDUAL_SUBGAP | 1 | The sign of adiponectin's effect on inflammation is unresolved and appears to depend on multimer state and target-cell polarisation. HMW adiponectin induces MCP-1 and IL-8 in peripheral blood mononuclear cells and microvascular endotheli… |
| ADIRF | gene | OPEN | BIOLOGY | MF_DARK | 1 | ADIRF has no known molecular function of any kind. It is a 76-residue protein whose UniProt feature table contains a single CHAIN 1..76 and nothing else - no domain, no signal peptide, no transmembrane segment, no active or binding site … |
| ADIRF | gene | OPEN | BIOLOGY | CC_DARK | 2 | The route by which ADIRF reaches the extracellular space is unknown. The protein is measured in human serum at microgram-per-millilitre concentrations, detected as an intact species in lipoaspirate fluid, and recovered from two independe… |
| ADIRF | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 1 | ADIRF's function in vascular smooth muscle is entirely uncharacterised, despite artery being the tissue in which the gene is most abundant. Its GO record contains no vascular annotation of any kind. |
| ADIRF | gene | OPEN | BIOLOGY | CC_DARK | 1 | Whether ADIRF is actively retained in the nucleus is unknown. At 76 residues and 7855 Da it is far below the nuclear-pore passive-diffusion limit and has no annotated nuclear localisation signal, so its presence in the nucleus is the def… |
| ADIRF / positive regulation of fat cell differentiation | annotation | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | It is unknown whether ADIRF is required for adipocyte differentiation in any cell that expresses it endogenously. Every functional experiment on the gene is ectopic over-expression in mouse 3T3-L1 preadipocytes, and the mouse lineage car… |
| ADIRF / positive regulation of transcription by RNA polymerase II | annotation | OPEN | BIOLOGY | MF_DARK | 1 | The mechanism by which ADIRF increases C/EBP-alpha and PPAR-gamma expression is unknown. No DNA-binding activity, promoter occupancy, chromatin association or transcriptional cofactor has been reported for the protein, so it is not known… |
| ADISSP | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The receptor ADISSP acts through is unknown. Its existence is inferred from specific, competable binding to the adipocyte surface and from two downstream cascades that the purified protein switches on, but no candidate has been named, an… |
| ADISSP | gene | NARROWING | BIOLOGY + CURATION | MF_DARK | 2 | No functional experiment has been performed on the human protein. Human ADISSP has been shown to leave a cell - adenoviral expression in mouse liver put it into the circulation - and human adipocytes secrete it and human plasma contains … |
| ADISSP | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Nothing connects the two activities recorded for this protein. ADISSP is a leaderless secreted hormone acting on a surface receptor, and it is also a cytosolic binder of protein phosphatase 1; the two literatures do not cite each other a… |
| ADNP | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 1 | The relationship between NAP treatment effects and the activities of endogenous ADNP molecular species remains incompletely resolved. |
| ADNP | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The cell-state determinants of ADNP effects on Wnt signaling need to be reconciled across developmental and cancer contexts. |
| ADNP | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Intrinsic methyltransferase catalysis by purified ADNP is not established by the accessible immunoprecipitate evidence. |
| ADNP2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | What ADNP2 itself contributes catalytically or allosterically inside ChAHP2 is unknown. Its established roles are structural - it holds HP1beta and CHD4 together and is dispensable for the H3K9me3 mark - and the repressive step is attrib… |
| ADNP2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether ADNP2 binds DNA at all has never been measured. It carries a homeodomain and nine C2H2 zinc fingers with intact zinc-coordinating residues, so GO:0003677 is annotated from the fold, but no binding assay has been reported, the res… |
| ADNP2 | gene | OPEN | CURATION | — | 2 | Two experimentally reported human ADNP2 interactions are absent from GOA. CHD4 co-purifies with ADNP2 as one of the top two enrichments and forms a defined complex with purified full-length human ADNP2 and human HP1beta, yet no GO:000551… |
| ADNP2 | gene | OPEN | ONTOLOGY | — | 2 | GO has no term for the ChAHP2 complex, nor for ChAHP, and no term for silencing that is targeted by heterochromatin without establishing it. ADNP2's defining biological identity therefore cannot be recorded as complex membership, and its… |
| ADNP2 | gene | NARROWING | BIOLOGY | BP_DARK | 1 | The whole functional description of ADNP2 rests on mouse embryonic stem cells and zebrafish. Human ADNP2 has never been depleted in a human cell line, so whether it silences human retrotransposons, and which ones, is untested; correspond… |
| ADP-heptose precursor biosynthesis | module_node | — | BIOLOGY + CURATION | — | 0 | The terminal stereoisomer required by downstream glycoconjugate assembly differs among bacterial realizations and cannot be inferred solely from the presence of the four ADP-D,D-heptose reactions. |
| ADPRH | gene | OPEN | BIOLOGY + CURATION | — | 2 | Whether human ARH1 hydrolyses O-acetyl-ADP-ribose and poly(ADP-ribose) in addition to ADP-ribosyl-arginine is unresolved in the literature this review can read, and the two sources disagree in emphasis. |
| ADPRH | gene | OPEN | BIOLOGY + CURATION | — | 2 | The subcellular localisation of human ADPRH has never been determined experimentally. UniProt assigns no SUBCELLULAR LOCATION at all, and the only location annotation in GOA is an Ensembl Compara projection of a rat cerebrospinal-fluid w… |
| ADPRHL1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | ADPRHL1 has no known molecular function. No ligand, no substrate, no verified protein partner and no measured biochemical activity of any kind has been reported. The genetics say the vestigial substrate cleft is what matters, but what th… |
| ADPRHL1 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | The subcellular localisation of endogenous ADPRHL1 has never been imaged, in any species. Every localisation statement in the record - UniProt's SUBCELLULAR LOCATION line, the SubCell IEA row and the ISS row - descends from a single Xeno… |
| ADPRHL1 | gene | NARROWING | BIOLOGY | BP_DARK | 2 | Whether a mammal actually requires ADPRHL1 for heart development is untested. The only published mammalian allele deletes exons 3-4, and those animals are normal - but the allele still produces the smaller ADPRHL1 protein species, so it … |
| ADTRP | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The physiological substrate-to-phenotype link for human ADTRP is unknown: no study connects its measured FAHFA hydrolase activity to any of the endothelial, coagulation or atherosclerosis phenotypes attributed to the gene. |
| ADTRP | gene | OPEN | ONTOLOGY | BP_DARK | 1 | GO can express FAHFA hydrolysis as a molecular function but not as a biological process, so FAHFA catabolism has to be annotated with the much broader GO:0042758 long-chain fatty acid catabolic process. |
| ADTRP | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 1 | The ADTRP/AIG1 family is pan-eukaryotic with 5788 members, but only four proteins have ever been characterised biochemically: human and mouse ADTRP and human and mouse AIG1. No substrate is known for any fungal, plant or invertebrate mem… |
| AEBP2 | gene | NARROWING | BIOLOGY + CURATION | MF_DARK | 3 | Whether AEBP2 stimulates or inhibits PRC2 is unresolved as a statement about the gene, because the answer depends on which protein isoform is present and the two directions rest on different bodies of work. |
| AEBP2 | gene | NARROWING | CURATION | MF_DARK | 2 | AEBP2 has no molecular function annotation in GOA, and the measured molecular activities that could fill the gap are either isoform-specific, complex-level, or measured only on the mouse protein. |
| Aerobic nicotinate degradation through 2,5-dihydroxypyridine | module_node | — | ONTOLOGY | — | 0 | GO lacks a substrate-specific molecular-function term for the cytochrome-linked NicAB nicotinate dehydrogenase reaction. |
| Aerobic nicotinate degradation through 2,5-dihydroxypyridine | module_node | — | ONTOLOGY | — | 0 | GO lacks substrate-specific molecular-function terms for N-formylmaleamate deformylase and maleamate amidohydrolase activities. |
| Aerobic nicotinate degradation through 2,5-dihydroxypyridine | module_node | — | CURATION | — | 0 | Broad PANTHER and fold-level families for NicC, NicD, and NicF do not by themselves establish the substrate specificity of these reactions. |
| AFAP1 | gene | OPEN | BIOLOGY + CURATION + ONTOLOGY | MF_DARK | 3 | The structural mechanism separating AFAP1 actin cross-linking, multimerization, autoinhibition, and Src activation remains incompletely resolved. |
| AFAP1 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | AFAP1's contribution to cancer invasion, metastasis, and S403C variant-dependent Src activation remains incompletely resolved in vivo. |
| AFAP1 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | AFAP1 locus disease associations, including glaucoma risk and AFAP1-AS1 cancer biology, are not yet cleanly mapped to AFAP1 protein function. |
| AFF1 | gene | OPEN | BIOLOGY | CC_DARK | 3 | Whether AFF1 and AFF4 can occupy the same super elongation complex is unresolved, and the evidence points both ways. UniProt models them as alternative occupants of one slot and PMID:28955517's discussion states they are not found togeth… |
| AFF1 | gene | OPEN | BIOLOGY | CC_DARK | 2 | AFF1's subnuclear distribution is described inconsistently. Older immunofluorescence reports discrete punctate compartments ('AF4 bodies') where AF4 and AF9 co-localise, while PMID:28955517's discussion describes AFF1 as diffuse and rese… |
| AFF1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | Whether AFF1 has any molecular function outside a super elongation complex is unknown. Every measurement on the protein is made either within SEC or on a short peptide from it, and its only solved structure is 42 residues bound to a part… |
| AFF1 | gene | OPEN | BIOLOGY | BP_DARK | 2 | What the wild-type AFF1 protein contributes to t(4;11) leukaemogenesis, as distinct from the MLL-AFF1 chimera, is not established. The chimera is a different molecule with its own composition, and the peptide inhibitor PFWT that kills t(… |
| AFF3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | No structure of AFF3 in complex with any partner exists, so which segments of AFF3 contact P-TEFb, ENL and AF9 is unknown, in contrast to AFF1 and AFF4 where the cyclin T1 and ELL interfaces are mapped. |
| AFF3 | gene | OPEN | BIOLOGY | BP_DARK | 1 | Whether human AFF3 binds immunoglobulin switch regions and promotes AID recruitment in human B cells has not been tested; the mechanism is established in mouse, and the human arm of the same study is an expression association only. |
| AFF3 | gene | OPEN | ONTOLOGY | — | 1 | GO has no term for maintenance of allele-specific silencing by a protein that reads DNA methylation at a differentially methylated region, which is what AFF3 does at the XIST DMR and at imprinted gametic DMRs. |
| AFF4 | gene | NARROWING | CURATION | RESIDUAL_SUBGAP | 1 | AFF4 has no experimental biological-process annotation in GO, and no experimental molecular-function annotation other than bare protein binding, despite being the structurally best-characterised subunit of the super elongation complex. |
| AFF4 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether AFF4's stimulation of polymerase II elongation requires anything beyond holding P-TEFb and an ELL-family factor in proximity is not known. |
| AFF4 | gene | OPEN | CURATION | CC_DARK | 1 | The human euchromatin localisation of AFF4 has no human experiment behind it. |
| AFP | gene | NARROWING | CURATION | MF_DARK | 0 | This gene's GO problem is coverage rather than over-annotation, and the review should be read that way. |
| AFP | gene | OPEN | BIOLOGY | BP_DARK | 0 | What alpha-fetoprotein is for in humans is unknown, and the usual answer given is a rodent answer. |
| AFP | gene | OPEN | BIOLOGY | CC_DARK | 0 | Whether the intracellular alpha-fetoprotein described in hepatocellular carcinoma is a distinct functional pool or a by-product of very high biosynthetic flux is unresolved. |
| AFP | gene | OPEN | BIOLOGY | — | 0 | The functional significance of alpha-fetoprotein glycosylation is unresolved even though it carries the clinical assay. |
| AFP (core function) | core_function | OPEN | BIOLOGY + CURATION | — | 0 | Binding is established; delivery is not. No experiment on the human protein demonstrates the second half of a carrier activity, namely release of a bound fatty acid to an acceptor or at a destination. |
| AFP (core function) | core_function | OPEN | BIOLOGY | — | 0 | Which fatty acids the protein actually carries in human fetal plasma has not been measured on protein purified from fetal serum. |
| AFP (core function) | core_function | OPEN | BIOLOGY | — | 0 | How many metal sites alpha-fetoprotein has, and which metal each prefers in vivo, is unresolved. |
| AFP (core function) | core_function | OPEN | BIOLOGY | — | 0 | Whether metal binding has any physiological consequence is untested. |
| AFP / protein binding | annotation | OPEN | BIOLOGY | — | 0 | The AFP literature invokes a cell-surface AFP receptor, AFPR, repeatedly, but its molecular identity has never been established. |
| AGFG1 (core function) | core_function | — | BIOLOGY | — | 1 | Whether the acrosomal role uses the same VAMP7-longin-domain interaction as the somatic one is undetermined: no study has examined VAMP7 localisation or the VAMP7-AGFG1 contact in Agfg1-null spermatids. |
| AGFG1 (core function) | core_function | — | BIOLOGY | — | 1 | The host function of AGFG1's nuclear pool is undetermined. Every characterised activity of the nuclear fraction is the appropriated HIV-1 Rev role; no endogenous nuclear substrate, cargo or process has been identified. |
| AGFG1 (core function) | core_function | — | ONTOLOGY | — | 1 | GO has no term for Rev-dependent export of intron-retaining viral RNA, so this role can only be recorded with a general viral-transport parent. |
| AGFG2 | gene | OPEN | BIOLOGY | MF_DARK | 4 | The catalytic activity and substrate specificity of the AGFG2 ArfGAP-type domain remain unresolved. |
| AGFG2 | gene | OPEN | BIOLOGY | — | 3 | The domain and interaction requirements of endothelial secretion, inherited germ-cell functions and viral cofactor activity remain incompletely resolved. |
| AGGF1 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | Whether AGGF1's G-patch acts as a DEAH-box helicase activator, the function every structurally characterised G-patch has, is untested on this protein. |
| AGGF1 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 0 | It is not known whether AGGF1 contacts RNA directly or is recruited to NEAT1 through the paraspeckle core proteins it binds. |
| AGGF1 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | How AGGF1 leaves the cell is unknown. It has no signal peptide and no transmembrane segment, yet it is measurably secreted and measurably present in human vitreous fluid. |
| AGGF1 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | Two laboratories report opposite effects of AGGF1 on the TWEAK-Fn14 axis, and neither result is annotated. |
| AGO1 | gene | OPEN | BIOLOGY | — | 2 | Endogenous AGO1 stop-codon readthrough efficiency and the quantitative contribution of AGO1x differ among the reported assays and remain disputed after the 2025 critique and response. |
| AGT | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Whether the Cys42-Cys162 redox switch has any physiological role is unresolved, and the two decisive experiments disagree. The bridge is Cys18-Cys138 in human mature numbering (UniProt DISULFID 42..162 on a chain beginning at residue 25)… |
| AGT | gene | OPEN | BIOLOGY | MF_DARK | 2 | Why the angiotensin peptides are carried on a serpin scaffold at all is unknown. The fold is retained but the mechanism that defines the superfamily has been lost, and no function has been assigned to the retained body of the molecule be… |
| AGT | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | Angiotensinogen has no curated protein interaction partner outside the renin-angiotensin cascade that is supported by anything better than a large-scale yeast two-hybrid screen. |
| AGT | gene | OPEN | ONTOLOGY + CURATION | MF_DARK | 2 | GO cannot express the distinction between a precursor protein and the peptides cleaved from it, so every function of angiotensin I, II, III, IV and (1-7) is recorded indistinguishably on the 476-residue precursor. |
| AGTRAP (core function) | core_function | — | BIOLOGY | RESIDUAL_SUBGAP | 2 | The AGTRAP-AGTR1 interface is unmapped. No structure of the complex exists, and UniProt's REGION 110..122 'Interaction with AGTR1' feature carries no evidence code at all, so no individual contact residue on either partner has been ident… |
| AGTRAP (core function) | core_function | — | BIOLOGY | RESIDUAL_SUBGAP | 1 | Where AGTRAP acts on the receptor is unknown: whether it intercepts AT1R during biosynthetic delivery, accelerates retrieval from the plasma membrane, or both. |
| AGTRAP (core function) | core_function | — | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether the human protein stimulates SERCA2a at all is untested, and in no species is the binding site, the stoichiometry, or the relationship to phospholamban known - so it is unknown whether AGTRAP is an independent activator or a comp… |
| AHCY (core function) | core_function | — | — | — | 0 | The quantitative contribution and regulation of nuclear versus cytosolic SAH hydrolysis are context-dependent; the reported FTO interaction is a distinct mechanism that requires broader physiological assessment. |
| AHDC1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The examined cell-based studies do not resolve intrinsic AHDC1 DNA-sequence preferences or whether AHDC1 itself physically bridges regulatory regions. |
| AHDC1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether AHDC1 directly regulates the DNA-methylation machinery or changes methylation and chromatin contacts through downstream transcriptional effects remains unresolved. |
| AHDC1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The molecular pathway connecting mouse Ahdc1 deficiency to systemic metabolic phenotypes is unresolved at the abstract-level evidence examined here. |
| AHDC1 (core function) | core_function | — | — | — | 1 | The molecular step connecting AHDC1 to reduced DNA methyltransferase activity remains unresolved. |
| AHI1 (core function) | core_function | OPEN | BIOLOGY | — | 0 | The precise AHI1-dependent structural or recruiting step within the transition-zone assembly is unresolved. |
| AHI1 (core function) | core_function | OPEN | BIOLOGY + CURATION | — | 0 | The human expression-construct provenance and endogenous contribution in different human tissues warrant further resolution. |
| AHI1 (core function) | core_function | OPEN | BIOLOGY | — | 0 | The endogenous human OTUD1–TYK2 bridging dependency and its cell-type range remain to be tested directly. |
| ahk1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | Whether S. pombe ahk1 (SPAC7D4.03c) actually functions as a MAP-kinase scaffold, or has any scaffold activity at all, has never been tested. The molecular function is inferred entirely from the S. cerevisiae ortholog via the shared UPF05… |
| ahk1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The direct binding partners of ahk1 in S. pombe are unknown. It is undetermined whether it interacts with the fission-yeast stress-MAPK components (Sty1/Spc1, the MAPKK Wis1, the MAPKKKs Win1/Wis4, or membrane osmosensors such as Wsc1/Mt… |
| ahk1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | Whether ahk1 has a specific, non-redundant role in the S. pombe Sty1/Spc1 stress-activated MAPK pathway is undetermined. The budding-yeast function (preventing Hkr1-to-Kss1 cross-talk) may not map onto fission yeast, whose stress core (W… |
| ahk1 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 1 | The molecular activity of the DUF1765 domain that defines the UPF0592 family, and hence the biochemical basis of any ahk1 function, is entirely unknown. DUF1765 is a domain of unknown function with no assigned catalytic or binding activity. |
| ahk1 | gene | OPEN | BIOLOGY | CC_DARK | 1 | The subcellular localization of ahk1 in S. pombe has not been experimentally determined. The membrane / multi-pass membrane assignment is a sequence-based prediction (three predicted transmembrane helices) with no microscopy or fractiona… |
| AHNAK (core function) | core_function | — | — | BP_DARK | 0 | Every electrophysiological measurement of AHNAK's effect on L-type current has been made in rat or mouse cardiomyocytes, or in mouse T cells and neurons. The binding data are on recombinant AHNAK fragments, and one functional result uses… |
| AHNAK (core function) | core_function | — | — | BP_DARK | 0 | Whether AHNAK contributes to plasma membrane repair, the process its partners dysferlin, annexin A2 and S100A10 all serve, is unresolved and currently annotated in the direction the only experiment contradicts. The single laser-wounding … |
| AHNAK (core function) | core_function | — | ONTOLOGY | MF_DARK | 0 | GO has no molecular-function term that fits 'binds an oligomerization domain and caps the degree of self-association'. GO:0140311 protein sequestering activity is the nearest fit but is defined for preventing interaction or mislocalising… |
| AHNAK (core function) | core_function | — | BIOLOGY | BP_DARK | 0 | AHNAK has a second, entirely unconnected nuclear biochemical activity: it binds the DNA ligase IV-XRCC4 complex and stimulates its double-stranded ligation activity with purified proteins (PMID:15177040). Whether that is the same nuclear… |
| AHNAK2 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | No binding partner has been mapped to the AHNAK2 PDZ domain, so it is unknown what the protein scaffolds through the only interaction module it has. |
| AHNAK2 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | Whether the domain-swapped dimer forms at native concentrations in cells, or is a crystallisation-favoured state, has not been tested. |
| AHNAK2 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | It is undetermined whether AHNAK2 acts as a translocation-machinery component, a submembrane tether that holds FGF1 at the membrane, or a carrier that delivers it there. |
| AHNAK2 (core function) | core_function | OPEN | ONTOLOGY | BP_DARK | 0 | GO cannot express what AHNAK2 does here at the right granularity. There is no unconventional- or non-classical-secretion term anywhere in the ontology, and no fibroblast-growth-factor child of GO:0009306, so a machinery component of stre… |
| AHNAK2 (core function) | core_function | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 1 | The role has not been tested on the full-length human protein at native levels: the loss of function is on mouse AHNAK2 and the binding on an overexpressed human C-terminal fragment. |
| AHNAK2 (core function) | core_function | OPEN | BIOLOGY | BP_DARK | 1 | No force-transmission, membrane-repair or mechanical phenotype has been measured for AHNAK2 itself, so it is unknown whether AHNAK2 contributes to costamere function or merely resides there. |
| AHSP | gene | OPEN | ONTOLOGY | MF_DARK | 2 | GO has no molecular function term for a chaperone that binds a folded or partially folded client, holds it soluble in situ without unfolding it or translocating it, and releases it to an assembly partner. GO:0044183 requires the chaperon… |
| AHSP | gene | OPEN | ONTOLOGY | MF_DARK | 1 | GO has no molecular function term for suppressing the redox reactivity of a bound client's cofactor. AHSP does not itself react with oxygen or peroxide; it reconfigures the haem coordination sphere of the protein it binds. |
| AHSP | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | Whether AHSP has any function in the nucleus of maturing erythroblasts is unknown. A single imaging study reports the protein becoming predominantly nuclear in late erythroblasts and being expelled with the nucleus at enucleation, and no… |
| AIFM1 (core function) | core_function | — | — | — | 0 | Which physiological electron acceptor accounts for conserved human AIF redox function in each cellular context? |
| AIG1 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 2 | Where AIG1 executes its hydrolase activity is unresolved, and the two available answers are incompatible: GOA and UniProt say plasma membrane, while the only study that examined the question places the protein in the ER membrane with a d… |
| AIG1 | gene | OPEN | ONTOLOGY | BP_DARK | 1 | GO can express FAHFA hydrolysis as a molecular function but not as a biological process, so FAHFA catabolism has to be annotated with the much broader GO:0042758 long-chain fatty acid catabolic process. |
| AIG1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether AIG1 alone sets endogenous FAHFA tone in vivo is untested; the published genetic evidence comes from Adtrp single knockouts and AIG1/ADTRP double knockouts. |
| AIG1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Whether AIG1's Pirh2/p53 function requires its hydrolase activity is unknown, so the gene has two functional descriptions with no established relation between them. |
| AIM33 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 0 | The specific catalytic activity of AIM33 and its physiological electron acceptor are undetermined. It is not known whether AIM33 reduces cytochrome b5, coenzyme Q, a cytochrome P450, or another (possibly mitochondrial) redox partner, nor… |
| AIM33 (core function) | core_function | OPEN | BIOLOGY + CURATION | CC_DARK | 0 | The subcellular membrane in which AIM33 acts is unresolved: PAINT propagates a PGA3-seeded plasma-membrane IBA and negates an ancestral mitochondrial IBD at the AIM33/PGA3 clade, while AIM33's loss-of-function phenotype implicates mitoch… |
| AIM33 (core function) | core_function | OPEN | BIOLOGY | BP_DARK | 1 | The molecular mechanism by which AIM33 loss alters mitochondrial genome maintenance is unknown, and even the direction of the petite-frequency change is reported inconsistently across curated sources. |
| AIM6 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 1 | The molecular function of AIM6 is unknown. Although the mature protein adopts the PLC-like phosphodiesterase (PI-PLC/GDPD-type) TIM-barrel fold, it is undetermined whether AIM6 has any catalytic activity at all, and if so what its substr… |
| AIM6 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biological role of AIM6 and the mechanism behind its deletion phenotype are unknown. It is unresolved whether AIM6 acts directly in mitochondrial biogenesis/respiration or whether the respiratory-growth defect of the deletion is an i… |
| AIRE (core function) | core_function | — | — | — | 0 | How do the in-vitro DNA motif-binding properties contribute to target selection in native human medullary thymic epithelial cells? |
| AIRE (core function) | core_function | — | — | — | 0 | The coordinated PHD1/CARD/CTT model includes human thymic epithelial cell experiments and selected mouse-domain biochemical experiments; the full architecture of endogenous human assemblies remains to be resolved. |
| AK4P3 (core function) | core_function | — | BIOLOGY | MF_DARK | 3 | Whether the AK4P3 locus yields endogenous protein, and whether that protein has any adenylate kinase activity, is undetermined. No AK4P3 protein has been purified or assayed, and the only demonstration of translation is from a transfecte… |
| AK4P3 (core function) | core_function | — | CURATION | MF_DARK | 2 | Whether UniProt's PE=1 for this entry reflects peptides that actually discriminate AK4P3 from AK4 is unresolved, and it is resolvable from existing data rather than requiring new experiments. |
| AKAIN1 (core function) | core_function | — | BIOLOGY | BP_DARK | 2 | Whether AKAIN1 at endogenous levels displaces PKA from AKAPs in neurons, and what that does to cAMP signalling there, is undetermined. |
| AKAIN1 (core function) | core_function | — | CURATION | BP_DARK | 2 | Human AKAIN1 is not annotated to GO:0031333 negative regulation of protein-containing complex assembly, although its mouse ortholog carries that term by IDA from the same paper. |
| AKAP10 (core function) | core_function | OPEN | BIOLOGY | CC_DARK | 0 | How AKAP10 attaches to any membrane is unknown. The protein has no transmembrane segment and no lipid-binding domain, and its mitochondrial transit peptide is a sequence-based prediction rather than a measured feature. |
| AKAP10 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 0 | Whether the PKA-anchoring arm and the Rab-binding arm are ever used together is untested. The two activities sit at opposite ends of the protein and were characterised in separate studies, and no experiment has asked whether anchored PKA… |
| AKAP12 (core function) | core_function | NARROWING | BIOLOGY | MF_DARK | 0 | The binding half is human (gravin residues 265-556 bind PKC), but the damping half is rodent: the demonstration that binding lowers kinase activity was made on SSeCKS, and no published experiment measures whether human AKAP12 inhibits th… |
| AKAP12 (core function) | core_function | NARROWING | BIOLOGY | MF_DARK | 0 | Calmodulin binding has been mapped biochemically only on the rodent orthologue; no published measurement demonstrates calmodulin binding by human AKAP12, although all three WSK motifs are present at conserved positions. The site count al… |
| AKAP7 (core function) | core_function | — | BIOLOGY | BP_DARK | 2 | Whether AKAP7 is required for beta-adrenergic regulation of the cardiac L-type calcium channel in vivo is contested. |
| AKAP7 (core function) | core_function | — | CURATION | BP_DARK | 1 | Human AKAP7 carries no annotation for its role at hippocampal mossy fiber synapses, although the mouse ortholog carries synaptic-transmission terms by IDA and IMP from the same study. |
| AKIP1 (core function) | core_function | — | BIOLOGY + CURATION | CC_DARK | 2 | Whether AKIP1 localizes to mitochondria in human cells, and what it does there, is undetermined. |
| ALDH4A1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | ALDH4A1 binding and enhancement of MPC1-MPC2 transport are supported experimentally, but the native occupancy, stoichiometry and precise activation mechanism remain unresolved. |
| ALG13 (core function) | core_function | — | — | — | 1 | Whether the assayed human ALG13–ALG14 dimer participates in a native DPAGT1-containing multienzyme assembly is unresolved by these experiments. |
| ALG13 (core function) | core_function | — | BIOLOGY | — | 1 | The physiological molecular functions of long isoform 1 and isoforms 3 and 4 remain unresolved. |
| Alginate O-acetylation | module_node | — | BIOLOGY | — | 0 | The immediate acetyl donor and covalent relay intermediates used by AlgI, AlgJ, and AlgF remain unresolved. |
| Alginate O-acetylation | module_node | — | BIOLOGY + CURATION | — | 1 | AlgJ has acetylesterase activity in vitro, but the physiological substrate and whether it transfers a relay intermediate to AlgX remain unresolved. |
| Alginate O-acetylation | module_node | — | ONTOLOGY | — | 0 | GO lacks an alginate-substrate-specific molecular-function term for AlgX. |
| Alginate polymerization and export | module_node | — | ONTOLOGY | — | 0 | GO lacks a substrate-specific molecular-function term for bacterial mannuronan C5-epimerase activity. |
| Alginate polymerization and export | module_node | — | ONTOLOGY | — | 0 | GO lacks an alginate-specific outer-membrane channel or transporter molecular-function term for AlgE. |
| Alginate polymerization and export | module_node | — | BIOLOGY + CURATION | — | 1 | Whether AlgX has an independently required noncatalytic chain-protection or conduit role separable from its O-acetyltransferase activity remains unresolved. |
| algJ | gene | — | BIOLOGY + CURATION | — | 1 | The physiological substrate and direction of the AlgJ-catalyzed step in the periplasmic acetyl relay are unresolved. |
| Aliphatic glucosinolate-myrosinase defense system | module_node | OPEN | BIOLOGY + CURATION | — | 1 | The enzyme(s) that conjugate the CYP83A1 product to glutathione in aliphatic glucosinolate biosynthesis are not biochemically established, nor is it known how much of the conjugation is enzymatic. |
| Aliphatic glucosinolate-myrosinase defense system | module_node | OPEN | ONTOLOGY | — | 0 | GO has no molecular-function term for the CYP83A1 reaction (aliphatic aldoxime oxidation with glutathione conjugation; EC 1.14.14.43) or for the AOP2 reaction (methylsulfinylalkyl to alkenyl glucosinolate). |
| ALMS1 (core function) | core_function | — | — | — | 1 | The ALMS1 interaction interface and structural contribution that connect the actin-associated machinery to human endosomal recycling remain unresolved. |
| ALPG (core function) | core_function | — | BIOLOGY | BP_DARK | 0 | Nothing is known about what germ cell alkaline phosphatase does. No physiological substrate, no pathway, and no loss-of-function phenotype have been reported, and the biological reason for maintaining a second, nearly identical copy of t… |
| ALPP (core function) | core_function | — | BIOLOGY | BP_DARK | 0 | No physiological substrate has been established for placental alkaline phosphatase. Its in vitro specificity is broad, and the substrates that are firmly established for the family -- inorganic pyrophosphate and pyridoxal 5'-phosphate --… |
| AMD2 | gene | OPEN | BIOLOGY | MF_DARK | 5 | The physiological substrate and the exact in-vivo reaction of AMD2 are undetermined. It is unknown which monocarboxylic acid amide is hydrolysed, so its generic amidase activity cannot be resolved to a specific molecular function. It is … |
| AMD2 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biological process in which AMD2 participates is unknown. There is no pathway placement and no defined physiological role; the only functional data are non-specific high-throughput deletion phenotypes (decreased resistance to nutrien… |
| AMD2 | gene | OPEN | BIOLOGY | CC_DARK | 1 | The subcellular localization of AMD2 is unknown. It carries no experimentally determined location and the sequence has no predicted signal peptide, transit peptide, or transmembrane segment to guide a confident prediction. |
| AMD2 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 2 | The physiological substrate and the specific reaction catalysed by AMD2 in vivo are unknown. EC 3.5.1.4 and Rhea:12020 are generic parent activities ("a monocarboxylic acid amide"); which carboxamide AMD2 actually hydrolyses has never be… |
| ANO5 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Which molecular activity of ANO5 supports muscle membrane repair independently of its phospholipid-scrambling domain remains unresolved in the reviewed experiments. |
| Anti-CRISPR suppression of host CRISPR-Cas immunity | module | NARROWING | ONTOLOGY | — | 0 | GO has no molecular-function term for two characteristic anti-CRISPR mechanisms: nucleic acid mimicry (competitive occupancy of a nucleic-acid-binding site by a protein that structurally imitates the nucleic acid) and cleavage of a cycli… |
| Anti-CRISPR suppression of host CRISPR-Cas immunity | module | OPEN | CURATION | — | 0 | Most characterised Acr proteins have no reviewed UniProt entry, and several carry uninformative names: the AcrF3-family exemplar L7P7R7 is named only "Phage protein", and the AcrIIC1 exemplar A0A2D0TCG3 only "Anti-CRISPR protein", despit… |
| Anti-CRISPR suppression of host CRISPR-Cas immunity | module | RESOLVED | CURATION | — | 0 | Which DUF1874-family protein was assayed as the AcrIII-1 ring nuclease was not establishable when this module was written, so UniProtKB:Q8QL27 was cited only as an orienting family exemplar. |
| ANXA11 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The examined evidence does not resolve the molecular activity through which ANXA11 supports midbody-matrix formation and terminal cell separation. |
| AP1S1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | What distinguishes the sigma subunits that bind dileucine signals from the one that does not is unidentified. The AP-4 epsilon-sigma4 hemicomplex demonstrably fails to bind these signals, yet sigma4 retains the same pocket residues as th… |
| AP1S1 | gene | OPEN | BIOLOGY | BP_DARK | 2 | Why loss of sigma1A specifically produces the MEDNIK organ spectrum -- skin, intestine, ear, peripheral nerve, brain and copper handling -- is unknown. The cellular basis for the division of labour between the three sigma1 isoforms has n… |
| AP1S1 | gene | NARROWING | BIOLOGY + CURATION | BP_DARK | 2 | The cargo repertoire that sigma1A selects is not systematically mapped. Individual cargoes are known -- ATP7A and ATP7B, LIMP-II, tyrosinase, EGFR, tight-junction proteins -- but they were found one at a time, and no unbiased survey has … |
| AP1S1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | Whether the coat-independent role reported for sigma1A -- promoting early-endosome maturation by raising endosomal Rabex-5 and Vps34 activity through ArfGAP1 -- operates in human cells, and whether it is separable from the complex's sort… |
| AP1S1 (core function) | core_function | OPEN | ONTOLOGY + CURATION | MF_DARK | 3 | No GO term expresses what sigma1A actually does at the molecular level: bind an acidic dileucine sorting signal. The activity has to be annotated through GO:0035615 clathrin-cargo adaptor activity, whose definition -- bringing a cargo pr… |
| AP1S2 | gene | OPEN | BIOLOGY | BP_DARK | 2 | No AP1S2-specific animal model exists outside the mouse. In particular there is no zebrafish ap1s2 mutant or morphant in the published literature, although zebrafish models exist for the AP-1 large subunit ap1g1, so the hydrocephalus and… |
| AP1S2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | How loss of sigma1B produces a brain-restricted phenotype is unexplained at the mechanistic level. Patient fibroblasts show no AP-1 defect at all, so the disease mechanism cannot be a general failure of AP-1 assembly, but the specific br… |
| AP1S2 | gene | OPEN | BIOLOGY | CC_DARK | 1 | Whether AP1S2 has any postsynaptic role is untested. No study has examined dendritic spine number or morphology in sigma1B-deficient neurons, so the possibility that the cognitive phenotype has a postsynaptic component is open rather tha… |
| AP1S2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The functional meaning of the MAB21L2 interaction is unknown. It is the only non-AP-1 partner in the curated interaction set for human AP1S2 and no study has tested whether it reflects cargo selection, a regulatory interaction, or an ass… |
| AP1S2 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 1 | Which sigma1 isoform operates in the melanocyte and platelet AP-1 complexes has never been determined, which is why the melanosome and platelet dense granule annotations on this gene cannot be evaluated on their merits. |
| AP1S2 (core function) | core_function | OPEN | ONTOLOGY | MF_DARK | 1 | GO has no molecular-function term for the sigma subunit's own contribution to an AP complex - the recognition of a (D/E)XXXL(L/I) dileucine sorting signal at the sigma/large-subunit interface - so the only MF available for AP1S2 is the c… |
| AP1S2 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Which synaptic-vesicle cargo proteins the AP-1/sigma1B hemicomplex actually selects is undetermined. No sigma1B cargo has been identified in neurons, in contrast to adipose tissue where sortilin is defined; the neuronal evidence is a pro… |
| AP1S3 | gene | OPEN | ONTOLOGY | MF_DARK | 3 | No GO term expresses the one molecular activity the AP-complex sigma subunit performs by itself - binding the [DE]XXXL[LI] dileucine sorting signal of a cargo tail - so the best available annotation for AP1S3 is either a complex-level te… |
| AP1S3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 3 | No cargo is known that the sigma-1C form of AP-1 selects and the sigma-1A or sigma-1B forms do not, so it is not established that AP1S3 has any biological process of its own as opposed to inheriting the complex's. |
| AP1S3 | gene | NARROWING | BIOLOGY | BP_DARK | 4 | Why loss of a broadly expressed, functionally redundant subunit produces a phenotype confined to the skin is unresolved; the proposed explanation - relative abundance in keratinocytes plus an IL-36 amplification loop - has not been teste… |
| AP1S3 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | Which sigma-1 paralogue serves the AP-1-dependent termination of STING signalling is not established, because the structural and the loss-of-function halves of that work used different paralogues. |
| AP1S3 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 4 | Nothing is known about isoform-specific function, even though the MANE-Select transcript encodes isoform 4 rather than the UniProt canonical isoform 1, and no GO annotation on this gene is isoform-qualified. |
| AP2S1 | gene | OPEN | ONTOLOGY | — | 2 | GO cannot express the one molecular activity that is specific to sigma2 rather than to the AP-2 complex: binding of the acidic dileucine sorting signal. |
| AP2S1 | gene | OPEN | ONTOLOGY + BIOLOGY | — | 2 | The obvious GO term for AP2S1's best-documented cargo function, GO:0002031 G protein-coupled receptor internalization, cannot be used because its ontological ancestry asserts a regulatory sign the data contradict. |
| AP2S1 | gene | OPEN | BIOLOGY + CURATION | — | 3 | Whether AP-2 is a genuine component of the budded clathrin-coated vesicle, or only of the coated pit, is unresolved, and the two best experiments disagree. |
| AP2S1 | gene | OPEN | BIOLOGY | — | 1 | The reported endocytosis-independent role of AP2S1 in amyloid precursor protein turnover, acting through late-endosome-to-lysosome fusion, rests on a single laboratory and has no mechanistic link to sigma2's known activity. |
| AP2S1 | gene | OPEN | BIOLOGY | — | 3 | Why complete loss of AP2S1 is embryonic-lethal and blocks endocytosis generally, while the human Arg15 alleles produce only a narrow calcium-homeostasis disorder, is not explained. |
| AP3B2 | gene | NARROWING | BIOLOGY + CURATION + ONTOLOGY | MF_DARK | 3 | The relationship between AP3B2/AP-3 clathrin binding and Arf1-driven, clathrin-independent AP-3 coat initiation remains incompletely resolved. |
| AP3B2 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | The complete neuronal AP-3 trafficking itinerary and cargo repertoire remain unresolved, including how AP3B2-containing AP-3 differs from ubiquitous AP3B1-containing AP-3 at shared endosomal compartments. |
| AP3B2 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | The causal chain from AP3B2 loss to DEE48 seizures, developmental delay, and region-specific synaptic dysfunction remains incompletely defined. |
| AP3D1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | It is not established whether the amphipathic helix at the delta N-terminus actually deforms the membrane or merely binds it. Both structural papers stop at a proposal, and the 2026 coat paper attributes the helix array to mu3 'and possi… |
| AP3D1 | gene | NARROWING | BIOLOGY + CURATION | BP_DARK | 2 | Whether mammalian AP-3 has a functional trans-Golgi pool that performs the Golgi-to-lysosome route its yeast ortholog performs, or whether the tubular sorting endosome is the only productive site, is unresolved. |
| AP3D1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | No function is assigned to the ~200-residue disordered, heavily phosphorylated region of delta C-terminal to the VAMP7-binding hinge (UniProt REGION 726-920, with phosphoserines at S758, S759 and elsewhere). It is not known what phosphor… |
| AP3D1 | gene | NARROWING | BIOLOGY | BP_DARK | 2 | The cargo whose mis-sorting causes the hearing loss in AP3D1-deficient humans and the otoconial and inner-ear defects in mocha mice has not been identified. |
| AP3D1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | Why BLOC-1 controls AP-3-dependent synaptic-vesicle biogenesis in the dentate gyrus but not in the striatum is unknown, even though both complexes are ubiquitously expressed. |
| AP3M1 | gene | OPEN | BIOLOGY | — | 5 | No experiment has perturbed AP3M1 itself in a human cell. Every process and localisation statement on this gene traces either to the complex - beta3A mutations in Hermansky-Pudlak syndrome fibroblasts, the mouse mocha Ap3d1 null, melanoc… |
| AP3M1 | gene | OPEN | BIOLOGY + CURATION | — | 3 | Whether mu3A and mu3B partition with beta3A and beta3B respectively, or whether the subunits mix and match, has been an open question since AP-3 was characterised, and I found nothing settling it for human cells. ComplexPortal models str… |
| AP3M1 | gene | OPEN | ONTOLOGY | — | 2 | The ontology cannot express three distinctions this gene needs: the ubiquitous versus neuronal AP-3 complexes, tyrosine-motif sorting-signal binding as distinct from organelle-import signal receptors, and AP-3 cargo loading without a cla… |
| AP3M1 | gene | NARROWING | BIOLOGY + ONTOLOGY | — | 3 | AP-3's residual clathrin association has never been given a function. AP-3 carries a clathrin-binding motif in the beta3 hinge and partially colocalises with clathrin, yet carrier formation demonstrably does not require a clathrin lattic… |
| AP3M2 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | It is not known whether human AP3M2 is functionally a neuronal protein. The 'neuron-specific mu3B' description rests on a 1994 rat Northern blot, while human expression atlases report the gene detected in all tissues with low tissue spec… |
| AP3M2 | gene | OPEN | CURATION + BIOLOGY | WHOLLY_DARK | 1 | There is no experimental GO annotation of any kind on human AP3M2. All 26 GOA rows are propagated - phylogenetic, orthology-based, rule-based, or author-statement - so every claim about the human protein rests on rodent genetics, on the … |
| AP3M2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Whether mu3B can assemble into AP-3 without beta3B, and therefore whether AP3M2 has any function independent of the AP-3B complex, is undetermined. Only one direction of the interdependence has been tested. |
| AP3M2 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | No cargo that requires mu3B specifically, as opposed to AP-3 generally, has been identified. The best candidate, the vesicular GABA transporter, is proposed to be read through a dileucine signal, which is the sigma3/delta site rather tha… |
| AP3S1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 4 | Nothing is known that functionally separates sigma3A from sigma3B. The two paralogs are both broadly expressed, both delta-sigma3A and delta-sigma3B bind the LIMP-II dileucine tail, and no cargo, tissue or trafficking step has been shown… |
| AP3S1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | It is not known what displaces the beta3 N-terminal extension from the sigma3 dileucine pocket, or whether that occupancy is a genuine autoinhibited state of human AP-3 rather than a feature of the reconstituted, cargo-free complex. |
| AP3S1 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | Whether AP3S1 has any role outside AP-3 is undetermined. The one published claim of an independent activity -- that sigma3A acts as a membrane receptor for IRS-1 in adipocytes -- has never been tested again. |
| AP3S1 | gene | OPEN | BIOLOGY | MF_DARK | 4 | What decides whether a given acidic dileucine signal is read by the AP-1 gamma1-sigma1A hemicomplex or by the AP-3 delta-sigma3 hemicomplex is not understood, and the sigma-side contribution to that choice has not been isolated. |
| AP3S1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 4 | The delta-ear/sigma3 interaction that gates AP-3 membrane recruitment has no known regulator: it is not known what relieves it in cells, nor where on sigma3A the ear binds. |
| AP3S1 (core function) | core_function | OPEN | ONTOLOGY + CURATION | MF_DARK | 3 | No GO term expresses what sigma3A does at the molecular level: bind an acidic dileucine sorting signal. The activity can only be annotated through GO:0140312 cargo adaptor activity, a complex-level term whose definition is about binding … |
| AP3S2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 4 | Nothing is known that distinguishes the sigma-3B form of AP-3 from the sigma-3A form. No cargo has been found that one selects and the other does not, no tissue or cell type is known to use one preferentially, and no phenotype has been a… |
| AP3S2 | gene | NARROWING | BIOLOGY + CURATION | MF_DARK | 4 | No structure, knockout, knockdown, patient allele or cargo screen has ever used sigma-3B. Every mechanistic statement about the AP-3 sigma subunit in the structural literature is an observation on sigma-3A that is assumed to transfer. |
| AP3S2 | gene | OPEN | BIOLOGY | BP_DARK | 6 | The reason AP3S2 appears in the literature at all - a type 2 diabetes association at 15q26 - has never been connected to AP-3 function, and the evidence available points away from AP3S2 being the effector gene. |
| AP3S2 | gene | NARROWING | BIOLOGY + ONTOLOGY | BP_DARK | 4 | Whether AP-3's documented clathrin binding has any residual physiological role is unresolved, and GO currently encodes the superseded answer. |
| AP3S2 | gene | OPEN | BIOLOGY | BP_DARK | 5 | It is not known which cargoes the ubiquitous, non-neuronal, non-pigment-cell AP-3 delivers, so the function of this ubiquitously expressed subunit in the tissues where it is most abundant is uncharacterised. |
| AP3S2 (core function) | core_function | OPEN | ONTOLOGY | MF_DARK | 4 | No GO term expresses what the sigma subunit does on the cargo side - bind an acidic dileucine sorting signal - and for AP-3 there is not even a usable complex-level substitute, because the one GO offers commits to clathrin. |
| AP4B1 | gene | NARROWING | BIOLOGY + CURATION | BP_DARK | 2 | The complete AP-4 cargo repertoire, and which AP4B1-dependent cargoes drive distinct disease-relevant phenotypes, remains incompletely defined. |
| AP4B1 | gene | OPEN | BIOLOGY + CURATION + ONTOLOGY | MF_DARK | 3 | The mechanism by which AP-4 forms a clathrin-independent coat, and the precise role of AP4B1-bound tepsin in that process, remains unresolved. |
| AP4B1 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | The neuronal selectivity of AP-4 deficiency and the balance between developmental cargo-missorting defects and progressive neurodegeneration are not fully resolved. |
| AP4M1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | The sorting signal in ATG9A that mu4 reads has not been defined, so the connection between AP4M1's measured binding specificity and its only established physiological cargo is still missing. |
| AP4M1 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 2 | Whether AP-4 has an endogenous lysosomal cargo is unresolved, and two GO annotations on this gene depend on the answer. |
| AP4M1 | gene | NARROWING | BIOLOGY | RESIDUAL_SUBGAP | 2 | How a defect in a ubiquitously expressed trans-Golgi network coat produces a disease that is almost entirely neurological is unexplained. |
| AP4S1 | gene | NARROWING | BIOLOGY | MF_DARK | 5 | Sigma4 has no assigned molecular activity outside the AP-4 core, and the one question that could have given it one - whether it helps read a cargo sorting signal, as the sigma subunits of AP-1, AP-2 and AP-3 do - has been answered negati… |
| AP4S1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 5 | The causal step between ATG9A missorting and neurodegeneration in AP-4 deficiency is unidentified, and the obvious candidate has been excluded in the cells where the missorting is measured: bulk autophagic flux is intact in AP-4-deficien… |
| AP4S1 | gene | OPEN | CURATION | CC_DARK | 3 | Neither of the two ARBA-derived annotations on this gene can be reproduced from its own rule's published condition sets, so there is no recoverable reason why these particular terms were assigned to this particular protein. |
| AP4S1 | gene | OPEN | CURATION + BIOLOGY | RESIDUAL_SUBGAP | 4 | The clinical and the reference literature on AP4S1 number residues on different isoforms, and nothing in the annotation record says so. Variant nomenclature is standardised on NM_007077 (Q9Y587-2), while UniProt's canonical sequence and … |
| AP4S1 | gene | OPEN | ONTOLOGY | MF_DARK | 3 | GO has no molecular function that fits the complex-level activity of a non-clathrin AP coat. GO:0140312 cargo adaptor activity, the only term that names the coat-adaptor role, is defined in terms of binding the structural scaffolding ele… |
| AP5B1 | gene | OPEN | ONTOLOGY + CURATION | CC_DARK | 2 | GO has no cellular component term for the AP-5/SPG11/SPG15 complex, so the annotation that would correctly describe five of AP5B1's twelve protein-binding rows cannot be made. |
| AP5B1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | No ligand or function is known for the AP5B1 appendage domain, which is the most complete appendage in the family and the location of the recurrent disease allele. |
| AP5B1 | gene | NARROWING | BIOLOGY | BP_DARK | 2 | Why AP-5 subunit loss produces a retinal phenotype in some genes and a spastic paraplegia phenotype in others is unexplained, and for AP5B1 specifically no spastic paraplegia has been reported despite bi-allelic null alleles. |
| AP5B1 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 2 | No molecular activity of AP-5 beyond holding itself together has been demonstrated. No sorting signal recognised by the complex has been identified, and no cargo has been shown to bind AP-5 or any of its subunits directly. |
| AP5B1 (core function) | core_function | NARROWING | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 1 | Which subunit of the AP-5/SPG11/SPG15 assembly provides the curvature-sensing surface, and whether AP5B1 contributes to it at all, is undetermined. |
| AP5M1 | gene | OPEN | BIOLOGY | MF_DARK | 3 | No molecular function has been established for mu-5 itself. It has the mu-homology domain fold but not the tyrosine-signal binding site, and no sorting motif of any kind has been identified for AP-5, so it is not known whether mu-5 recog… |
| AP5M1 | gene | NARROWING | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | It is not known which subunits of the AP-5-SPG11-SPG15 assembly carry out the membrane deformation the complex performs in vitro, so mu-5's contribution to the one demonstrated molecular activity of the assembly cannot be stated more pre… |
| AP5M1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 5 | Whether the cell-death phenotypes reported for this protein under the name MUDENG reflect anything it does at physiological levels is unresolved, and the published effects point in opposite directions. |
| AP5M1 | gene | OPEN | ONTOLOGY + CURATION | BP_DARK | 2 | GO cannot express the process that AP-5, SPG11 and SPG15 are best characterised for, regenerating lysosomes from autolysosomes by tubulation and scission, so the most specific thing known about this gene's biology is annotated to a gener… |
| AP5S1 | gene | OPEN | BIOLOGY | MF_DARK | 4 | No sorting signal, and no direct cargo, has ever been identified for AP-5, so sigma-5 has no molecular function that can be stated - not merely none that GO can express. |
| AP5S1 | gene | OPEN | ONTOLOGY | CC_DARK | 2 | GO has no term for the AP-5/spatacsin/spastizin assembly, although that six-protein complex, not the AP-5 tetramer, is the entity that has been purified, phenotyped and solved. |
| AP5S1 | gene | OPEN | BIOLOGY | — | 3 | AP5S1 is the only AP-5 subunit with no reported disease-causing variant, and no AP5S1 knockout has been characterised, so it is unknown whether losing sigma-5 has the same consequences as losing the other three subunits. |
| AP5S1 | gene | OPEN | BIOLOGY + CURATION | — | 3 | Whether the reduction in homologous recombination on sigma-5 knockdown reflects a direct role or a downstream consequence of disrupted endolysosomal traffic has never been tested. |
| apc11 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | No purified-protein ubiquitination assay or RING mutagenesis has been reported for the S. pombe Apc11 protein itself; the catalytic mechanism is inferred from the budding-yeast and human orthologues and from assays of the intact fission-… |
| apc11 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The ubiquitin chain linkage assembled by the S. pombe APC/C (K48 as in budding yeast, or K11 as in human) has not been established. |
| apc11 / nucleus | annotation | OPEN | BIOLOGY | CC_DARK | 1 | No direct imaging of tagged Apc11 in living or fixed S. pombe cells has been reported; the nuclear site of activity is inferred from the localisation of APC/C substrates and other APC/C subunits. |
| APLN | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 4 | Which processed apelin peptide does what, in which tissue, is unresolved - and the gene record cannot express the difference, because every annotation is made against the 77-residue precursor rather than against the chains UniProt alread… |
| APLN | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 3 | Whether apelin should be treated as a hormone or as a locally released autocrine/paracrine mediator is unsettled, and the ontology forces a choice that the data do not support. |
| APLN | gene | OPEN | CURATION | BP_DARK | 3 | Apelin's role in angiogenesis is absent from the human GO record entirely, although it is one of the two things the protein is best known for. |
| APLN | gene | OPEN | CURATION | RESIDUAL_SUBGAP | 3 | The phylogenetic annotation of the apelin family propagates a localisation and nothing else, although the family's function is known and conserved. |
| APLN | gene | OPEN | BIOLOGY | BP_DARK | 2 | Whether apelin regulates glucose metabolism in humans is unknown; the entire case rests on acute peptide infusion into rodents. |
| APLP1 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 3 | It is undetermined whether APLP1 acts as a bona fide neuronal receptor for fibrillar alpha-synuclein in its own right, or only as an obligate partner within an APLP1-LAG3 complex. No binding constant, stoichiometry or uptake requirement … |
| APOC4 | gene | OPEN | BIOLOGY | BP_DARK | 3 | What apolipoprotein C-IV does at its endogenous concentration is unknown. Every functional claim about the protein comes from adding more of it - a supraphysiological transgene in mouse, or a transient transfection of a hepatoma line - a… |
| APOC4 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | The mechanism by which apoC-IV raises plasma triglyceride has never been measured for apoC-IV. The apoE-displacement model is asserted for APOC1, APOC3 and APOC4 as a group, and the experimental work behind it is on the relatives, not on… |
| APOC4 | gene | OPEN | CURATION | MF_DARK | 3 | The only direct lipid-binding measurement anywhere in the apolipoprotein C-IV family is uncurated in GO, so the family's experimental anchor is invisible to every inference pipeline that uses GO as input. |
| APOC4 | gene | OPEN | BIOLOGY | BP_DARK | 3 | Why apoC-IV is abundant in rabbit plasma and a trace protein in human plasma is unexplained, and so is the function of the conserved N-glycan and sialoform heterogeneity the protein carries in both species. |
| APOF | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 3 | How apolipoprotein F, once bound to LDL, prevents CETP from acting on that particle is unknown at the molecular level. There is no structure of apolipoprotein F, no mapped LDL-binding surface, no mapped inhibitory determinant, and no dem… |
| APOF | gene | OPEN | BIOLOGY | MF_DARK | 4 | What apolipoprotein F does in species that have no CETP is unknown, and since the family is conserved across bony vertebrates while CETP is absent from mice and rats and defective in several other mammals, there is probably a second func… |
| APOF | gene | OPEN | BIOLOGY | CC_DARK | 3 | Why most of the plasma pool sits inactive in a 470 kDa apolipoprotein A-I-containing particle, what holds it there, and whether that pool has a function of its own rather than being a reservoir, are all unresolved. |
| APOF | gene | OPEN | CURATION | CC_DARK | 2 | Whether apolipoprotein F associates with VLDL at all is unsettled, and the disagreement is between a direct negative result and a secondary report of a weak positive. |
| APOF | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 2 | The direction in which apolipoprotein F affects reverse cholesterol transport is not a fixed property of the protein: knockdown impairs it on one diet and enhances it on another, and no account of the switch exists. |
| APOF | gene | OPEN | CURATION + BIOLOGY | MF_DARK | 4 | The post-translational maturation of this precursor is only partly captured and its functional consequences are untested: the N-glycosylation sites of the mature circulating protein are absent from UniProt, the one site UniProt does anno… |
| APOO | gene | OPEN | BIOLOGY | MF_DARK | 4 | MIC26 has no demonstrated molecular activity of its own. No biochemical assay has been performed on purified MIC26, so it is undetermined whether it contributes to crista junction formation by deforming the bilayer through its amphipathi… |
| APOO | gene | NARROWING | BIOLOGY | MF_DARK | 2 | Whether MIC26 binds cardiolipin directly is unknown, and so is the mechanism by which its loss lowers the cellular cardiolipin pool - whether synthesis falls, turnover rises, or the lipid is destabilised by the loss of a binding site. |
| APOO | gene | OPEN | BIOLOGY | BP_DARK | 3 | Why MIC26, but not its paralogue MIC27, is required for a tubular mitochondrial network is unknown. Loss of MIC26 fragments mitochondria in human cells without changing OPA1 levels or the balance of its long and short forms, so the pheno… |
| APOO | gene | OPEN | BIOLOGY | CC_DARK | 2 | The membrane topology of MIC26 is not experimentally determined. UniProt annotates one transmembrane helix (108-128); the paralogue MIC27 is annotated with two, and a 2026 structure-prediction and simulation study models two short transm… |
| APOO | gene | OPEN | CURATION | CC_DARK | 2 | The Q9BUR5 UniProt record still asserts Secreted, Golgi apparatus membrane and endoplasmic reticulum membrane subcellular locations and a chondroitin-sulfate O-glycosylation, all of which trace to a protein species shown not to be MIC26;… |
| APOO | gene | OPEN | ONTOLOGY | MF_DARK | 1 | There is no molecular function term in GO for a structural constituent of the MICOS complex, so the only MF assignable to MIC26 is the generic GO:0005198 structural molecule activity, which conveys nothing specific to this complex. |
| APOOL | gene | OPEN | BIOLOGY | MF_DARK | 2 | No cardiolipin-binding-deficient APOOL mutant has ever been made, so the protein's only demonstrated molecular activity has never been connected to any cellular phenotype. |
| APOOL | gene | OPEN | BIOLOGY | BP_DARK | 2 | Whether MIC26 and MIC27 act directly on respiratory chain supercomplexes and the F1Fo-ATP synthase, or only indirectly through reduced cardiolipin and lost crista junctions, is unresolved, and the authors who reported the phenotype say s… |
| APOOL | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | The mechanism by which MIC26 and MIC27 reciprocally control each other's protein abundance is unknown, and it is the confound that made a decade of single-gene depletion studies of this pair difficult to interpret. |
| APPL2 | gene | OPEN | BIOLOGY | — | 2 | It is not known what determines the sign of APPL2's effect on PI3K/Akt signalling: in macrophages APPL2 restrains Akt downstream of TLR4 but promotes it downstream of the Fc-gamma receptor. |
| APPL2 | gene | OPEN | BIOLOGY | — | 2 | Whether APPL2 recruits or regulates a PI3K directly has never been tested, even though the proposed mechanism for its role in phagocytosis depends on it. |
| APPL2 | gene | OPEN | BIOLOGY | — | 3 | How the nuclear pool of APPL2 is generated is unknown: the proposed nuclear localisation signal at residues 151-157 has never been mutated. |
| APPL2 | gene | OPEN | CURATION | — | 2 | APPL2's individual contribution to TGF-beta-driven TbetaRI-ICD nuclear transport is unresolved because only simultaneous APPL1 + APPL2 knockdowns were performed. |
| APPL2 | gene | OPEN | BIOLOGY | — | 2 | The assembly state of full-length APPL2 is unestablished; all structural work is on the BAR-PH fragment and the PTB domain's contribution is unknown. |
| APPL2 | gene | OPEN | CURATION | — | 2 | Most of what is annotated for human APPL2 - adiponectin antagonism, endotoxin hypersensitivity, phagocytosis, adipose beiging, neurogenesis - has only been demonstrated in mouse. |
| ARC | gene | NARROWING | BIOLOGY | RESIDUAL_SUBGAP | 0 | Almost nothing about Arc's function has been measured on the human protein. Of the 57 GOA rows, three IDAs rest on one structural paper and two more on an overexpression experiment in a carcinoma cell line; everything mechanistic is rat … |
| ARC | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 0 | It is unresolved whether the Arc protein is a component of canonical dendritic transport RNP granules, or whether its only RNA-containing assembly is the virus-like capsid. |
| ARC | gene | OPEN | ONTOLOGY | RESIDUAL_SUBGAP | 0 | GO can say that Arc forms a virus-like capsid but not that it assembles one, and not that it is a structural constituent of one. |
| ARC | gene | OPEN | BIOLOGY | MF_DARK | 0 | How the two halves of Arc's biology relate is unknown: whether capsid-mediated intercellular mRNA transfer is part of the same mechanism as AMPA receptor endocytosis, or a second function that happens to use the same interface. |
| ARFGEF1 | gene | — | BIOLOGY | — | 2 | What BIG1 does in the nucleus and nucleolus is unknown. It concentrates there on serum starvation, associates with nucleolin, fibrillarin and U3 snoRNA in a nucleic-acid-dependent complex, and notably does not bring ARF with it, so the n… |
| ARFGEF1 | gene | — | BIOLOGY | — | 3 | The PKA phosphorylation site that lowers BIG1 exchange activity has not been identified. Ser-883 is often named for it, but that residue's demonstrated consequence is cAMP-induced nuclear accumulation, and BIG2 - which has alanine at the… |
| ARFGEF1 | gene | — | ONTOLOGY | — | 1 | GO can no longer express the substrate specificity of a guanine-nucleotide exchange factor. Fourteen ids were merged into GO:0005085, which has no substrate-specific is_a children; the activities they named survive only as narrow synonym… |
| ARFGEF1 | gene | — | CURATION | — | 2 | The great majority of what is known about human BIG1 has never reached GO. Of the twenty-six functional papers returned by the affinage deep-research provider, only six have produced any GO annotation on ARFGEF1 and seventeen have produc… |
| ARFGEF2 (core function) | core_function | — | ONTOLOGY | — | 1 | GO cannot state which GTPase an exchange factor acts on. GO:0005086 ARF guanyl-nucleotide exchange factor activity, together with eight sibling substrate-specific GEF terms, was merged into GO:0005085 and survives only as one of its seco… |
| ARFGEF3 | gene | OPEN | BIOLOGY | — | 0 | No experiment has directly measured whether ARFGEF3 can load GTP onto any ARF protein. The conclusion that it cannot rests on absence of the catalytic glutamate and on the authors' repeated sequence-level statements. PMID:24997568 assert… |
| ARFGEF3 | gene | OPEN | BIOLOGY | — | 0 | ARFGEF3 is reported in four different compartments in four cell types - cytoplasm in breast carcinoma, TGN and secretory granules in islet cells, lysosomes in hippocampal neurons, mitochondria in osteosarcoma lines - and no study has com… |
| ARFGEF3 | gene | OPEN | CURATION | — | 0 | UniProt's SubCell mapping sends SL-0244 Secretory vesicle to GO:0030133 transport vesicle and SL-0245 to GO:0030658, but the secretory-granule and transport-vesicle branches are disjoint in GO, so the mapping places proteins in the const… |
| ARFGEF3 | gene | OPEN | CURATION | — | 0 | The interpro2go line mapping IPR000904 to GO:0005085 fires on a profile match to the Sec7 fold without testing whether the catalytic glutamate is present, so it assigns exchange activity to Sec7-fold pseudo-GEFs. |
| ARGLU1 | gene | NARROWING | BIOLOGY | RESIDUAL_SUBGAP | 1 | No experimental structure of ARGLU1 exists and the protein has no domain-level sequence signature of any kind, so no molecular function can be inferred from its fold. The complete signature content of the Swiss-Prot entry is IPR033371 (t… |
| ARGLU1 | gene | OPEN | ONTOLOGY | — | 1 | GO cannot express regulation of promoter-proximal RNA polymerase II pausing. The term GO:0160239 transcription pausing by RNA polymerase II exists and describes the process, but it has no children and there is no regulation-level term be… |
| ARGLU1 | gene | NARROWING | ONTOLOGY + CURATION | — | 1 | GO can express that ARGLU1 binds a splicing factor but not which step of splice-site recognition that contact serves. GO:1990935 splicing factor binding covers U2AF2 and PUF60, but it is a single flat term with no children, so the U2AF2 … |
| ARGLU1 | gene | NARROWING | BIOLOGY | — | 1 | It is not known what phosphorylation does to ARGLU1. Six phosphosites are annotated in UniProt from mass spectrometry, SRPK2 phosphorylates ARGLU1 in vitro, and PAK1 phosphorylates Ser-77, but no study has tested how any of these modific… |
| ARHGAP21 | gene | OPEN | ONTOLOGY | — | 0 | GO cannot record which GTPase a GAP acts on. ARHGAP21's best-characterised and most contested property is its substrate preference -- Cdc42 versus RhoA versus RhoC -- and the molecular-function branch has no vocabulary for it. |
| ARHGAP21 | gene | OPEN | ONTOLOGY | — | 0 | GO has no term for the PDZ-domain side of a PDZ/PDZ-binding-motif interaction, so neither the quantitative affinity survey of ARHGAP21's PDZ domain nor its one reported cellular ligand can be recorded as anything more informative than ge… |
| ARHGAP21 | gene | NARROWING | CURATION | — | 0 | Seven of the ten primary papers on human ARHGAP21 have produced no GO annotation anywhere in GOA. This gene's problem is missing curation, not over-annotation. |
| ARHGAP23 | gene | OPEN | ONTOLOGY | MF_DARK | 0 | No GO molecular-function term can record which GTPase ARHGAP23 acts on. GO:0005100 "Rho GTPase activator activity" is obsolete and merged into GO:0005096, which now carries "Rho GAP activity", "Rho GTPase activator activity", "Rac GAP ac… |
| ARHGAP23 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | It is not known whether ARHGAP23's catalytic arginine is required for its measured activity, and the one published point mutant described as its arginine-finger mutant does not target that residue. ARHGAP23-R986K, from the family-wide sc… |
| ARHGAP23 | gene | OPEN | BIOLOGY | MF_DARK | 1 | No ligand is known for ARHGAP23's PDZ domain, and the domain has never been assayed. It was one of ten PDZ domains that could not be amplified for the human PDZome resource, so it is absent from the one systematic experimental survey of … |
| ARHGAP36 (core function) | core_function | — | BIOLOGY | RESIDUAL_SUBGAP | 1 | What the retained Rho-GAP domain of ARHGAP36 does is unknown. It is required for full Gli activation and it binds PREPL, but no molecular activity has been assigned to it, and a molecular function for it cannot yet be written. |
| ARHGAP36 (core function) | core_function | — | BIOLOGY + CURATION | MF_DARK | 0 | Whether blocking PKAC catalysis and driving PKAC lysosomal degradation are separable activities of the same motif, and which dominates at endogenous expression levels, is undetermined; every direct measurement so far has used overexpress… |
| ARHGAP36 (core function) | core_function | — | BIOLOGY + CURATION | CC_DARK | 0 | Whether the Patched1-dependent centrosomal pool exists in human cells is untested. The mother-centriole localisation, the Inversin phosphorylation step and the knockdown result are all from mouse cells. |
| ARHGAP4 | gene | OPEN | BIOLOGY | BP_DARK | 8 | ARHGAP4 has no non-redundant physiological function demonstrated in any organism. Every functional result in the literature is a gain-of-function or knockdown experiment in a cell line; no loss-of-function phenotype has been attributed t… |
| ARHGAP4 | gene | OPEN | CURATION | RESIDUAL_SUBGAP | 2 | The GO record for ARHGAP4 is not wrong so much as absent. Sixteen of the nineteen primary papers about this gene produced no GO annotation on ARHGAP4 in any species, and the human protein has no experimental molecular-function or biologi… |
| ARHGAP4 (core function) | core_function | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 3 | Which Rho-family GTPase ARHGAP4 acts on in cells is undetermined, and it is not expressible in GO even if it were determined. |
| ARHGAP4 / cytoplasm | annotation | OPEN | BIOLOGY + CURATION | CC_DARK | 2 | Whether human ARHGAP4 is concentrated at the cell cortex is stated only as a 1996 author observation and has never been re-examined, so the compartment in which the GAP acts is not established at better than whole-cytoplasm resolution. |
| ARHGAP6 (core function) | core_function | OPEN | ONTOLOGY | RESIDUAL_SUBGAP | 0 | GO cannot record that ARHGAP6's GAP activity is RhoA-directed, so the annotation is indistinguishable from that of a GAP with any other substrate. |
| ARHGAP6 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 0 | The molecular activity underlying ARHGAP6's GAP-independent actin remodelling is unidentified: no direct actin-binding, nucleating, bundling or severing activity has been measured for the N-terminal region. |
| ARHGAP6 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | Whether ARHGAP6 regulates PLC-delta1 under physiological expression, and in which cells, is unknown; the cellular evidence is from overexpression, and the one disease association is correlative. |
| ARHGEF15 (core function) | core_function | — | BIOLOGY + ONTOLOGY | — | 0 | Which Rho-family GTPase ARHGEF15 acts on in a given human tissue is unsettled, and GO's molecular-function branch cannot express the answer even where it is known. |
| ARHGEF15 (core function) | core_function | — | BIOLOGY | — | 0 | Whether the human protein uses EPHB2 at all is untested; that half of the receptor pairing is a By-similarity transfer from mouse. |
| ARHGEF16 | gene | OPEN | ONTOLOGY | MF_DARK | 2 | GO has no term in which to state that this protein's exchange substrate is RhoG and only RhoG. Every substrate-specific handle has been merged into a general parent: GO:0005089 Rho guanyl-nucleotide exchange factor activity, GO:0030676 R… |
| ARHGEF16 | gene | OPEN | CURATION | BP_DARK | 1 | Almost nothing in this protein's literature has reached GO. Of the 26 PubMed records naming Ephexin4 or ARHGEF16, exactly two produced a GO annotation on the human or mouse protein. The autoinhibition mechanism, the anoikis role, the Eph… |
| ARHGEF16 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | Where in the cell ARHGEF16 sits has never been measured. Both cellular-component terms on the gene are inferences - cytoplasm from a UniProt keyword mapping and cytosol from an ARBA rule and two Reactome reactions - and UniProt's own SUB… |
| ARHGEF18 (core function) | core_function | OPEN | ONTOLOGY | MF_DARK | 0 | GO cannot record which GTPase this exchange factor acts on, and the merge that removed the vocabulary was deliberate. |
| ARHGEF18 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 0 | The two primary papers disagree about Rac1, and the experiment that would settle it has never been done on this protein. |
| ARHGEF18 (core function) | core_function | OPEN | CURATION + ONTOLOGY | MF_DARK | 0 | No annotation anywhere records that ARHGEF18 binds activated RhoA through its PH domain, and the term that would name the partner class has been merged away. |
| ARHGEF18 / guanyl-nucleotide exchange factor activity | annotation | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 0 | Whether ARHGEF18 is a RhoA-only exchange factor or acts on Rac1 as well is unresolved, and the answer is not expressible in GO either way. |
| ARHGEF19 | gene | OPEN | ONTOLOGY | — | 1 | The best-established fact about this protein - that it is a RhoA exchange factor and specifically not a Rac1 or Cdc42 exchange factor - cannot be stated in a GO term. |
| ARHGEF19 | gene | OPEN | CURATION | MF_DARK | 1 | Almost none of the published experimental work on this gene has reached GO. Eleven of the fourteen primary papers on ARHGEF19 have produced no GO annotation of any gene in any species, and twelve of fourteen have produced no annotation o… |
| ARHGEF19 | gene | OPEN | BIOLOGY | — | 2 | Which region of ARHGEF19 binds Dishevelled is disputed between the two papers that measured it, and neither result has been independently reproduced. |
| ARHGEF19 | gene | OPEN | BIOLOGY | — | 2 | The physiological input that relieves the C-terminal SH3 brake on ARHGEF19 is unidentified, and no Eph receptor partner has ever been found despite the protein being named Ephexin-2. |
| ARHGEF19 | gene | OPEN | BIOLOGY | — | 1 | How ARHGEF19 activates MEK/ERK is unexplained, and whether the reported BRAF and HRAS interactions are direct is untested. |
| ARHGEF19 (core function) | core_function | OPEN | BIOLOGY | CC_DARK | 1 | Where in the cell the human protein performs this exchange is unmeasured. No human localisation experiment on ARHGEF19 worth annotating has been published - the one human observation that exists is qualitative and in a neuroblastoma line. |
| ARID2 (core function) | core_function | NARROWING | BIOLOGY | MF_DARK | 1 | The molecular activity linking ARID2–RAD51 association to productive repair and the contributions of distinct ARID2 complexes remain incompletely resolved. |
| ARL13B (core function) | core_function | NARROWING | BIOLOGY | MF_DARK | 1 | The physiological factor that stimulates ARL13B GTP hydrolysis and couples its nucleotide state to particular effectors remains unresolved. |
| ARL13B (core function) | core_function | NARROWING | BIOLOGY | BP_DARK | 1 | The spatial and temporal contributions of ARL13B and BART to endogenous ciliary ARL3 nucleotide gradients remain incompletely measured. |
| ARL2BP (core function) | core_function | NARROWING | BIOLOGY | BP_DARK | 2 | The physiological connection between ARL2BP GTPase regulation and ciliary microtubule architecture remains unresolved. |
| ARMC2 (core function) | core_function | NARROWING | BIOLOGY | MF_DARK | 2 | The mammalian ARMC2 cargo-binding partners and molecular mechanism linking it to axonemal assembly remain unresolved. |
| ArnE/ArnF lipid A L-Ara4N donor flipping | module_node | — | BIOLOGY | — | 0 | The exact ArnE/ArnF stoichiometry, coupling chemistry, and residue-level substrate-recognition mechanism remain unresolved. |
| ArnE/ArnF lipid A L-Ara4N donor flipping | module_node | — | ONTOLOGY | — | 0 | GO lacks a specific child term for directional, undecaprenyl-phosphate-L-Ara4N intramembrane flippase activity. |
| ARSI | gene | NARROWING | BIOLOGY | RESIDUAL_SUBGAP | 1 | The principal native proteoglycan substrates and exact chain-position specificity of human ARSI are unknown. |
| ARSI | gene | NARROWING | BIOLOGY | CC_DARK | 1 | The relative physiological importance of lysosomal and extracellular ARSI pools is unresolved. |
| ARSI | gene | OPEN | BIOLOGY | BP_DARK | 1 | The human developmental and disease consequences of ARSI loss remain uncertain. |
| ATP13A1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | Whether ATP13A1 is exclusively a membrane-protein dislocase or can also directly promote insertion, secretion, or topogenesis for selected clients remains unresolved. |
| ATP13A1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | The human ATP13A1 client spectrum and selection rules are still incompletely defined. |
| ATP13A1 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 2 | The connection between ATP13A1 membrane-protein quality control and reported immune or developmental phenotypes remains unresolved. |
| AVT2 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 2 | The physiological substrate, transport direction, driving force, and biological role of AVT2 are all undetermined. It is one of the functionally dark members of the yeast AVT family: a bona fide amino-acid-transporter-fold protein with n… |
| AVT2 | gene | OPEN | BIOLOGY | CC_DARK | 1 | The in-vivo compartment where AVT2 acts is unresolved. AVT2 has been directly localized to the endoplasmic reticulum, yet the family is canonically vacuolar (tonoplast) and UniProt maps AVT2 to the vacuole membrane. It is unknown whether… |
| AVT2 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | The transported substrate, transport direction (vacuolar uptake vs. efflux), and driving force of AVT2 are unknown, so no molecular function more specific than the generic "L-amino acid transmembrane transporter activity" can be assigned… |
| Bacterial 2,3-butanediol and acetoin catabolism | module_node | — | — | — | 0 | The KT2440 dihydrolipoyl dehydrogenase serving as E3 for AcoABC is unknown. |
| Bacterial 2,3-butanediol and acetoin catabolism | module_node | — | — | — | 0 | The biochemical or assembly role of AcoX is unknown. |
| Bacterial 2,3-butanediol and acetoin catabolism | module_node | — | — | — | 0 | The stereoisomer-specific entry dehydrogenases that substitute for BdhA across bacteria are incompletely mapped. |
| Bacterial 2,3-butanediol and acetoin catabolism | module_node | — | — | — | 0 | The preferred 2,3-butanediol stereoisomer and pyridine-nucleotide cofactor of KT2440 BdhA are untested. |
| Bacterial 4-hydroxybutyrate oxidation to succinate | module_node | — | ONTOLOGY + CURATION | — | 0 | GO lacks a specific biological-process term for the free-acid bacterial pathway that oxidizes 4-hydroxybutyrate through succinate semialdehyde to succinate. |
| Bacterial alkanesulfonate uptake and FMN-dependent desulfonation | module_node | — | BIOLOGY | — | 0 | Substrate spectra and division of labor among paralogous sulfonate binding proteins, permeases, and monooxygenases remain unresolved in many bacterial genomes. |
| Bacterial alkanesulfonate uptake and FMN-dependent desulfonation | module_node | — | BIOLOGY | — | 0 | The identity and taxonomic distribution of alternative flavin reductases that can replace SsuE during aliphatic-sulfonate utilization are unresolved. |
| Bacterial aminoacyl-tRNA charging | module | OPEN | BIOLOGY | — | 1 | In bacteria that encode both GlnRS and GatABC, the physiological extent of indirect Gln-tRNA formation depends on whether their GluRS recognizes tRNA(Gln), and may vary with growth condition or lineage. |
| Bacterial and eukaryotic selenocysteine biosynthesis and incorporation | module_node | — | BIOLOGY + CURATION | — | 0 | Archaea use PSTK and SepSecS chemistry but have a distinct selenocysteine-recoding implementation that is not modeled here. |
| Bacterial assimilatory nitrate uptake and reduction | module_node | — | BIOLOGY | — | 0 | The physiological electron donor and pathway assignment cannot always be resolved from the broad prokaryotic molybdopterin-oxidoreductase family alone. |
| Bacterial cellulose biosynthesis | module_node | — | BIOLOGY + CURATION | — | 0 | UPA00694 captures bcsA, bcsB, and PP_2638, but the local KT2440 locus also contains nearby bcs-associated genes not in this bucket, including PP_2634/BcsQ. |
| Bacterial cellulose biosynthesis | module_node | — | CURATION | — | 0 | PP_2634 has a generic UniProt protein name, "Cellulose synthase", but its domain architecture indicates BcsQ/YhjQ rather than BcsA-like glycosyltransferase activity. |
| Bacterial cellulose biosynthesis | module_node | — | BIOLOGY + CURATION | — | 0 | PP_2638 is linked to maximal cellulose synthesis and outer-membrane localization, but its exact molecular activity is not represented by a specific GO molecular-function term here. |
| Bacterial choline uptake and glycine betaine biosynthesis | module_node | — | CURATION | — | 0 | Direct substrate-discrimination evidence for PSEPK BetT-I Q88CW9 is unavailable. |
| Bacterial choline-O-sulfate uptake and desulfation | module_node | — | BIOLOGY | — | 0 | The physiological substrate range and energy-coupling mechanism of the adjacent BetD and SLC26A/SulP-family BetE candidates are unresolved, as is whether they function together. |
| Bacterial choline-O-sulfate uptake and desulfation | module_node | — | BIOLOGY | — | 0 | Direct enzymology has not been reported for KT2440 Q88RQ2 in isolation. |
| Bacterial D-ribose uptake and entry | module_node | — | BIOLOGY | — | 0 | RbsD catalyzes pyranose-to-furanose conversion, while ribofuranose anomers can exchange spontaneously in solution; the quantitative contribution of the RbsD-catalyzed step to pathway flux varies with physiological demand. |
| Bacterial D-ribose uptake and entry | module_node | — | BIOLOGY + CURATION | — | 0 | The PP_2454-PP_2459 locus strongly supports a ribose-specific route, but direct KT2440 transport assays have not yet been located for the RbsB/RbsC/RbsA-I complex. In particular, the RbsB and RbsA-I PANTHER selectors carry D-allose-relat… |
| Bacterial D-ribose uptake and entry | module_node | — | BIOLOGY + CURATION | — | 0 | PP_2759 RbsA and PP_2760 form a second ATPase/permease pair, but their transported substrate and substrate-binding component are unresolved. |
| Bacterial divisome peptidoglycan synthesis | module_node | — | ONTOLOGY | — | 0 | GO lacks a specific molecular-function term for serine-type peptidoglycan D,D-transpeptidase activity. |
| Bacterial DNA-directed RNA polymerase core enzyme | module_node | — | CURATION | — | 0 | This first-pass module does not model sigma-factor recruitment, promoter-specific initiation, transcription elongation factors, or termination factors. |
| Bacterial DnaK/DnaJ/GrpE protein refolding cycle | module_node | — | BIOLOGY | — | 0 | The endogenous clients that require DnaJ-mediated transfer into the DnaK cycle versus autonomous DnaJ or DnaK protection remain incompletely partitioned. |
| Bacterial ethanolamine uptake and cobalamin-dependent catabolism | module_node | — | BIOLOGY | — | 0 | Direct transport assays are needed to establish PP_0544 substrate range and coupling mechanism. |
| Bacterial ethanolamine uptake and cobalamin-dependent catabolism | module_node | — | BIOLOGY | — | 0 | KT2440 AldB-I acetaldehyde preference and requirement during ethanolamine growth remain untested. |
| Bacterial ethanolamine uptake and cobalamin-dependent catabolism | module_node | — | BIOLOGY | — | 0 | KT2440 EutB/EutC microcompartment localization remains unresolved and requires direct, reproducible evidence. |
| Bacterial fatty acid beta-oxidation spiral | module_node | — | CURATION | — | 0 | Pseudomonas putida KT2440 contains additional acyl-CoA dehydrogenases, hydratases, and thiolases whose physiological substrates are unresolved. |
| Bacterial fused-relay fructose PTS uptake and catabolism | module_node | — | ONTOLOGY | — | 0 | GO lacks a molecular-function term for phosphate transfer from a fructose-PTS EIIA histidine to the cognate EIIB phosphocysteine at the FruB-to-FruA handoff. |
| Bacterial gallate catabolism by the GalA-D-B-C route | module | OPEN | BIOLOGY + CURATION | — | 1 | The substrate specificity and pathway requirement of the GalP-associated outer-membrane porin are not established directly. |
| Bacterial gallate catabolism by the GalA-D-B-C route | module | OPEN | ONTOLOGY | — | 1 | GO:0047443 already maps to RHEA:28935 for CHA cleavage, but its label names only 4-hydroxy-4-methyl-2-oxoglutarate rather than the characterized physiological CHA substrate. |
| Bacterial glutamate-to-P5C branch of proline biosynthesis | module_node | OPEN | CURATION | — | 1 | The terminal P5C reductase step is outside this precursor-module boundary. |
| Bacterial glycogen and related alpha-glucan metabolism | module_node | — | BIOLOGY | — | 0 | Q88FN9 nucleotide-sugar donor specificity has not been measured directly. UDP-glucose specificity is assigned from the experimentally characterized PAO1 ortholog in the same PTHR45825:SF8 subfamily and the shared GlgC-negative Pseudomona… |
| Bacterial glycogen and related alpha-glucan metabolism | module_node | — | BIOLOGY | — | 0 | The partitioned KT2440 locus also encodes TreY-TreZ and TreS-Mak-GlgE alpha-glucan routes, but the fate of Q88FN9-derived alpha-glucan and its physiological division of labor with GlgE-derived polymer are unresolved in KT2440. |
| Bacterial GroEL/GroES chaperonin folding | module_node | — | BIOLOGY | — | 0 | The extent to which CnoX acts by direct carrier-like handoff to GroEL versus release and recapture by GroEL or DnaK remains unresolved. |
| Bacterial GroEL/GroES chaperonin folding | module_node | — | ONTOLOGY | — | 0 | GO lacks a current molecular-function term for ATP-independent in-situ holdase chaperone activity after GO:0051082 obsoletion. |
| Bacterial Kdp potassium-homeostasis system | module_node | — | BIOLOGY | — | 0 | The quantitative requirement for KdpF and KdpC in different bacterial KdpFABC complexes is incompletely characterized. |
| Bacterial lipoprotein maturation | module_node | — | CURATION | — | 0 | GO currently lacks a specific lipoprotein signal peptidase activity term for LspA, so the module uses the broad aspartic-type endopeptidase activity term at the LspA step. |
| Bacterial lipoprotein maturation | module_node | — | ONTOLOGY | — | 0 | GO currently lacks a specific apolipoprotein N-acyltransferase activity term for Lnt; the formerly used GO:0016410 is obsolete in current GO and replaced by GO:0016747, so the module uses the valid but broad GO:0016747 term. |
| Bacterial lipoprotein maturation | module_node | — | BIOLOGY | — | 0 | Direct KT2440 biochemical evidence for Lgt, LspA, and Lnt remains limited; assignments are high-confidence transfers from reviewed UniProt/HAMAP rules, conserved domains, catalytic residues, and close bacterial orthologs. |
| Bacterial lipoprotein maturation | module_node | — | CURATION | — | 0 | PP_4236/Q88F63 carries an Lgt-like propagated annotation in the UPA00664 species-aware report, but its domain architecture is more consistent with a DsbE/CcmG-like thiol-disulfide oxidoreductase. |
| Bacterial lipoprotein maturation | module_node | — | CURATION | — | 0 | The local pathway partition places lspA primarily in KEGG ppu03060 Protein export and does not resolve UPA00665 as a complete local bucket, so an automated pathway candidate list can incorrectly show only the signal-peptidase-II step. |
| Bacterial Lol-dependent outer-membrane lipoprotein trafficking | module_node | — | ONTOLOGY | — | 0 | GO lacks specific molecular-function terms for LolA carriage, LolB delivery, and LolCDE lipoprotein extraction. |
| Bacterial Lol-dependent outer-membrane lipoprotein trafficking | module_node | — | CURATION | — | 0 | PANTHER:PTHR30489:SF0 is assigned locally to both PSEPK LolC and LolE and therefore does not discriminate the two membrane-subunit roles. |
| Bacterial Lol-dependent outer-membrane lipoprotein trafficking | module_node | — | BIOLOGY | — | 0 | Diderm lineages vary between heterodimeric LolC/LolE and homodimeric LolF-like extractors, and some lack a canonical LolB receptor. |
| Bacterial Lol-dependent outer-membrane lipoprotein trafficking | module_node | — | BIOLOGY | — | 0 | LolA and LolB are normally required in the canonical relay but can be genetically bypassed under specific envelope-stress conditions in a characterized model. |
| Bacterial medium-chain-length PHA synthesis and mobilization | module_node | — | — | — | 0 | Native PhaG chemistry remains unresolved between direct ACP:CoA transacylation and ACP thioester hydrolysis followed by a separate CoA-ligase step, potentially involving PP_0763. |
| Bacterial medium-chain-length PHA synthesis and mobilization | module_node | — | — | — | 0 | The relative physiological contributions, substrate preferences, and granule occupancy of KT2440 PhaC1 and PhaC2 have not been resolved. |
| Bacterial medium-chain-length PHA synthesis and mobilization | module_node | — | — | — | 0 | GO:0050527 is specific to poly(3-hydroxyoctanoate) and does not fully represent intracellular PhaZ enzymes that hydrolyze compositionally diverse medium-chain-length PHA polymers. |
| Bacterial methionine cycle and remethylation | module_node | — | BIOLOGY + CURATION | — | 0 | The distribution and physiological use of direct AhcY versus the two-step MtnN/Pfs-LuxS route vary across bacterial lineages and growth conditions. |
| Bacterial Mla intermembrane phospholipid transport | module_node | — | BIOLOGY | — | 0 | The physiologically dominant net direction of Mla-mediated phospholipid transfer is not universally resolved. |
| Bacterial Mla intermembrane phospholipid transport | module_node | — | BIOLOGY | — | 0 | The exact MlaB-equivalent role of the KT2440 STAS protein Ttg2E has not been directly tested. |
| Bacterial Mla intermembrane phospholipid transport | module_node | — | CURATION | — | 0 | PP_1737 is a second MlaA-family protein without the canonical VacJ assignment, and PP_0140-PP_0142 form a separate Mce-like transporter with overlapping MlaF/E/D-like signatures. |
| Bacterial Mla intermembrane phospholipid transport | module_node | — | BIOLOGY | — | 0 | MlaA proteins occur with and without a canonical lipoprotein signal, porin partners vary by lineage, and MlaB's precise regulatory effect remains incompletely resolved. |
| Bacterial NADPH-dependent GS-GOGAT ammonia assimilation | module_node | OPEN | BIOLOGY | — | 1 | The relative flux through GS-GOGAT and direct GdhA-mediated ammonium assimilation varies with organism, nitrogen concentration, and carbon status. |
| bacterial naringenin A-ring degradation | module_node | OPEN | BIOLOGY + CURATION | — | 1 | The biochemical roles of FdeD and FdeH and the exact R13076-R13079 reactions remain unverified experimentally. |
| Bacterial nitrogen-regulatory PTS phosphorelay | module_node | — | ONTOLOGY | — | 0 | GO lacks a dedicated biological-process term for the nitrogen-regulatory PtsP-NPr-PtsN phosphorelay; GO:0009401 is explicitly the sugar PTS and must not be propagated to this non-transport branch. |
| Bacterial nitrogen-regulatory PTS phosphorelay | module_node | — | ONTOLOGY | — | 0 | GO lacks a specific molecular-function term for the NPr histidyl phosphocarrier step between EI(Ntr) and EIIA(Ntr). |
| Bacterial nitrogen-regulatory PTS phosphorelay | module_node | — | BIOLOGY | — | 0 | The metabolites or physiological signals controlling EI(Ntr) input and the rules connecting EIIA(Ntr) phosphostate to particular downstream targets remain incompletely resolved across bacteria. |
| Bacterial non-homologous end joining | module_node | — | BIOLOGY | — | 0 | The relative contributions and ordering of LigD polymerase and phosphoesterase activities depend on the chemistry of each DNA end. |
| Bacterial non-homologous end joining | module_node | — | CURATION | — | 0 | Ku-LigD systems with split catalytic proteins or backup ligases require separately grounded implementation variants. |
| Bacterial Ntr nitrogen-regulatory phosphorelay | module_node | — | CURATION | — | 0 | The NtrB (NRII/GlnL) sensor kinase has no gene review in this repository, so the sensor tier is grounded only by molecular function. |
| Bacterial Ntr nitrogen-regulatory phosphorelay | module_node | — | BIOLOGY | — | 0 | Whether the PII protein acts on NtrB alone or also directly on other nitrogen-regulatory targets varies between bacteria, and the KT2440 partner set is not fully established. |
| Bacterial nucleotide-excision repair system | module_node | — | BIOLOGY | — | 0 | The physiological contribution of divergent bacterial UvrA2-family paralogs is lineage-specific. |
| Bacterial nucleotide-excision repair system | module_node | — | BIOLOGY | — | 0 | Bacterial taxa differ in whether they encode Cho-family alternative incision proteins. |
| Bacterial phosphatidylglycerol and cardiolipin biosynthesis | module | OPEN | BIOLOGY + CURATION | — | 0 | Does PSEPK PP_5276/Q88CA5 catalyze phosphatidylglycerol-dependent cardiolipin synthesis in vivo, and under which conditions relative to ClsA and ClsB? |
| Bacterial phosphatidylglycerol and cardiolipin biosynthesis | module | OPEN | BIOLOGY + CURATION | — | 0 | Is PP_0892/Q88PF8 an active ClsB-like cardiolipin synthase despite its incomplete catalytic-domain annotation, or a diverged inactive paralog? |
| Bacterial preQ1 incorporation and queuosine maturation | module_node | — | ONTOLOGY | — | 0 | GO:0008479 formally defines free-queuine insertion, while the GOC-maintained IPR004803 and MF_00168 rules apply it to bacterial preQ1-inserting Tgt. |
| Bacterial purine base oxidation to urate | module | OPEN | BIOLOGY + CURATION | — | 0 | Direct biochemical reconstitution of the PP_4278/PP_4279 XdhAB complex from Pseudomonas putida KT2440 with both hypoxanthine and xanthine substrates has not been identified. |
| Bacterial purine base oxidation to urate | module | OPEN | BIOLOGY | — | 0 | Dedicated XdhC-mediated molybdenum-cofactor maturation is established in a homologous two-subunit XDH, but the requirement and exact role of the corresponding maturation factor have not been demonstrated for each representative bacterial… |
| Bacterial putrescine biosynthesis by arginine and ornithine routes | module_node | — | BIOLOGY | — | 0 | Relative route usage and redundancy vary among bacteria and have not been measured directly in Pseudomonas putida KT2440. |
| Bacterial putrescine biosynthesis by arginine and ornithine routes | module_node | — | BIOLOGY | — | 0 | KT2440 contains AguA but lacks a verified canonical or noncanonical N-carbamoylputrescine amidohydrolase completing that alternative branch. |
| Bacterial putrescine biosynthesis by arginine and ornithine routes | module_node | — | BIOLOGY | — | 0 | TIGR01230 and shared InterPro signatures do not distinguish SpeB agmatinase from the PP_4523 K12255 guanidinobutyrase paralog. |
| Bacterial pyruvate oxidation, anaplerosis, and PEP interconversion | module_node | — | BIOLOGY | — | 0 | The distribution and physiological weighting of pyruvate carboxylase and phosphoenolpyruvate carboxylase vary with bacterial lineage and carbon source. |
| Bacterial pyruvate oxidation, anaplerosis, and PEP interconversion | module_node | — | BIOLOGY | — | 0 | Pyruvate-forming lactate oxidation, malic-enzyme activity, acetate conversion, and numerous substrate-specific degradative reactions can intersect the pyruvate node without defining this reusable core. |
| Bacterial pyruvate oxidation, anaplerosis, and PEP interconversion | module_node | — | BIOLOGY | — | 0 | Phosphoenolpyruvate is partitioned between pyruvate kinase and phosphoenolpyruvate carboxylase, while opposing PpsA activity can create a potentially wasteful PEP-pyruvate cycle. The condition-specific flux split and regulatory controls … |
| Bacterial RecBCD double-strand-end resection | module_node | — | BIOLOGY | — | 0 | The sequence or structural signal controlling the RecBCD recombinogenic switch in KT2440 is unknown. |
| Bacterial RecBCD double-strand-end resection | module_node | — | CURATION | — | 0 | Direct biochemical partitioning of RecB, RecC, and RecD roles has not been performed in KT2440. |
| Bacterial RecBCD double-strand-end resection | module_node | — | CURATION | — | 0 | The broader PTHR43788:SF6 family cannot by itself distinguish canonical RecBCD RecD from standalone RecD2 or HelB helicases. |
| Bacterial Rod complex peptidoglycan synthesis | module_node | — | ONTOLOGY | — | 0 | GO lacks a specific molecular-function term for serine-type peptidoglycan D,D-transpeptidase activity. |
| Bacterial RuvABC Holliday-junction processing | module_node | — | BIOLOGY | — | 0 | The relative use of RuvAB and RecG branch migration has not been measured directly in KT2440. |
| Bacterial RuvABC Holliday-junction processing | module_node | — | CURATION | — | 0 | No RusA-type backup resolvase was identified in the KT2440 candidate set. |
| Bacterial RuvABC Holliday-junction processing | module_node | — | BIOLOGY | — | 0 | The nuclease that resolves RecG-remodeled junctions in KT2440 has not been demonstrated. |
| Bacterial sodium-coupled proline uptake and fused-PutA catabolism | module_node | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The physiological quinone species that accepts electrons from PutA in P. putida KT2440 has not been established in the reviewed evidence. |
| Bacterial succinylarginine catabolism to glutamate and succinate | module_node | — | BIOLOGY | — | 0 | KT2440 AstA-I/AstA-II complex stoichiometry and the division of catalytic residues between the two chains have not been directly tested. |
| Bacterial succinylarginine catabolism to glutamate and succinate | module_node | — | BIOLOGY | — | 0 | PP_4481 has not been assayed directly against succinylornithine and acetylornithine, so its AstC specialization and residual anabolic activity remain inferred. |
| Bacterial twin-arginine protein translocation | module_node | — | BIOLOGY | — | 0 | The physiological substrate sets and condition-specific use of paralogous TatABC systems are often unresolved. |
| Bacterial twin-arginine protein translocation | module_node | — | ONTOLOGY | — | 0 | GO molecular-function terms describe whole-transporter activity more readily than the distinct TatA, TatB, and TatC mechanistic roles. |
| Bacterial type II secretion | module_node | — | BIOLOGY | — | 0 | The individual stoichiometry and substrate-dependent dynamics of the four minor pseudopilins remain incompletely resolved across T2SS lineages. |
| Bacterial type II secretion | module_node | — | BIOLOGY | — | 0 | GspN-like accessory proteins occur in some type II secretion loci but are not uniformly required across characterized systems. |
| Bacterial undecaprenyl-phosphate carrier supply | module_node | — | BIOLOGY | — | 0 | Pseudomonas putida KT2440 encodes PAP2-family phosphatases PP_0251, PP_0900, and PP_4813 that may overlap UppP-mediated C55-PP dephosphorylation, but their physiological substrates are unresolved. |
| bag-1 | gene | OPEN | BIOLOGY | BP_DARK | 2 | No in-vivo client or substrate of C. elegans BAG-1 has been identified, and it is untested whether worm BAG-1 biases Hsc70-bound clients toward productive refolding or, via its ubiquitin-like domain, toward proteasomal degradation (the f… |
| bag-1 | gene | OPEN | BIOLOGY | BP_DARK | 2 | No loss-of-function phenotype has been reported for the bag-1 gene itself in C. elegans, so it is unknown whether bag-1 is essential, is functionally redundant with its paralog unc-23, or has a distinct tissue-restricted role. |
| bag-1 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 2 | A direct physical BAG-1-to-HSP-1/Hsc70 complex in C. elegans has not been demonstrated, and the subcellular site of BAG-1 action in the worm is untested; the only experimentally reported worm partner is the DUF727 protein Y43F8B.2, whose… |
| bbs-4 | gene | OPEN | ONTOLOGY + BIOLOGY | MF_DARK | 2 | There is no GO molecular-function term that expresses the role of a BBSome coat/cargo- adaptor subunit, and the specific cargo(es) that BBS-4's TPR array directly recognizes within the BBSome are undefined. BBS-4 has no experimentally me… |
| bbs-4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The molecular mechanism by which the BBSome triggers degradative (lysosome-targeted) removal of ciliary sensory receptors — the direct effectors linking the ciliary-base BBSome to the endocytic/ubiquitin machinery — and the molecular bas… |
| bbs-9 | gene | OPEN | ONTOLOGY + BIOLOGY | MF_DARK | 2 | There is no GO molecular-function term that expresses the role of a BBSome coat/scaffold subunit, and BBS-9 has no experimentally measured biochemical activity of its own. Unlike the peripheral subunit BBS-4, worm BBS-9 has no molecular-… |
| bbs-9 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Whether BBS-9, as a β-propeller "core" (BBS-2/BBS-7/BBS-9) subunit, plays a distinct nucleating/assembly role separable from the peripheral subunits, and what its individual contribution is to IFT-particle assembly at the ciliary base ve… |
| BBS12 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 0 | The molecular activity performed by BBS12 in BBSome assembly, and whether that activity depends on nucleotide binding, remains unresolved by the reviewed experiments. |
| BCCIP | gene | NARROWING | BIOLOGY + CURATION | MF_DARK | 2 | The GO representation and physiological scope of BCCIPalpha-mediated FAM46/TENT5 inhibition remain unresolved. |
| BCCIP | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 2 | How BCCIP's isoform-specific activities are coordinated across DNA repair, RNA metabolism, ribosome biogenesis, spindle assembly, and CDK regulation remains incompletely understood. |
| BCCIP | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | BCCIP's cancer biology remains context-dependent: partial loss can promote genome instability and tumor initiation, while retained or elevated BCCIP activity may support proliferation in some established cancers. |
| Benzoate upper degradation pathway | module | OPEN | CURATION | — | 2 | The modules KB has no home for fungal oxidative decarboxylation of lignin-derived aromatic acids to hydroquinones, and the one enzyme now reported to catalyse it cannot be grounded as a module participant. PcMNX1 (PMID:42567519) converts… |
| betA (core function) | core_function | — | — | — | 0 | Direct assay of NAD-dependent betaine-aldehyde oxidation by purified KT2440 BetA is unavailable. |
| betT-I (core function) | core_function | — | — | — | 0 | Direct transport kinetics and checkable substrate-assignment evidence for KT2440 BetT-I versus BetT-II and BetT-III are unavailable. |
| Betv1 (core function) | core_function | — | BIOLOGY + CURATION | — | 1 | The specific physiological ligand and in-planta function of Bet v 1 are unresolved; it binds many lipophilic ligands in vitro but its endogenous cargo and role (defence vs. hormone/sterol transport) are not established. |
| bglX | gene | OPEN | BIOLOGY | — | 1 | The physiological beta-glucoside or glucan substrate of bglX is unknown. |
| BIT2 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 1 | BIT2's specific molecular function within TORC2 is unknown. No experiment defines a BIT2-specific biochemical activity, and its molecular_function is annotated ND. It is undetermined whether BIT2 regulates Tor2 kinase activity, effector/… |
| BIT2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | BIT2's non-redundant function relative to its whole-genome-duplication paralog BIT61 is unknown. TORC2 contains "Bit61 or its paralog Bit2", but whether the two are fully interchangeable or have distinct, condition-specific roles has not… |
| BIT2 (core function) | core_function | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 1 | The specific, BIT2-distinct molecular activity within TORC2 is undetermined. It is not known whether BIT2 modulates Tor2 kinase activity, substrate/effector (e.g. Slm1/Slm2, Ypk1/Ypk2) selection, complex assembly/stability, or subcellula… |
| BLOC1S1 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 0 | It remains unresolved whether GCN5L1 supplies an intrinsic protein-lysine acetyl-transfer catalytic site or enables acetylation through another component of the machinery. |
| BLOC1S3 (core function) | core_function | — | — | — | 3 | Whether BLOS3 is specifically required for BLOC-1 binding to AP-3, and where any BLOS3 contribution acts within that interface, remain unresolved. |
| BLOC1S5 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 0 | The distinct molecular activity and contact topology of MUTED within BLOC-1 remain incompletely resolved. |
| BLOC1S6 (core function) | core_function | OPEN | BIOLOGY | — | 0 | How pallidin-specific interfaces couple BLOC-1 assembly to SNARE-associated cargo sorting remains incompletely resolved. |
| branched-chain amino acid biosynthesis | module_node | OPEN | BIOLOGY | — | 0 | KT2440 encodes two full-length IlvA-family threonine deaminases, Q88HB4/PP_3446 and Q88CN1/PP_5149, with the same predicted reaction and isoleucine-pathway assignment. |
| branched-chain amino acid biosynthesis | module_node | OPEN | BIOLOGY | — | 0 | The exact Q88CQ2 record assigns a 2Fe-2S cluster, whereas other IlvD family literature commonly describes a 4Fe-4S catalytic cluster. |
| BRWD3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether human BRWD3, BRWD1, or PHIP conserves the fly BRWD3-dependent degradation of KDM5-family demethylases remains unresolved. |
| BRWD3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 3 | The histone-recognition and effector-recruitment activities of human BRWD3 are not yet resolved separately from the related PHIP and BRWD1 proteins in the inspected biochemical evidence. |
| C18orf21 | gene | NARROWING | BIOLOGY + CURATION | MF_DARK | 2 | The strongest current functional lead identifies C18orf21 as an RNase MRP-specific subunit, but this assignment still needs peer-reviewed consolidation before the review should replace the historical unknown-function framing with definit… |
| C18orf21 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | The precise biochemical contribution of C18orf21 within RNase MRP remains incompletely resolved. |
| C18orf21 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 2 | The cellular and disease contexts in which C18orf21/RNase MRP activity is limiting remain unclear. |
| C5orf46 | gene | OPEN | BIOLOGY | MF_DARK | 2 | No molecular function is known. The peptide demonstrably kills Gram-negative bacteria, but the route is unresolved: the authors offer cell-envelope damage and an intracellular target as alternatives and settle neither, no molecular targe… |
| C5orf46 | gene | OPEN | BIOLOGY | BP_DARK | 2 | Nothing establishes that the endogenous peptide is required for anything. Every functional experiment adds purified peptide from outside: to bacterial cultures, and by intraperitoneal injection into mice already challenged with a pathoge… |
| C5orf46 | gene | OPEN | CURATION | BP_DARK | 3 | The gene's functional literature is entirely absent from GO, in every organism, and so is its family's. A QuickGO query by reference returns zero annotations citing PMID:33804835 anywhere in GOA, against 396 for the control reference PMI… |
| C5orf46 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The relationship between the antibacterial activity and the general cytotoxicity is unresolved, and it is the question that decides whether this peptide is a host-defence molecule or simply a membrane-active amphipathic peptide. At 10 mi… |
| C5orf46 | gene | OPEN | BIOLOGY | BP_DARK | 2 | The one loss-of-function phenotype on record has no mechanism and no connection to the peptide's known activity. siRNA knockdown in two renal-carcinoma lines reduces proliferation and migration and raises apoptosis. That is a cancer-cell… |
| CACUL1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The direct biochemical mechanism by which CACUL1 promotes CDK2 kinase activity remains unresolved: it is unclear whether CACUL1 allosterically activates CDK2, alters cyclin/CDK-inhibitor availability, changes substrate engagement, or act… |
| CACUL1 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | The role of CACUL1's cullin-repeat-like domain in CRL3-Keap1/Nrf2 regulation is unresolved, and CACUL1 should not be curated as a bona fide cullin-RING scaffold unless future experiments show that it assembles or positions an E3 ubiquiti… |
| CACUL1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The physiological context and directionality of CACUL1 nuclear-receptor coregulation remain only partly defined, especially whether ERalpha, androgen receptor, and PPARgamma effects represent one general chromatin mechanism or distinct r… |
| CAF120 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular function of CAF120 is unknown. No catalytic, nucleic-acid-binding, adapter, or scaffolding activity has been demonstrated, and the ligand and role of its divergent N-terminal PH domain (Skg3/CAF120-like PH subfamily) are un… |
| CAF120 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 1 | It is unresolved whether CAF120 is a bona fide, stable core subunit of the CCR4-NOT complex or merely a transient / substoichiometric associated factor, and — if it does associate — whether it makes any functional contribution to CCR4-NO… |
| CAF120 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The molecular mechanism by which CAF120 promotes meiotic crossing-over is unknown: it is not established how (or whether directly) CAF120 acts on the MutLgamma-Exo1 crossover machinery, what its meiosis-specific binding is to within that… |
| CAF120 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biological role and physiological significance of CAF120's bud-neck localization and of its DNA-damage-induced relocalization are unknown, as is the basis of its subtle deletion phenotypes (reduced competitive fitness, altered free a… |
| CAK1 (core function) | core_function | — | — | — | 0 | Whether the reported phosphorylation-independent contribution of Cak1 to Cdc28 maturation (suppression of Cdc28 C-terminal mutants by catalytically compromised Cak1) reflects a chaperone-like role is unresolved. |
| CAK1 (core function) | core_function | — | — | — | 0 | The quantitative in vivo contribution of Cak1-mediated T-loop phosphorylation to each transcriptional CDK, and to RNA polymerase II transcription overall, is not established. |
| Canf1 (core function) | core_function | — | BIOLOGY | — | 1 | The native (in-vivo) ligand and physiological role of Can f 1 remain unconfirmed: fatty acids are demonstrated as surrogate ligands in vitro, but the endogenous cargo carried in the dog and the biological function are not established. |
| Canonical Notch signaling pathway | module_node | — | — | — | 0 | The C. elegans ligand-activating E3 ubiquitin ligase is not identified. |
| Canonical Notch signaling pathway | module_node | — | — | — | 0 | Whether nematode LAG-3/SEL-8 is a diverged Mastermind homolog or a functional analog is unresolved. |
| Canonical Notch signaling pathway | module_node | — | — | — | 0 | The CSL corepressor adaptor used in nematodes and cnidarians is not established. |
| Canonical Notch signaling pathway | module_node | — | — | — | 0 | Whether cnidarian Notch signaling is canonical (Su(H)/Hes-dependent) in all contexts is debated. |
| Canonical Notch signaling pathway | module_node | — | — | — | 0 | CSL-independent (non-canonical) and ligand-independent Notch signaling are outside this module boundary. |
| cao-1 | gene | — | BIOLOGY | BP_DARK | 1 | The natural physiological substrate and biological role of CAO-1 in Neurospora crassa are undetermined. The in vitro substrates resveratrol and piceatannol are plant stilbenoids of uncertain ecological relevance to this fungus, and it is… |
| cao-1 | gene | — | BIOLOGY | BP_DARK | 2 | The retinal-forming (beta-carotene cleaving) enzyme of Neurospora crassa is unidentified. The hypothesis that motivated the study of cao-1 - that it supplies retinal, the chromophore of the NOP-1 rhodopsin - was disproven, and its paralo… |
| Carotene backbone biosynthesis (GGPP -> phytoene -> lycopene -> cyclic carotenes) | module_node | OPEN | ONTOLOGY | — | 1 | GO:0016120 carotene biosynthetic process (and its children phytoene biosynthetic process GO:1901174 and lycopene biosynthetic process GO:1901177) is not a descendant of GO:0016117 carotenoid biosynthetic process, even though carotenes ar… |
| Carotene backbone biosynthesis (GGPP -> phytoene -> lycopene -> cyclic carotenes) | module_node | OPEN | CURATION | — | 2 | Additional lycopene cyclase families are known (heterodimeric CrtYc/CrtYd of actinobacteria and archaea, and the CruA/CruP cyclases of green sulfur bacteria and some cyanobacteria) but are not grounded here because no reviewed exemplar w… |
| Carotene backbone biosynthesis (GGPP -> phytoene -> lycopene -> cyclic carotenes) | module_node | OPEN | CURATION | — | 2 | PANTHER's classification of the homologous LCYB/CrtL/LCYE lycopene cyclases is split: cyanobacterial CrtL (Q55276) and plant LCYE (Q38932) sit in the unnamed family PTHR39757 (SF5 and SF3), whereas PANTHER's per-organism classification p… |
| Carotene backbone biosynthesis (GGPP -> phytoene -> lycopene -> cyclic carotenes) | module_node | OPEN | BIOLOGY + CURATION | — | 2 | In the poly-cis route, light-driven photoisomerization can substitute for Z-ISO and CRTISO in illuminated photosynthetic tissue, so the two isomerase steps are enzymatically required only in the dark or in non-photosynthetic tissue. |
| cas1 | gene | OPEN | BIOLOGY | — | 2 | The non-catalytic partner that Pseudomonas aeruginosa PA14 Cas1 works with during spacer integration has not been identified experimentally. Type I-F encodes no standalone Cas2, so the partner is presumed to be the N-terminal Cas2 module… |
| cas3 | gene | OPEN | BIOLOGY + CURATION | — | 2 | No nuclease or helicase activity has been measured on purified Pseudomonas aeruginosa Cas3 in isolation, so the mode of DNA cleavage (endonucleolytic versus exonucleolytic, strand preference, processivity) and the duplex substrate of the… |
| cas6f | gene | OPEN | ONTOLOGY | — | 1 | GO has no cellular-component term for a CRISPR RNA-guided surveillance complex, so Csy complex membership can only be asserted with the generic GO:1990904 ribonucleoprotein complex, which does not distinguish it from a ribosome, a splice… |
| CASP4 (core function) | core_function | NARROWING | BIOLOGY + ONTOLOGY | RESIDUAL_SUBGAP | 2 | It is not established whether the physical entity CASP4 recognises is an individual lipopolysaccharide molecule or an LPS-containing membrane surface of positive curvature, and consequently which molecular function term describes the rec… |
| CASP4 (core function) | core_function | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | The physiological substrate repertoire of CASP4 is not settled: beyond gasdermin D and pro-IL-18 it is undetermined whether CASP3, CASP7 and pro-IL-1beta are genuine in-cell substrates, and what share of gasdermin D cleavage during non-c… |
| cct-1 | gene | OPEN | ONTOLOGY + BIOLOGY | MF_DARK | 2 | There is no GO molecular-function term that expresses "substrate-binding subunit of the CCT chaperonin". The alpha (CCT-1) subunit's own activity can therefore only be annotated as the complex-level foldase (GO:0140662) or as generic ATP… |
| cct-1 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | Whether CCT-1 has any genuine, function-relevant nuclear localization in C. elegans is unresolved. A nucleus located_in annotation exists (from the 1997 CCT-1 paper) but its experimental basis cannot be verified, and the chaperonin is ca… |
| cct-8 | gene | OPEN | ONTOLOGY + BIOLOGY | MF_DARK | 2 | The native C. elegans client repertoire that specifically depends on the theta (CCT8) subunit is undefined, and there is no GO molecular-function term that expresses "substrate-binding subunit of the CCT chaperonin". The theta subunit's … |
| cct-8 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | It is unknown whether the germ-granule protein PGL-1 is a direct CCT/TRiC client of cct-8 or whether the pgl-1 mislocalization seen on cct-8 depletion is an indirect consequence of impaired folding of another substrate (for example actin… |
| Cd44 / positive regulation of ATF6-mediated unfolded protein response | annotation | OPEN | BIOLOGY | MF_DARK | 1 | How CD44 raises basal ATF6 output is undetermined. CD44 does not bind ATF6, IRE1 or PERK directly, and the proposed mechanism - altering ER membrane properties - is inferred from an ATF6 point mutant that is blind to membrane lipid chang… |
| CFAP300 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 2 | The biochemical activity of CFAP300 is unknown. It is unresolved whether it acts as a chaperone/co-chaperone, a scaffold, or an adaptor; what its client/substrate is; and whether it acts at one common step upstream of both dynein arm typ… |
| Cgas (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The molecular step by which chromatin-retained cGAS strengthens the FANCI-RAD50 interaction is undetermined: it is not known whether cGAS contacts FANCI or RAD50 directly, acts as a chromatin-tethered scaffold that raises their local con… |
| Cgas (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The quantitative DNA-dose response, cGAMP production and interferon output of naked-mole-rat cGAS remain unmeasured in the inspected evidence. |
| CH1 (core function) | core_function | — | BIOLOGY | — | 1 | The endogenous biological function of Fel d 1 is undetermined: it is not known whether the protein acts in skin/epithelial barrier protection, in transport of a lipophilic ligand, or in another role. |
| CH1 (core function) | core_function | — | BIOLOGY | — | 1 | The physiological ligand and the in-cat role of Fel d 1's ligand binding are unconfirmed. Candidate ligands (lauric acid, androsterone) and LPS binding are reported in vitro, but which ligand the protein carries in vivo, and to what biol… |
| CH2 (core function) | core_function | — | BIOLOGY | — | 1 | The endogenous biological function of Fel d 1 is undetermined: it is not known whether the protein acts in skin/epithelial barrier protection, in transport of a lipophilic ligand, or in another role. |
| CH2 (core function) | core_function | — | BIOLOGY | — | 1 | The physiological ligand and the in-cat role of Fel d 1's ligand binding are unconfirmed. Candidate ligands (lauric acid, androsterone) and LPS binding are reported in vitro, but which ligand the protein carries in vivo, and to what biol… |
| che-11 | gene | OPEN | ONTOLOGY + CURATION | MF_DARK | 1 | CHE-11 has no molecular_function annotation and there is no adequate GO term to express one. Its role is to be a structural constituent of the IFT-A particle, but GO has no "structural constituent of the intraflagellar transport particle… |
| che-11 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The subunit-resolved architecture of the worm IFT-A complex and the precise role of CHE-11 in the retrograde turnaround are not solved: how CHE-11 (IFT140) contacts the other IFT-A subunits (DAF-10/IFT122, DYF-2/WDR19, IFT-139, IFT-43, I… |
| che-11 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 1 | Whether CHE-11 has any direct role in anterograde intraflagellar transport, as opposed to an indirect requirement, is unresolved. che-11 mutants lose both anterograde and retrograde processive movement of ciliary cargo, but IFT-A is mech… |
| che-13 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 1 | The specific intra-complex protein contacts of CHE-13/IFT57 within the C. elegans IFT-B particle have not been experimentally mapped. In vertebrates IFT57 sits in the peripheral IFT-B1 region and helps couple IFT-B to the IFT-A/dynein-2 … |
| che-13 | gene | OPEN | BIOLOGY | MF_DARK | 2 | It is not resolved whether the severely truncated axoneme of che-13 mutants reflects failure to deliver specific axonemal cargo (e.g. tubulin or motility- related proteins) versus a general loss of IFT-B particle integrity that mislocali… |
| Chemoreceptor-to-flagellar-motor signaling | module_node | — | BIOLOGY | — | 0 | PSEPK encodes multiple chemoreceptors and chemotaxis systems; exact ligand assignments and component cross-talk are incompletely resolved. |
| Chemoreceptor-to-flagellar-motor signaling | module_node | — | CURATION | — | 0 | FliM and FliN are required to represent CheY-P engagement of the C-ring, but dedicated PSEPK reviews for these proteins are not yet available. |
| Chemoreceptor-to-flagellar-motor signaling | module_node | — | BIOLOGY | — | 0 | PP_4332 and the adjacent CheW-domain protein PP_4333 may have distinct or partially redundant receptor-array coupling roles. |
| Chemoreceptor-to-flagellar-motor signaling | module_node | — | BIOLOGY | — | 0 | The environmental and regulatory determinants that recruit KT2440 MotAB versus MotCD to individual motors remain incompletely resolved. |
| CLHC1 | gene | OPEN | BIOLOGY + CURATION | WHOLLY_DARK | 1 | CLHC1's direct molecular activity, physiological interaction partners or native complex, and the biological process in which it acts are undetermined. |
| clk-1 | gene | OPEN | BIOLOGY | BP_DARK | 2 | How the quinone change in clk-1 mutants (loss of ubiquinone UQ9, accumulation of the DMQ9 precursor) is transduced into the pro-longevity signal is undetermined: it is unclear whether the signal comes from DMQ itself, from altered respir… |
| clk-1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | Whether CLK-1 has a genuine, physiologically significant non-mitochondrial (nuclear) function in C. elegans is unresolved: how a nuclear pool is targeted (the worm N-terminus lacks the COQ7 nuclear-targeting residues), whether it binds D… |
| clk-1 | gene | OPEN | ONTOLOGY | CC_DARK | 0 | There is no Gene Ontology cellular-component term for the multi-subunit ubiquinone-biosynthetic (COQ) complex ("CoQ synthome") of which CLK-1/COQ7 is a component and which it is proposed to structurally stabilize, so this membership cann… |
| cmc4 | gene | OPEN | BIOLOGY | MF_DARK | 2 | cmc4 is a functionally dark gene: its molecular activity, its direct binding partner(s)/client in S. pombe, and its in vivo biological role are all undetermined. It is unresolved whether cmc4 acts in cytochrome c oxidase (COX II) assembl… |
| cmc4 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | No molecular activity or direct client/partner has been demonstrated for cmc4; whether it is a metallochaperone, a disulfide-relay accessory factor, or an adaptor coupling to a COX assembly factor (e.g. an Sco1 ortholog) is unresolved. |
| cmc4 / biological_process | annotation | OPEN | BIOLOGY | BP_DARK | 1 | The in vivo biological role of cmc4 in S. pombe is unknown: whether it contributes to cytochrome c oxidase assembly/respiration (as suggested for the human ortholog) or has a distinct meiosis-related role implied by its tam2 expression p… |
| cmc4 / molecular_function | annotation | OPEN | BIOLOGY | MF_DARK | 1 | The molecular activity of cmc4 is undetermined. It is unknown whether it acts as a metallochaperone, a redox/disulfide-relay accessory factor, or a protein-interaction adaptor within the mitochondrial IMS, and no direct binding partner h… |
| cms1 (core function) | core_function | OPEN | BIOLOGY + CURATION | MF_DARK | 1 | The molecular function of cms1 is undetermined: no catalytic activity, no direct nucleic-acid- or protein-binding partner, and no biochemically demonstrated activity are known for the protein in any species. Whether the degenerate helica… |
| coITGB2 (core function) | core_function | — | — | — | 0 | The integrin complex (GO:0008305) membership is inferred, not shown: no integrin alpha partner of integrin beta2 has been identified biochemically in Capsaspora, and talin coupling through the NPxY tail motif is predicted from sequence o… |
| con-10 (core function) | core_function | — | — | — | 0 | No demonstrated role in conidium formation: the only evidence is conidiation-specific expression timing, which GO does not accept as process involvement. No con-10 loss-of-function conidiation phenotype has been reported, and PMID:151263… |
| con-6 (core function) | core_function | — | — | — | 0 | No demonstrated role in conidium formation: con-6 inactivation had no effect on conidium formation or germination, so GO:0048315 involvement is not supportable from expression timing alone. Whether CON-6 contributes to spore desiccation … |
| COS9 | gene | OPEN | BIOLOGY | BP_DARK | 1 | Whether COS9 is functionally equivalent to the characterized paralog COS5 (i.e. an active, redundant MVB-sorting factor) or is instead specialized, expressed only under particular conditions, or effectively dispensable, is undetermined. … |
| COS9 (core function) | core_function | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 2 | The molecular function of Cos9 is unknown. No catalytic activity or specific binding partner has been assigned to Cos9 or to any member of the DUP/COS family; even the proposed family-level activity — supplying a ubiquitin sorting signal… |
| coVIN (core function) | core_function | — | — | — | 0 | Actin filament binding, talin binding and talin-dependent activation are inferred from sponge and vertebrate vinculins and have not been measured for coVIN. No vinculin knockout or knockdown exists in Capsaspora, so its requirement for s… |
| CPR4 | gene | OPEN | BIOLOGY | BP_DARK | 2 | No physiological in vivo substrate or client protein of CPR4 has been identified. It is unknown which secretory/membrane/vacuolar proteins (if any) require CPR4-catalyzed peptidyl-prolyl isomerization for their folding, assembly, or tran… |
| CPR4 | gene | OPEN | BIOLOGY | MF_DARK | 1 | It is unknown whether CPR4 has measurable PPIase activity and whether that catalytic activity is required in vivo for any process. No direct biochemical measurement of CPR4 PPIase kinetics, substrate specificity, or catalysis-dependent p… |
| CPR4 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The extent of functional redundancy between CPR4 and its closest paralog CPR8 (and other ER/secretory folding factors) is unknown. Viability data show non-essentiality but do not test substrate-level or conditional redundancy. |
| CPR4 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether CPR4 binds cyclosporin A is untested and predicted to be atypical: the tryptophan equivalent to human cyclophilin A W121, which lines the cyclosporin A binding pocket, is not conserved in CPR4. |
| Cpx envelope-stress periplasmic quality control | module_node | — | BIOLOGY | — | 0 | The native client ranges that distinguish CpxP-DegP adaptor substrates from Spy holdase/refolding substrates remain incompletely mapped. |
| Cpx envelope-stress periplasmic quality control | module_node | — | ONTOLOGY | — | 0 | GO lacks a current molecular-function term for ATP-independent in-situ holdase chaperone activity after GO:0051082 obsoletion. |
| CRISP1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The direct human oolemma partner and molecular mechanism by which CRISP1 promotes sperm-egg plasma-membrane fusion are unknown. |
| CRISP1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | It is not known whether human CRISP1 regulates endogenous PMCA4b or calcium channels in human sperm during capacitation and fertilization. |
| CRISP1 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 2 | The functional distinction between CRISP1 isoforms and loosely versus tightly sperm-associated pools is unresolved, and the reported sperm-nuclear pool is unverified. |
| CRISPLD1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | CRISPLD1's direct molecular activity, extracellular target/receptor, calcium-handling effector, and activity-bearing domain are unknown. |
| CRISPR-Cas adaptive immunity | module | NARROWING | ONTOLOGY | — | 0 | GO has no molecular-function term for crRNA-guided (RNA-programmed) target recognition, so surveillance complexes and single effectors can only be annotated with generic nucleic-acid-binding and nuclease terms that do not distinguish the… |
| CRISPR-Cas adaptive immunity | module | OPEN | ONTOLOGY | — | 0 | No GO term exists for cyclic oligoadenylate synthase activity, the Palm/ cyclase output of Cas10, nor for the cOA-activated state of CARF-domain ribonucleases. |
| CRISPR-Cas adaptive immunity | module | NARROWING | ONTOLOGY | — | 0 | GO has no cellular-component term for a CRISPR surveillance complex. Its entire CRISPR vocabulary is biological-process terms (GO:0099048, GO:0043571, GO:0098672, plus two obsoleted regulation terms), so every curated Cascade, Csy, Csm a… |
| CRISPR-Cas adaptive immunity | module | OPEN | ONTOLOGY + CURATION | — | 0 | No GO molecular-function term expresses the molecular-ruler behaviour that fixes spacer length: the Cas1-Cas2 assembly measures the protospacer duplex (23 bp plus 5-nucleotide 3' splays, giving a 33 bp spacer) and that measuring is what … |
| crtB | gene | OPEN | BIOLOGY | CC_DARK | 1 | Where in the bacterial cell CrtB carries out catalysis is undetermined: it is not known whether the enzyme is freely soluble in the cytoplasm or associates with the cytoplasmic face of the inner membrane where its hydrophobic product par… |
| crtB | gene | OPEN | BIOLOGY | — | 1 | The substrate specificity of CrtB has not been mapped: no panel of alternative prenyl diphosphates has been tested, so it is unknown whether the enzyme is strictly selective for the C20 geranylgeranyl diphosphate or will accept shorter o… |
| crtY | gene | OPEN | BIOLOGY | — | 1 | No experimental three-dimensional structure of CrtY has been determined, so the residues that bind FAD and lycopene and the geometry that positions the psi end group for proton-initiated ring closure are not directly known. |
| crtY | gene | OPEN | BIOLOGY | — | 1 | The membrane association of CrtY has not been characterized at the level of topology or orientation: it is treated as a peripheral, membrane-associated enzyme, but whether and how it docks onto the cytoplasmic face of the inner membrane … |
| csy1 | gene | OPEN | ONTOLOGY | — | 2 | GO has no molecular-function term for crRNA-guided, PAM-licensed target recognition, which is the activity the assembled Csy complex has and which Cas8f licenses. The component activities that can be annotated (DNA binding, RNA binding) … |
| csy1 | gene | OPEN | BIOLOGY | — | 2 | How Cas8f signals a verified target to Cas3 is undetermined. The docking site is placed on the Cas8f C-terminal helical bundle only by inference, and no structure of a Cas8f-Cas3 interface exists for this system. |
| csy2 | gene | OPEN | BIOLOGY | — | 1 | Whether Cas5f contributes to target DNA engagement in its own right, beyond donating one thumb residue to a pocket dominated by Cas8f, is undetermined. No Cas5f DNA-contact mutant has been tested, and no term is asserted for a Cas5f DNA-… |
| csy2 | gene | OPEN | ONTOLOGY | — | 1 | GO has no molecular-function term for crRNA-guided, PAM-licensed target recognition, the activity the assembled Csy complex has, so Cas5f can only be annotated with generic nucleic-acid-binding terms. |
| csy3 | gene | OPEN | ONTOLOGY | — | 2 | GO has no molecular-function term for crRNA-guided, PAM-licensed target recognition, the activity the assembled Csy complex has and in which the Cas7f backbone does the segment-by-segment base-pairing work. The terms that can be asserted… |
| csy3 | gene | OPEN | BIOLOGY | — | 1 | Whether the lysine-rich Cas7f patch binds target DNA directly, or only as part of the complex-level DNA-binding surface, has not been separated experimentally; isolated Cas7f has not been assayed for DNA binding. |
| D-amino-acid supply for peptidoglycan precursor biosynthesis | module_node | — | BIOLOGY + CURATION | — | 2 | Pseudomonas putida KT2440 lacks an identified canonical cytoplasmic biosynthetic Alr assignment for the D-alanine-supply step. |
| dacB | gene | OPEN | BIOLOGY + CURATION | — | 0 | The relative D,D-endopeptidase and D,D-carboxypeptidase activities of Q88L37 have not been measured directly. |
| dacB | gene | OPEN | BIOLOGY | — | 0 | The extent to which KT2440 DacB participates in beta-lactam-response signaling analogous to Pseudomonas aeruginosa DacB remains unresolved. |
| daf-10 | gene | OPEN | ONTOLOGY + CURATION | MF_DARK | 1 | DAF-10 has no molecular-function annotation and no GO term that can express one. Its role is to be a structural constituent of the IFT-A particle, but GO has no "structural constituent of the intraflagellar transport particle" molecular-… |
| daf-10 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The subunit-resolved architecture of the C. elegans IFT-A complex, and which of DAF-10's ciliary functions (retrograde transport, axoneme assembly, GPCR import) are directly and specifically mediated by DAF-10 versus emerging from IFT-A … |
| dapA | gene | — | BIOLOGY | — | 1 | The relative in-vivo contributions and lysine-feedback responses of the Q88JL0 and Q88NH2 DapA paralogs are unresolved. |
| dapA | gene | — | BIOLOGY | — | 1 | The relative in-vivo contributions and lysine-feedback responses of the Q88NH2 and Q88JL0 DapA paralogs are unresolved. |
| dapB | gene | — | BIOLOGY + CURATION | — | 1 | Q88DU4 has not been assayed directly, so its cofactor preference, kinetics, and physiological contribution have not been established in KT2440. |
| dapF | gene | — | BIOLOGY + CURATION | — | 1 | Q88GD4 has not been assayed directly, and its paired-serine active-site assignment does not establish substrate specificity or physiological flux. |
| dca7 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular function of S. pombe dca7 (SPBC17D11.08) is undetermined: it is not known whether its WD40 beta-propeller merely binds Ppk15 or acts as a functional kinase scaffold, whether it is a ubiquitin-ligase substrate receptor, or h… |
| dca7 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biological process dca7 participates in within S. pombe is unknown. PomBase records the biological process as ND, deletion is viable, and only broad, non-specific high-throughput stress-resistance/sensitivity and quiescence-survival … |
| DCAF10 | gene | OPEN | BIOLOGY + ONTOLOGY + CURATION | MF_DARK | 3 | The breadth and physiological specificity of DCAF10's Ac-Gly/MO N-degron substrate-recognition activity remain unresolved. A recent primary study supports direct recognition and ubiquitination of acetylated Src-family kinases, but it is … |
| DCAF10 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | DCAF10's normal testis and spermatogenesis role is still largely undefined. Transcript-level evidence points to strong testis/sperm expression, but the relevant germ-cell substrates, developmental stage, and reproductive phenotype have n… |
| DCAF10 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 3 | The compartment-specific and regulatory context of DCAF10 activity is underdetermined. GOA/Reactome place DCAF10 in nucleoplasm, the literature synthesis points to both nuclear and cytoplasmic substrate contexts, and the N-terminal regio… |
| DCAF12L2 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | Whether DCAF12L2 directly binds DDB1/CUL4 and assembles into a functional CRL4 ubiquitin ligase complex remains unresolved. |
| DCAF12L2 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | The direct substrates and degron-recognition rules of DCAF12L2 are not established. It is unknown whether DCAF12L2 recognizes DCAF12-like C-terminal acidic degrons or has diverged to a distinct substrate-recognition mode. |
| DCAF12L2 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biological role of DCAF12L2 in testis-enriched or epididymal cell contexts is unknown. |
| dcar-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The structural and biochemical basis of ligand recognition by DCAR-1 is unknown: there is no direct binding assay, no structure, and no defined ligand-binding pocket or residues. Whether DCAR-1 is the direct receptor for HPLA (versus an … |
| dcar-1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | It is unknown whether DCAR-1 has ligands or roles beyond HPLA/DHCA - including its natural neuronal ligand, whether it recognizes any microbe-associated molecular pattern, and whether it contributes to pathogen-avoidance behaviour as a s… |
| dcar-1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biosynthetic origin of the DAMP ligand HPLA, and the mechanism by which infection and cuticle damage raise its levels, are uncharacterized - including whether the invading fungus contributes to HPLA production or the increase is enti… |
| DCV1 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 1 | The molecular function of DCV1 is unknown. No catalytic activity, transport activity, or specific binding partner has been assigned to DCV1, and the Sur7/PalI/Rim9 family to which it belongs has no defined molecular activity — its member… |
| DCV1 | gene | NARROWING | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 1 | The exact GO biological-process term for DCV1's pheromone-response polarity role remains unresolved. PMID:36601911 establishes that Dcv1 influences mating-specific front-rear polarity, pheromone-gradient tracking, cell fusion and plasma-… |
| DCV1 | gene | NARROWING | BIOLOGY | RESIDUAL_SUBGAP | 1 | The relationship between DCV1's plasma-membrane pool and its curated nuclear-envelope pool remains unresolved. PMID:36601911 establishes plasma-membrane localization in vegetative and pheromone-responding cells, while SGD curates a nucle… |
| de novo biotin biosynthesis | module_node | OPEN | BIOLOGY + CURATION | — | 1 | The ppu00780 bucket lists several generic fatty-acid-synthesis enzymes, but it does not establish which paralogs carry the masked pimelate intermediate in KT2440. |
| de novo biotin biosynthesis | module_node | OPEN | CURATION | — | 1 | No direct biochemical or genetic characterization of the six KT2440 pathway-specific proteins was identified in the module-level research. |
| De novo UMP biosynthesis | module_node | — | CURATION | — | 0 | Carbamoyl phosphate also feeds arginine biosynthesis, so pathway assignment of CarA/CarB requires process context rather than reaction identity alone. |
| Derp23 (core function) | core_function | — | BIOLOGY | — | 1 | The molecular function of Der p 23 is undetermined: it has a peritrophin-A chitin-binding-domain fold but does not bind chitin in vitro, and no alternative ligand or activity has been established. |
| dnaE2 (core function) | core_function | — | — | — | 0 | Q88I82 lesion specificity, fidelity, and the basis of its context-dependent mutation effects remain unresolved. |
| DNAJC16 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 3 | The direct molecular activity of DNAJC16/ERdj8 is unresolved: it is not known whether its J domain directly recruits and stimulates a specific HSP70 partner, whether its TRX domain has redox activity, or whether these domains support aut… |
| DNAJC16 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The mechanism by which ERdj8-containing ER subdomains control autophagosome size and large-target engulfment is not defined. |
| DNAJC28 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 3 | DNAJC28's direct HSP70 co-chaperone activity, obligate HSP70 partner, and client substrates have not been experimentally established. |
| DNAJC28 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 2 | DNAJC28's compartment of action is unresolved. |
| DNAJC28 | gene | OPEN | BIOLOGY | BP_DARK | 2 | No DNAJC28-specific cellular process or physiological role has been established. |
| DNAJC4 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 3 | DNAJC4's HSP70 co-chaperone activity is unverified. It is unresolved whether DNAJC4's J domain stimulates ATPase activity of a specific HSP70 paralog, what clients it recruits, and whether Hsp70 protein binding (GO:0030544) or ATPase act… |
| DNAJC4 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 3 | DNAJC4 membrane topology and subcellular destination are unresolved. The protein is predicted to be a single-pass membrane protein, but the membrane compartment, orientation of the J domain, and the validity of a mitochondrial proteostas… |
| DSF2 | gene | OPEN | BIOLOGY | MF_DARK | 2 | The molecular function of DSF2 is undetermined: no catalytic activity, no specific binding partner, and no scaffold/adaptor role has been experimentally demonstrated. The only structural clue is a C-terminal Sel1-like/TPR repeat solenoid… |
| DSF2 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biological process DSF2 participates in is unknown. The sole process annotation (negative regulation of the G2/M transition) is a phylogenetic (IBA) inference from the distant fission-yeast ortholog Nif1 and has never been tested in … |
| DSF2 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The mechanism by which loss of DSF2 suppresses the temperature- and hydroxyurea-sensitivity of a puf5/mpt5 deletion is unknown. It is not established whether this reflects a direct functional relationship between Dsf2 and the Puf5 RNA-bi… |
| DSF2 | gene | OPEN | BIOLOGY | CC_DARK | 1 | The functional significance of DSF2 relocalizing from the bud tip/neck to the cytoplasm during DNA-replication stress (HU/MMS) is unknown; it is not known whether this movement is part of a stress response or an incidental consequence of… |
| DUSP/MKP dephosphorylation of JNK | module_node | OPEN | CURATION | — | 1 | The p38-output -> DUSP1/MKP-1 -| JNK cross-cascade edge is not represented in any module: this module models JNK termination as an external input, and modules/p38_cascade.yaml wires p38-induced DUSP1 only onto p38. |
| DXP-dependent de novo PLP biosynthesis | module_node | — | CURATION | — | 0 | GO lacks a molecular-function term for the SerC/PdxF phosphohydroxythreonine aminotransferase reaction RHEA:16573. |
| dyf-1 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 2 | How DYF-1 activates OSM-3 kinesin at the molecular level is unknown: whether it binds the motor directly, relieves OSM-3 autoinhibition, or bridges OSM-3 to the IFT-B core, and which OSM-3 surface it engages, are undetermined. There is a… |
| dyf-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Whether DYF-1/IFT70 promotes axonemal tubulin polyglutamylation directly (for example by IFT-dependent delivery of a TTLL glutamylase or its tubulin substrate) or indirectly as a downstream consequence of the B-tubule/axoneme structural … |
| dyf-11 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 2 | The specific molecular function of DYF-11/IFT54 within IFT complex B is undefined. It has no catalytic domain and only a C-terminal coiled coil; whether it binds microtubules directly in C. elegans, and which specific IFT-B subunit(s) it… |
| dyf-11 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | How DYF-11 promotes assembly/loading of the kinesin-II motor and other IFT components onto trains at the ciliary base is not understood at the mechanistic level, nor is it resolved whether it acts specifically at an early step of IFT-B p… |
| dyf-11 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether C. elegans DYF-11 has an IFT-independent role — for example in dendrite/neurite protein trafficking, analogous to the vertebrate MIP-T3/DISC1 axis — is untested. |
| dyf-13 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 1 | The molecular activity of DYF-13/TTC26 beyond intraciliary-transport-particle-B binding is undefined. It is unknown which specific IFT-B subunit(s) DYF-13 contacts within the C. elegans complex and which ciliary cargo(es) it directly bin… |
| dyf-13 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | Whether C. elegans DYF-13 occupies the IFT-B core or peripheral sub-architecture has not been determined biochemically. Mammalian TTC26/IFT56 was assigned to the IFT-B core subcomplex, but the sub-complex position of the worm ortholog an… |
| dyf-2 | gene | OPEN | ONTOLOGY + CURATION | MF_DARK | 1 | DYF-2 has no assigned molecular function and no term to express one. Its role is to be a structural constituent of the IFT-A particle, but GO has no "structural constituent of the intraflagellar transport particle" molecular function ter… |
| dyf-2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The molecular interface by which the DYF-2/WDR19 WD40 domain docks the BBSome onto moving IFT particles, and the direct IFT-A subunit contacts of DYF-2 in the worm, are inferred (from point mutants, BiFC and cross-species proteomics), no… |
| dyf-3 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 2 | The direct molecular activity of DYF-3/CLUAP1 is undefined. It is unresolved whether it acts purely as a structural constituent of IFT-B, as a scaffold/adaptor that bridges specific subunits, and which of its partner interactions are loa… |
| dyf-3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Which specific ciliary cargoes DYF-3 is required to import or transport in C. elegans, and whether it confers cargo selectivity, is not established. UniProt only tentatively links it to entry of the dynein-2 heavy chain che-3 ("May be re… |
| dyf-5 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The complete set of in-vivo DYF-5 substrates that execute cilium-length and IFT control, and how their phosphorylation drives ciliary-tip cargo (tubulin) unloading, is undetermined. Only two direct substrates (IFT-74 and the OSM-3 C-term… |
| dyf-5 | gene | OPEN | BIOLOGY | MF_DARK | 2 | The molecular mechanism by which DYF-5 switches anterograde IFT from heterotrimeric kinesin-II to homodimeric OSM-3 at the end of the middle segment is not resolved. It is unknown whether DYF-5 triggers the handover directly by phosphory… |
| dyf-6 | gene | OPEN | ONTOLOGY + BIOLOGY | MF_DARK | 1 | The molecular function of DYF-6/IFT46 is undefined. It has a large disordered N-terminus and no recognizable catalytic domain, and no GO molecular-function term is assigned to it in C. elegans. Whether it acts as a cargo adaptor (Chlamyd… |
| dyf-6 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | dyf-6 is a complex locus that, besides the short conserved IFT46 isoforms, produces a longer nematode-specific transcript fusing the dyf-6 ORF to the upstream gene F46F6.3; the biological role of this long product is uncharacterized. All… |
| E. coli 23S rRNA m5U747 methylation | module_node | OPEN | BIOLOGY | — | 1 | The direct physiological RNA substrate state for RlmC has not been reconstituted biochemically. |
| E. coli AhpF-dependent peroxiredoxin regeneration | module_node | — | CURATION | — | 0 | The ECOLI AhpF review now covers the reductase half of the AhpC/AhpF system, but E. coli ahpC is not yet reviewed in this repository. |
| E. coli HdeA/HdeB periplasmic acid-stress holdases | module_node | OPEN | ONTOLOGY | — | 1 | GO lacks a current molecular-function term for ATP-independent in-situ holdase chaperone activity after GO:0051082 obsoletion. |
| E. coli HdeA/HdeB periplasmic acid-stress holdases | module_node | OPEN | BIOLOGY | — | 1 | HdeB supports refolding after neutralization, but whether HdeB releases clients directly for spontaneous refolding or hands them to another periplasmic folding factor remains unresolved. |
| E. coli ManXYZ mannose-family PTS | module_node | — | BIOLOGY | — | 0 | The ManXYZ apparatus imports several secondary sugars in addition to mannose, but the in vivo partitioning of those fluxes among ManXYZ and dedicated PTS transporters is condition-dependent. |
| E. coli ManXYZ mannose-family PTS | module_node | — | ONTOLOGY | — | 0 | GO currently represents the ManXYZ EII membrane complex with the generic cellular-component term GO:1902495 transmembrane transporter complex. |
| E. coli ManXYZ mannose-family PTS | module_node | — | BIOLOGY | — | 0 | ManY and ManZ are sufficient for bacteriophage lambda DNA penetration, and the ManXYZ apparatus also functions in sugar chemotaxis, but these secondary outputs need curator review before they are represented as ManXYZ pathway modules or … |
| E. coli periplasmic organophosphate scavenging | module_node | — | CURATION | — | 0 | Several historical PhoA interaction annotations derive from its use as a Sec-export model substrate or as an in-vitro dephosphorylation reagent rather than from this physiological scavenging activity. |
| ECM30 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Ecm30 forms a validated complex with Ubp15, but its biochemical contribution to that complex is unresolved; neither intrinsic enzyme activity nor a particular adaptor mechanism has been established. |
| ECM30 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biological process ECM30 acts in, and the mechanism linking it to the cell-wall phenotype, are unknown. It is unresolved whether ECM30 contributes directly to cell-wall (mannan/glucan) biogenesis or does so indirectly by supporting t… |
| ECM30 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | Determine the native Ecm30 distribution across cytosol, Golgi cisternae and other membranes and how sequence divergence affects dynamic targeting. |
| EF-P translation stall rescue | module_node | — | BIOLOGY + CURATION | — | 0 | The KT2440-specific EF-P-dependent stalled-transcript/protein targets have not been mapped. |
| EF-P translation stall rescue | module_node | — | CURATION | — | 0 | The adjacent EarP/rhamnose activation context is biologically important for pseudomonad EF-P but outside UPA00345. The PSEPK-specific OpenScientist report flags a likely UniProt text typo in Q88LS1/EarP describing the EF-P target as Lys-… |
| EFM6 | gene | OPEN | BIOLOGY | BP_DARK | 2 | The biological process served by EFM6-mediated methylation of eEF1A at Lys390 is undetermined. It is not known why this specific low-occupancy lysine methylation is installed, what phenotype (if any) it modulates, or which of eEF1A's can… |
| EFM6 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether EFM6 is enzymatically active as an isolated, purified protein, and its steady-state kinetic parameters and possible cofactor/partner requirements on eEF1A, are not established. |
| EFM6 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether EFM6 has any substrate other than eEF1A-Lys390 is untested beyond the exclusion of yeast Hsp70 proteins. |
| ELAVL1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The sequence and structural rules that determine whether a HuR-bound transcript is stabilized, destabilized, or translationally regulated remain incompletely resolved. |
| ELAVL1 | gene | OPEN | CURATION | MF_DARK | 1 | The reported double-stranded-RNA-binding activity cannot be verified from the locally available article body. |
| ELAVL4 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The functional differences among the six human ELAVL4 isoforms are unresolved, especially the hinge deletion present in isoforms 2-5. |
| ELAVL4 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The sequence and protein-context rules that determine whether HuD activates or represses translation remain unresolved. |
| ELAVL4 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The extent to which conserved HuD-dependent neuronal-development phenotypes translate into direct human ELAVL4 requirements is unresolved. |
| EN1 / dopaminergic neuron differentiation | annotation | OPEN | CURATION | BP_DARK | 0 | The cached source does not reveal which EN1-specific evidence was used to support dopaminergic neuron differentiation rather than survival or regional patterning. |
| Endogenous protein lipoylation | module_node | OPEN | CURATION | — | 0 | GO lacks a precise molecular-function term for the LipL reaction that transfers octanoyl from octanoyl-GcvH to a client protein lysine (RHEA:20213). |
| Endogenous protein lipoylation | module_node | OPEN | CURATION | — | 0 | The reaction-specific LIPT1 molecular-function term GO:7770091 is not yet available in the repository's configured GO release for validation. |
| Endogenous protein lipoylation | module_node | — | BIOLOGY + CURATION | — | 0 | Some archaea split sulfur insertion between LipS1 and LipS2 paralogs, but this first-pass module does not yet model that route. |
| Endogenous protein lipoylation | module_node | — | BIOLOGY | — | 0 | The timing of sulfur insertion relative to amidotransfer is not uniform across all reported GcvH-relay lineages. |
| Epe1 (core function) | core_function | — | — | — | 20 | Histone binding by Epe1 is directly shown (purified Epe1 preferentially binds H3K9me3 peptides and H3K9-methylated histones in vitro), and the JmjC-containing half (amino acids 1–600) binds H3K9me3 peptide and H3K9-methylated histones di… |
| Equc2 (core function) | core_function | — | BIOLOGY | — | 1 | The specific molecular function and ligand bound by Equ c 2, and its endogenous physiological role, are undetermined. |
| ERR1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether ERR1 is catalytically active as a phosphopyruvate hydratase (enolase) in vivo is unknown. No purified-protein enzyme assay or in-vivo activity measurement attributable specifically to ERR1 has been reported. |
| ERR1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The in-vivo biological role of ERR1 and the condition(s), if any, under which it is expressed are undetermined. It is not established that ERR1 contributes to glycolytic flux, and no ERR1-specific phenotype or expression dataset has been… |
| ERR1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether ERR1 has any function distinct from its paralogs ERR2 and ERR3, or from the true enolases ENO1/ENO2, cannot be determined from existing evidence, and no functional assay can attribute a phenotype to ERR1 rather than ERR2/ERR3 wit… |
| ERVMER34-1 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 2 | The primary biological function of ERVMER34-1/HEMO remains unknown. It is unresolved whether the shed ectodomain acts through a host receptor, whether membrane-bound HEMO has a distinct cell-surface role, and what downstream signaling pa… |
| ERVMER34-1 | gene | OPEN | BIOLOGY | BP_DARK | 3 | The proposed placental anti-fusion or immunomodulatory function of HEMO is untested. The Suppressyn-like localization and ISD-like sequence motivate hypotheses, but it is unknown whether HEMO blocks syncytin-mediated trophoblast fusion, … |
| ERVMER34-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 3 | The enzyme and regulatory logic responsible for HEMO ectodomain shedding are not known. Broad ADAM/MMP inhibitor sensitivity and mapped Q432/R433 cleavage sites show metalloproteinase-sensitive processing, but do not identify the in vivo… |
| ESL1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | The direct molecular activity of Esl1 is undetermined. It is unknown whether Esl1 is a catalytically active endoribonuclease in vivo, and if so what its RNA substrates are; the conserved PIN catalytic residues are intact but no biochemic… |
| ESL1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular partners and substrates of Esl1 are unknown, including any protein-protein interaction mediated by its 14-3-3-like EOH domain (the domain that in metazoan SMG5/6 engages the NMD factor UPF1) and any direct link to the Rim10… |
| ESL1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The ESL1-specific (non-redundant) contribution and in vivo biological role are not resolved, because almost all phenotypes are stronger in esl1 esl2 double mutants and the transcriptome signature was measured only in the double mutant. |
| Eukaryotic hexosamine biosynthesis and GlcNAc salvage | module_node | — | CURATION | — | 0 | The bacterial route to UDP-GlcNAc is not represented by this eukaryotic implementation. |
| FBXL16 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | The exact E3-ligase architecture used by FBXL16 remains unresolved. FBXL16 can bind SKP1 and is mapped here to ubiquitin-like ligase-substrate adaptor activity, but reported failure to detect CUL1 leaves open whether the degradative HIF1… |
| FBXL16 | gene | OPEN | BIOLOGY + ONTOLOGY + CURATION | MF_DARK | 3 | The molecular basis of FBXL16's substrate-stabilizing mode is still dark. Current evidence indicates FBXL16 can degrade some clients while stabilizing others, but it is unresolved whether the stabilizing activity is direct substrate-adap… |
| FBXL16 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | The normal physiological substrate repertoire and tissue role of FBXL16, especially in brain, remain incompletely defined. APP and several cancer signaling proteins are useful leads, but it is not yet clear which clients and processes re… |
| FBXO17 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 3 | The physiological glycoprotein substrates and glycan determinants recognized by FBXO17 remain unresolved. |
| FBXO17 | gene | NARROWING | BIOLOGY + CURATION | MF_DARK | 3 | Whether recognition of the validated GSK3-beta substrate is glycan-dependent and how broad FBXO17's protein-substrate repertoire is remains unresolved. |
| FBXO17 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | How FBXO17 partitions canonical SCF substrate-receptor activity from F-box-independent IRF3/PP2A signaling and tissue-specific pathway effects remains unresolved. |
| FBXO34 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 3 | The endogenous substrate repertoire of human FBXO34-SCF remains largely undefined. HNRNPU is the only clearly supported human substrate in the retrieved mechanistic literature, while many high-throughput protein-binding partners have not… |
| FBXO34 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | The relationship between FBXO34's human HNRNPU/HIV-latency function and the mouse oocyte cell-cycle phenotype remains unresolved. Mouse data suggest FBXO34 can influence meiotic G2/M transition, MPF/CCNB1 activity, spindle checkpoint beh… |
| FBXO34 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 2 | Human FBXO34 subcellular localization remains experimentally underdefined. Mouse oocyte data suggest nuclear and F-actin-associated localization, but direct human localization evidence, and the compartment in which FBXO34 acts on HNRNPU … |
| fdx (core function) | core_function | — | — | — | 0 | The reductase partner and necessity of Q88PK3 for KT2440 Isc assembly are unknown. |
| Feld7 (core function) | core_function | — | BIOLOGY | — | 1 | The native (in-vivo) ligand and physiological role of Fel d 7 remain unconfirmed: fatty acids are demonstrated as surrogate ligands in vitro, but the endogenous cargo carried in the cat and the biological function are not established. |
| Feld8 (core function) | core_function | — | BIOLOGY | — | 1 | The specific lipid ligand and the precise physiological role of cat Fel d 8 are not experimentally established; current annotations are inferred from the PLUNC family. |
| fis-1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular mechanism by which FIS-1 couples completed mitochondrial fission to mitophagic disposal is undefined. In C. elegans FIS-1 is not the essential Drp1 receptor for fission (MFF is), yet its loss stalls a late intermediate step… |
| fis-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether C. elegans fis-1 has any endogenous loss-of-function role in mitochondrial or peroxisomal fission is unresolved: loss of fis-1/fis-2 is phenotypically silent for organelle morphology, while FIS-1 overexpression is sufficient to f… |
| fis-1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 1 | The direct binding partners of C. elegans FIS-1 are unmapped. It is unknown whether worm FIS-1 uses adaptor proteins analogous to the yeast Mdv1/Caf4 proteins, whether it binds DRP-1 directly under stress, and which downstream autophagy … |
| fis-2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular activity of FIS-2 is entirely undetermined experimentally. Its only molecular-function annotation ("molecular adaptor activity") is a phylogenetic (IBA) propagation from the FIS1 family; no C. elegans FIS-2 protein has been… |
| fis-2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether FIS-2 has any non-redundant, fis-2-autonomous role in mitochondrial disposal/mitophagy is unresolved. Every mitophagy/LGG-1-aggregate phenotype was scored in the fis-1(tm1867); fis-2(gk414) double mutant (the "Fis1 mutant"), and … |
| fis-2 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 1 | The direct binding partners and interactome of C. elegans FIS-2 are unmapped. It is unknown whether FIS-2 binds DRP-1 (directly or via an adaptor intermediate analogous to yeast Mdv1/Caf4), whether it joins an ER-mitochondria (MAM) fissi… |
| fis-2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The mechanism and biological significance of the fis-2-specific pro-apoptotic role are unknown. fis-2 promotes elimination of mitochondria in dying cells downstream of CED-3 and independently of DRP-1/CED-9, but whether this uses the sam… |
| fmc1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The specific molecular activity of the fission-yeast fmc1 protein is undetermined. Whether it acts as a protein-folding chaperone in its own right, as an adaptor that stabilizes a partner chaperone (an Atp12/ATPAF2 ortholog), or in some … |
| fmc1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | It is not known whether the F1-ATP-synthase-assembly role attributed to fmc1 is demonstrated in S. pombe or is purely inferred by orthology. All fission-yeast GO annotations are electronic or phylogenetic (IBA/IEA); none are experimental. |
| fmc1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | No loss-of-function phenotype has been reported for S. pombe fmc1, and it is unknown whether (as in budding yeast) its requirement is conditional (heat-stress specific) or broader, and whether a functional Atp12/ATPAF2 partner exists and… |
| fndc-1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | The molecular activity of FNDC-1 as a mitophagy receptor is not experimentally established in C. elegans. Its LC3-interacting region (LIR) motif has not been identified or mutated, and a direct physical interaction between FNDC-1 and the… |
| fndc-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | How FNDC-1 receptor activity is switched on and off in C. elegans is unknown. No phosphorylation or ubiquitination sites have been mapped on the worm protein, and the kinases, phosphatases, and E3 ligases that gate mammalian FUNDC1 (SRC,… |
| fndc-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Whether FNDC-1 is a broadly-acting mitophagy receptor in C. elegans (beyond the two described contexts of paternal-mitochondria elimination and hypoxia-reoxygenation) is unresolved, as is its epistatic relationship to the PINK-1/PDR-1 an… |
| FOXRED1 (core function) | core_function | — | BIOLOGY | MF_DARK | 1 | The physiological substrate, catalytic reaction, and EC sub-subclass of FOXRED1's oxidoreductase activity are undetermined, as is whether its redox activity (rather than a purely structural/chaperone role of the fold) is required for com… |
| FSH3 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The physiological substrate of FSH3 and the specific reaction it catalyzes are undetermined. Only an uncommitted esterase activity (EC 3.1.-.-) is assigned, and UniProt describes FSH3 as a "serine hydrolase of unknown specificity". |
| FSH3 | gene | NARROWING | BIOLOGY | BP_DARK | 2 | The precise biological role/pathway of FSH3 is not fully resolved. Its single deletion causes no growth defect under standard conditions, and its overexpression phenotypes (PC reduction, NUC1-dependent apoptosis) cannot be read as its na… |
| FSH3 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The degree and direction of functional redundancy among the three paralogous S. cerevisiae serine hydrolases FSH1, FSH2 and FSH3 is unresolved; whether they share substrates or act in overlapping/opposing pathways is unknown. |
| FSH3 | gene | OPEN | BIOLOGY | MF_DARK | 1 | It is unknown whether peroxisomal FSH3 acts directly on a glycerophospholipid substrate (e.g. phosphatidylcholine) or whether the phosphatidylcholine reduction seen on FSH3 overexpression is an indirect consequence of a different activity. |
| ftm3 | gene | OPEN | BIOLOGY | MF_DARK | 2 | The molecular function of ftm3 is completely unknown. No catalytic activity, transporter/channel activity, ligand, substrate, or biochemical activity has been demonstrated or is predictable for the protein. |
| ftm3 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biological process and cellular role of ftm3 are unknown. It is undetermined which pathway or process the protein participates in, and no loss-of-function phenotype has been reported for an ftm3 deletion. |
| ftm3 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | ftm3's own subcellular localization and membrane topology have not been measured directly. Its cytoplasm/nuclear-membrane assignment is inferred entirely by similarity from the paralog ftm2, and although the family is named "5TM", the Un… |
| FUN19 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular activity of FUN19 is unknown. No enzymatic activity, DNA/ nucleosome-binding activity, or binding partner has been demonstrated, and it is undetermined whether FUN19's own SWIRM domain binds DNA/nucleosomes as the Swi3/Rsc8… |
| FUN19 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biological process FUN19 participates in is unknown. Family-level annotations point toward chromatin-based transcriptional regulation, but no pathway, target genes, or process have been experimentally linked to FUN19. |
| FUN19 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | The subcellular localization of FUN19 and its membership (if any) in a defined protein complex are unverified. It is not established whether FUN19 is nuclear, nor whether it is a subunit of any S. cerevisiae Rpd3/Sin3-type or SAGA-type c… |
| Galactose catabolism (Leloir pathway) | module_node | OPEN | CURATION | — | 1 | Aldose 1-epimerase and UDP-glucose 4-epimerase families are substrate- and pathway-promiscuous, so family membership alone cannot establish Leloir catabolism. |
| galU (core function) | core_function | — | — | — | 0 | Direct flux from Q88GA4-produced UDP-glucose into Q88FN9-dependent alpha-glucan has not been demonstrated in KT2440. |
| Gamma-glutamyl putrescine catabolism to GABA | module_node | — | BIOLOGY | — | 0 | The physiological PuuC locus in KT2440 has not been experimentally established. |
| Gamma-glutamyl putrescine catabolism to GABA | module_node | — | BIOLOGY | — | 0 | Flux partitioning among the multiple KT2440 PuuA- and PuuD-family paralogs is unresolved. |
| Gamma-glutamyl putrescine catabolism to GABA | module_node | — | CURATION | — | 0 | PTHR43785 and its SF12 subfamily mix PuuA-like ligases with bona fide glutamine synthetases. |
| Gamma-glutamyl putrescine catabolism to GABA | module_node | — | CURATION | — | 0 | GO lacks substrate-specific molecular-function terms for the PuuB oxidase and PuuC aldehyde-dehydrogenase reactions. |
| GAT2 | gene | OPEN | BIOLOGY | BP_DARK | 2 | The direct DNA target genes of Gat2, the specific GATA DNA sites it occupies in vivo, and the physiological condition under which it acts are undetermined. It is also unresolved whether Gat2 functions as a transcriptional activator or re… |
| GAT2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether Gat2 is functionally redundant with, antagonistic to, or independent of the canonical nitrogen-catabolite-repression GATA factors (Gln3, Gat1, Dal80, Gzf3) is unknown, and its DNA-binding specificity relative to theirs has not be… |
| GAT2 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | Gat2's subcellular localization and its regulation (e.g. nuclear/cytoplasmic partitioning in response to nitrogen or TORC1 signaling, as seen for Gln3 and Gat1) have not been experimentally determined. |
| glgA (core function) | core_function | — | — | — | 0 | Q88FN9 nucleotide-sugar donor specificity has not been directly measured. |
| glgE (core function) | core_function | — | — | — | 0 | No direct enzymatic or structural characterization of Q88FM9 was found. |
| glgP (core function) | core_function | — | — | — | 0 | Q88CY8 substrate preference and allosteric regulation have not been directly characterized in P. putida KT2440. |
| glgX (core function) | core_function | — | — | — | 0 | Q88FN4 has not been directly assayed as a glycogen debranching enzyme. |
| glh-2 | gene | OPEN | BIOLOGY | MF_DARK | 2 | The non-redundant, GLH-2-specific molecular contribution to germline function is undetermined. It is unknown whether GLH-2 performs any unique step, substrate engagement, or regulatory role, or whether it acts purely as a partially redun… |
| glh-2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The direct in vivo RNA substrates of GLH-2 are unknown. Neither the RNAs bound by its six CCHC zinc fingers nor the transcripts it engages/remodels within P granules have been identified. |
| glh-2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Whether GLH-2 has catalytically active ATP-dependent RNA-unwinding activity, and whether that catalysis is required for its in vivo role, is untested. No in vitro helicase/ATPase assay and no catalytic-dead (DEAD-motif / ATPase-cycle) al… |
| glh-2 | gene | OPEN | BIOLOGY | MF_DARK | 2 | The mechanistic role of GLH-2 in P-granule assembly and organization is unresolved. Whether GLH-2 is required for, or merely present in, perinuclear condensate assembly and PGL recruitment has not been tested for GLH-2 individually. |
| GLIPR1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The direct physiological molecular activity, ligand, receptor, lipid, or substrate of human GLIPR1 is unknown. |
| GLIPR1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The normal physiological context and direction of GLIPR1 action are not established beyond disease-cell models. |
| GLIPR1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The topology and trafficking step that permit GLIPR1 to regulate cytosolic N-WASP, hnRNPK, Hsc70, and CK1alpha are unknown. |
| GLIPR1L1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 1 | The precise molecular activity of GLIPR1L1 within the IZUMO1-containing complex is unknown. |
| GLIPR1L1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Endogenous human GLIPR1L1 localization, IZUMO1 interaction, and fertilization function have not been directly demonstrated. |
| GLIPR1L1 | gene | OPEN | BIOLOGY | CC_DARK | 1 | The route by which human GLIPR1L1 reaches the sperm surface is unresolved. |
| GLIPR1L2 | gene | OPEN | BIOLOGY + CURATION | WHOLLY_DARK | 1 | GLIPR1L2's direct molecular activity, native interaction complex, and physiological biological process are unknown. |
| GLIPR1L2 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | The membrane topology, compartment, and isoform-specific localization of GLIPR1L2 have not been established experimentally. |
| GLIPR2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The endogenous site and complete molecular mechanism of PtdIns3K-C1 inhibition by GLIPR2 remain unresolved. |
| GLIPR2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | It is unknown whether GLIPR2 also inhibits PtdIns3K-C2 and how GORASP2 competition changes complex specificity. |
| GLIPR2 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The relationship between core autophagy inhibition and the reported EMT/ERK and TLR4/type-I-interferon phenotypes is unknown. |
| GLIPR2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The physiological relevance of GLIPR2's lipid- and metal-regulated amyloid-like assemblies is unknown. |
| GLO1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The catalytic competence and oligomeric behavior of splice isoform 2, which lacks residues 105-119 in the catalytic region, are unknown. |
| GLO1 | gene | OPEN | BIOLOGY | CC_DARK | 1 | It is unclear whether nucleoplasmic and plasma-membrane GLO1 signals represent stable, catalytically active pools. |
| GLOD4 (core function) | core_function | — | BIOLOGY | MF_DARK | 2 | The catalytic mechanism of GLOD4-mediated tyrosine nitration is undetermined: it is not known how the enzyme converts bound peroxynitrite into a nitrating species, whether zinc is the catalytic metal or a structural one, or what role Cys… |
| GLOD4 (core function) | core_function | — | BIOLOGY | BP_DARK | 2 | No biological process has been tied to GLOD4. Knockout mice lose most alpha-synuclein tyrosine nitration yet are outwardly normal, so what the activity is for - in development, in homeostasis, or only under oxidative or nitrosative chall… |
| GLOD4 (core function) | core_function | — | ONTOLOGY | MF_DARK | 1 | Even where the biology is established, it cannot be expressed: GO contains no term for protein tyrosine nitration in either the molecular-function or the biological-process branch, so GLOD4's characterised activity can only be recorded a… |
| Glucarate and galactarate catabolism to 2-oxoglutarate | module_node | — | ONTOLOGY | — | 0 | GO lacks a cofactor-neutral molecular-function term for 2,5-dioxovalerate dehydrogenase activity. |
| Glutathione-dependent formaldehyde detoxification | module_node | — | BIOLOGY | — | 0 | The quantitative contribution of this route relative to alternative formaldehyde oxidation branches varies among bacteria and often remains unresolved. |
| Glutathione-dependent formaldehyde detoxification | module_node | — | CURATION | — | 0 | KT2440 formaldehyde-tolerance phenotypes support roles for PP_1616 and PP_1617 but do not establish their proposed FrmA-FrmC reaction sequence. PP_3970 contributes to formaldehyde mineralization, but published names and glutathione-depen… |
| Glutathione-dependent methylglyoxal detoxification | module_node | — | BIOLOGY | — | 0 | Physiological metal preference can vary among glyoxalase-I family members and is not established by the generic reaction definition. |
| Glutathione-dependent methylglyoxal detoxification | module_node | — | BIOLOGY | — | 0 | Broad VOC- and metallo-beta-lactamase-superfamily assignments do not establish glyoxalase-I or glyoxalase-II substrate specificity. |
| Glycine cleavage system | module_node | — | BIOLOGY | — | 0 | The LpdG assignment in KT2440 is supported by orthology, locus context, and historical P. putida LPD-glc biochemistry, but has not been tested directly in KT2440. |
| Glycine cleavage system | module_node | — | BIOLOGY | — | 0 | The relative physiological use and regulation of the two P-, H-, and T-protein sets in P. putida KT2440 remain unresolved. |
| gpa-12 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The cognate receptor and activating input for GPA-12 are not biochemically defined. It is unknown which cell-surface receptor couples to GPA-12 to initiate epidermal immune signaling, what ligand/damage cue activates it, and whether GPA-… |
| gpa-12 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The immediate downstream effector of GPA-12 is undetermined. Genetic epistasis places GPA-12 upstream of phospholipase (PLC-3) and PKCdelta (TPA-1), but it is not known whether GPA-12 directly activates a phospholipase, a RhoGEF/Rho modu… |
| gpa-12 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The full endogenous tissue and physiological repertoire of GPA-12 is unresolved. Its immune requirement is epidermis/cell-type restricted, and hyperactive G12 separately perturbs pharyngeal pumping/feeding and growth, but why the immune … |
| GPM3 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 2 | It is unknown whether GPM3 has any catalytic or other molecular activity, what (if any) its in-vivo biological role is, and why S. cerevisiae retains a stably expressed third phosphoglycerate-mutase homolog that is dispensable and lacks … |
| GPR158 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether glycine is the dominant physiological input to GPR158 in vivo is undetermined, and it is unknown whether the bone hormone osteocalcin engages the receptor directly at all. |
| GPR158 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | It is undetermined how much GPR158 function is ligand-gated at all, because the postsynaptic GPR158-PLCXD2 module that controls spine apparatus abundance operates with no ligand invoked and is instead tuned by extracellular heparan sulfa… |
| GPR25 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether the TGF-beta-induced requirement for GPR25 in tissue-resident memory CD8 T cell formation is downstream of CXCL17 binding, or a separate output of the receptor, is undetermined. |
| GPR75 (core function) | core_function | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | The endogenous agonist of GPR75 is undetermined, and it is unresolved whether the receptor has a functional orthosteric ligand site at all. |
| Gram-negative bacterial post-translational Sec protein export | module_node | — | BIOLOGY | — | 0 | The substrate-level division between SecB/SecA post-translational targeting and SRP cotranslational targeting has not been mapped comprehensively in KT2440. |
| Gram-negative bacterial post-translational Sec protein export | module_node | — | CURATION | — | 0 | SecDF-YajC is conserved in KT2440, but SecDF assistance may be substrate-dependent and the individual contribution of YajC is unresolved. |
| Gram-negative bacterial post-translational Sec protein export | module_node | — | CURATION | — | 0 | Tat, YidC, lipoprotein maturation, and Xcp type II secretion are fully encoded but outside this module. |
| Gram-negative outer-membrane protein chaperone delivery | module_node | — | BIOLOGY | — | 0 | The BAM proteins that receive SurA- or Skp-bound clients have not yet been reviewed in this ECOLI campaign. |
| Gram-negative outer-membrane protein chaperone delivery | module_node | — | BIOLOGY | — | 0 | Skp can backstop OMP delivery when SurA is absent, but the physiological client split among SurA, Skp, and DegP is condition-dependent. |
| GRID1 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 4 | What, if anything, directly gates the GluD1 pore is undetermined. No agonist has been shown to open wild-type GluD1 in a preparation that survives the appropriate negative controls, and the coupling between the Gq-PLC-PKC cascade and por… |
| GSDMD | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The full complement of endogenous cofactors that tune GSDMD-NT pore assembly is not defined. A trans-spliced Gsdmd-Tmem106a chimeric protein was recently shown in mouse to localize to the plasma membrane and directly interact with canoni… |
| GTT3 | gene | OPEN | BIOLOGY | MF_DARK | 2 | The molecular function of Gtt3 (YEL017W) is unknown. Despite the name "glutathione transferase 3", no glutathione-conjugation (or any other) enzymatic activity, substrate, catalytic mechanism, transporter activity, or specific binding pa… |
| hgh1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 1 | Whether S. pombe hgh1 actually performs the eEF2 co-chaperone function is unmeasured: no fission-yeast experiment has shown hgh1 binds eEF2 (or its domain III), recruits TRiC/CCT or Hsp90, or is required for eEF2 folding, abundance, or s… |
| hgh1 | gene | OPEN | BIOLOGY | BP_DARK | 0 | The biological role and loss-of-function consequences of hgh1 in fission yeast are largely undefined. Deletion is viable with normal morphology, so any requirement is conditional/quantitative; the mechanistic basis for the pleiotropic st… |
| hgh1 | gene | OPEN | BIOLOGY | MF_DARK | 0 | Whether HGH1-family proteins act on clients other than eEF2, and whether hgh1 has any genuine nuclear function (as an "is_active_in nucleus" annotation suggests) rather than being exclusively a cytoplasmic eEF2 co-chaperone, is unknown. |
| hip-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The endogenous physiological clients/substrates of C. elegans HIP-1, and the loss-of-function phenotype of hip-1 under normal (non-transgenic) conditions, are undefined. The only direct in vivo worm evidence uses an overexpressed heterol… |
| hip-1 | gene | OPEN | BIOLOGY | CC_DARK | 1 | Where endogenous HIP-1 acts in the C. elegans cell is not directly measured. Cytosolic localization is inferred from mammalian orthologs, and the only worm localization data come from muscle-specific GFP overexpression that placed the pr… |
| hscA (core function) | core_function | — | — | — | 0 | Q88PK4 ATPase stimulation and transfer efficiency have not been measured with the KT2440 partners. |
| hscB (core function) | core_function | — | — | — | 0 | Q88PK5 interaction kinetics with KT2440 IscU and HscA have not been measured. |
| hsp-110 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Whether C. elegans HSP-110 is genetically and biochemically required for Hsp70/Hsp40-mediated protein DISAGGREGATION in vivo, and the identity of its physiological worm Hsp70 (HSP-1 vs STC-1 vs HSP-70) and J-protein/Hsp40 partners in tha… |
| hsp-110 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The endogenous C. elegans client repertoire of HSP-110 is undefined: which native metastable proteins depend on HSP-110 NEF/holdase activity, and in which tissues, is unknown. |
| hsp-110 | gene | OPEN | BIOLOGY | MF_DARK | 2 | Whether HSP-110's own weak/atypical ATPase activity, and any Hsp70-independent holdase function, have a physiological role in C. elegans is untested. |
| hsp-3 | gene | NARROWING | BIOLOGY | RESIDUAL_SUBGAP | 1 | The molecular basis of the division of labor between the two C. elegans BiP paralogs HSP-3 and HSP-4 is undetermined: which client proteins specifically require HSP-3 (versus HSP-4), and which tissue programs and signaling interfaces eac… |
| hsp-3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The functional consequence of HSP-3 AMPylation by FIC-1 is unknown: whether, where, and under what conditions this modification alters HSP-3 ATPase or chaperone activity in vivo has not been determined. |
| HSPA12A | gene | NARROWING | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 3 | The biochemical nucleotide behavior of HSPA12A remains unresolved at the boundary between divergent HSP70-family architecture and non-chaperone adaptor function. Current evidence argues against assigning canonical ATP-dependent protein-f… |
| HSPA12A | gene | OPEN | BIOLOGY + ONTOLOGY + CURATION | BP_DARK | 3 | The endogenous mechanism by which HSPA12A changes SorLA/SORL1 internalization and trafficking remains underdefined. SorLA-tail binding and delayed internalization are supported, but it is not clear whether HSPA12A acts by competing with … |
| HSPA12A | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 3 | HSPA12A's broader adaptor/regulatory interaction network outside SorLA is not settled. Disease-context studies report signaling or scaffold-like effects, but it is unclear which partners are direct endogenous HSPA12A clients and which ph… |
| HSPB9 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | Whether HSPB9 is a bona fide ATP-independent small-HSP holdase chaperone, and what clients or substrates it protects, remains experimentally unresolved. |
| HSPB9 | gene | OPEN | BIOLOGY | BP_DARK | 3 | The functional consequence of the HSPB9-TCTEL1/DYNLT1 interaction during spermatogenesis is unknown. |
| HSPB9 | gene | OPEN | BIOLOGY | CC_DARK | 3 | The significance and mechanism of HSPB9 nuclear localization are unclear. |
| Hyal2 (core function) | core_function | NARROWING | BIOLOGY | BP_DARK | 2 | It is not established whether Hyal2 makes any material contribution to the reduced hyaluronan degradation that underlies very-high-molecular-mass hyaluronan accumulation in Heterocephalus glaber, or whether that deficit is carried entire… |
| Hyal2 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | The magnitude of the naked mole rat HYAL2 catalytic deficit is unquantified. No kcat, Km, pH optimum or specific activity has been measured for this ortholog. |
| Hydroxycinnamate and vanillate catabolism to protocatechuate | module_node | — | CURATION | — | 0 | The exact KT2440 aromatic-acid transporters supplying ferulate and vanillate are not yet mapped into this module. |
| Hydroxycinnamate and vanillate catabolism to protocatechuate | module_node | — | CURATION | — | 0 | Formaldehyde produced by VanAB requires downstream detoxification that is not represented here. |
| hyuC (core function) | core_function | — | — | — | 0 | Direct comparison of N-carbamoyl-beta-alanine, allantoate, and N-carbamoyl-L-amino acids as Q88FQ3 substrates is unavailable. |
| hyuC (core function) | core_function | — | — | — | 0 | PP_0614 (Q88Q81) carries the same dual EC assignment and has not been compared with Q88FQ3. |
| IBSP | gene | OPEN | BIOLOGY | MF_DARK | 1 | The modification-dependent switch between hydroxyapatite nucleation, crystal-growth inhibition, and passive mineral binding is unresolved. |
| IBSP | gene | OPEN | BIOLOGY | BP_DARK | 1 | The relative contributions of direct mineral binding and RGD-integrin signaling to skeletal phenotypes are not fully separated. |
| ICY1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular function of ICY1 is entirely undetermined: no catalytic activity, ligand, RNA/DNA/protein-binding activity, or structural/scaffolding role has been demonstrated or can be inferred from sequence. |
| ICY1 | gene | OPEN | BIOLOGY | BP_DARK | 2 | The biological process in which ICY1 acts directly is unknown; whether its requirement for viability of mtDNA-less (rho0) cells reflects a direct role in mitochondrial function/protein import or an indirect cytosolic contribution is unre… |
| ICY1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 1 | The gene name "Interacting with cytoskeleton" is not supported by any verified molecular-interaction evidence in the reviewed literature; whether ICY1 physically or functionally associates with the cytoskeleton is unknown. |
| ICY1 | gene | OPEN | BIOLOGY | CC_DARK | 1 | The functionally relevant subcellular compartment for ICY1 is unresolved: it is reported at the vacuole membrane (GFP screen) yet described as cytosolic in the functional genetics study. |
| ILT1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Direct biochemical substrate, direction and transport mechanism of Ilt1 remain undetermined despite a supported inherited basic-amino-acid transporter assignment. The contribution of its plasma-membrane and any vacuolar pool to toxin tol… |
| ILT1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The mechanistic relationship between inherited amino-acid homeostasis and strain-dependent xenobiotic tolerance is unknown. |
| imuB (core function) | core_function | — | — | — | 0 | Q88I83 interaction interfaces and their contribution to lesion-specific synthesis have not been mapped directly. |
| irg-2 | gene | OPEN | BIOLOGY | MF_DARK | 3 | The molecular function of IRG-2 is undetermined. No catalytic, binding, or antimicrobial activity has been demonstrated, no physical interaction partner is known, and — unlike its co-regulated paralog irg-1, which carries a predicted NAD… |
| irg-2 | gene | OPEN | BIOLOGY | — | 1 | It is unknown whether the IRG-2 protein is functionally required for defense against P. aeruginosa. All evidence linking irg-2 to immunity is transcriptional (IEP/HEP); no irg-2 loss-of-function survival, colonization, or immune phenotyp… |
| iscA (core function) | core_function | — | — | — | 0 | The direct cluster donors and recipients of Q88PK6 are unknown in KT2440. |
| iscS (core function) | core_function | — | — | — | 0 | Sulfur-transfer partners and pathway allocation have not been measured directly in KT2440. |
| iscU (core function) | core_function | — | — | — | 0 | Q88PK7 cluster type, kinetics, and acceptor specificity have not been measured directly. |
| isp-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The molecular mechanism by which the isp-1(qm150) Rieske substitution is converted into the pro-longevity retrograde signal is undetermined. It is established that qm150 elevates mitochondrial superoxide and that this elevation is necess… |
| ITIH4 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The physiological occupancy, lifetime, and tissue distribution of endogenous ITIH4-protease inhibitory complexes are not established. |
| ITIH4 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The functions of the released proline-rich peptide and the 35-kDa C-terminal ITIH4 chain remain uncertain. |
| ITIH4 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | It is unclear whether ITIH4 is bona fide extracellular-vesicle cargo and whether the 70-kDa chain is truly stored in platelet dense granules. |
| ITIH5 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular receptor or binding partner that transduces ITIH5 signaling in adipose stromal and endothelial cells is unknown. |
| ITIH5 | gene | OPEN | BIOLOGY | CC_DARK | 1 | Isoform-specific secretion and function are unresolved, particularly for isoforms 3 and 4 that lack the canonical N-terminal signal peptide. |
| ITIH6 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 1 | It is unknown whether ITIH6 is processed into a canonical heavy chain and covalently incorporated into a bikunin-containing proteoglycan complex. |
| ITIH6 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 1 | Hyaluronan binding, TSG-6-mediated ITIH6 transfer, and any effect on extracellular-matrix organization remain untested. |
| iwr1 (core function) | core_function | OPEN | BIOLOGY + CURATION | MF_DARK | 4 | No targeted molecular assay has tested S. pombe Iwr1 binding to Pol II, its NLS, or its requirement for Pol II nuclear import. PomBase does record viable-deletion and pleiotropic high-throughput phenotypes, but none establishes this mech… |
| JIP4 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 1 | The molecular function of JIP4 is entirely unknown. No biochemical activity has been demonstrated, and its highly disordered sequence contains no recognizable catalytic or PWI/RRM nucleic-acid-binding domain. The animal-seeded spliceosom… |
| JIP4 | gene | OPEN | BIOLOGY | MF_DARK | 1 | It is unknown whether the metazoan SRRM1/SRm160 splicing function transfers to yeast JIP4 at all: whether JIP4 binds RNA, associates with the spliceosome, or regulates mRNA splicing has never been tested experimentally, and the current s… |
| JIP4 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The subcellular localization of JIP4 has not been experimentally determined, and its biological process/pathway and loss-of-function phenotype (beyond viability of the deletion) are unknown, including its functional relationship to the w… |
| JIP4 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular basis of the "Jumonji-interacting protein" name is not established: it is unclear whether JIP4 physically or functionally associates with the JmjC-domain transcription factor Gis1 (or another Jumonji-family protein), and if… |
| jumble (core function) | core_function | — | — | — | 0 | The glycosyltransferase activity rests on remote fold recognition alone (low-confidence CDD hit, HHpred/Phyre2 similarity to GalNAc-transferases); no donor sugar, acceptor or enzymatic activity has been shown. The loss of basal jacalin s… |
| K9IFY6 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | It is undetermined whether vampire bat CCL28 retains the direct, receptor-independent antimicrobial activity of its human orthologue, and therefore whether an antibacterial humoral response annotation is warranted. |
| K9IFY6 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | The receptor actually engaged by vampire bat CCL28 is undetermined: neither CCR10 nor CCR3 usage has been tested for this protein, and it is unknown whether it acts on bat leukocytes, on host leukocytes at the bite site, or both. |
| K9IIP0 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The function of the C-terminal CUB domain of TSG-6 is undetermined in any species, and for this protein the uncertainty is compounded: UniProt flags that the sequence lacks conserved residues required for propagating CUB feature annotati… |
| K9IIP0 (core function) | core_function | OPEN | BIOLOGY | BP_DARK | 1 | It is undetermined whether salivary TSG-6 acts on the host at the bite site, and if so whether its principal target there is inflammation, chemokine-driven leukocyte recruitment, or fibrinolysis via inter-alpha-inhibitor. |
| K9IWC0 (core function) | core_function | OPEN | BIOLOGY | BP_DARK | 1 | It is undetermined whether the vampire bat salivary CNP acts on the host at the bite site or on the bat's own tissues, and no vasodilator activity has been measured for the bat peptide at all. |
| K9IWC0 (core function) | core_function | OPEN | CURATION | MF_DARK | 2 | The UniProt protein name for this entry assigns the wrong natriuretic peptide paralogue, and the FUNCTION text describing NPR1 activation is BNP biology that does not apply to this protein. This is a curation gap that will keep producing… |
| K9IWX5 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 2 | The molecular activity of the vampire bat salivary antigen-5/CRISP protein is undetermined: neither a ligand for the CAP cavity nor an ion-channel or receptor target for the cysteine-rich C-terminal module has been identified for K9IWX5 … |
| K9IWX5 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | It is undetermined whether the C-terminal ShKT module of K9IWX5 is functional, because the sequence lacks conserved residues required for propagating ShKT feature annotation. |
| KCTD18 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 3 | It is unresolved whether KCTD18 is a bona fide CUL3-dependent ubiquitin-ligase substrate adaptor, and no KCTD18-specific ubiquitination substrate has been experimentally established. |
| KCTD18 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 3 | The subcellular localization of endogenous KCTD18 is unknown. It is not clear whether KCTD18 acts in cytosol, nucleus, mitochondria, another organelle-associated pool, or in a context-dependent complex with CUL3 or other KCTD proteins. |
| KCTD18 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | The biological role of KCTD18 is not defined. Existing genetic and cell-based clues point to adipocyte progenitor proliferation, restless-legs-syndrome locus biology, neurodevelopmental dosage observations, and cancer associations, but n… |
| KDX1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | Whether KDX1/Mlp1 has any residual protein kinase catalytic (phosphotransfer) activity in vivo is undetermined; no physiological substrate has been demonstrated and the field treats it as catalytically dead. |
| KDX1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 1 | The full set of KDX1/Mlp1 direct binding partners and any additional (non-Swi4, non-Rlm1) scaffolding targets are unknown. |
| KDX1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The non-redundant (unique) biological role of KDX1/Mlp1 relative to SLT2/MPK1 is undefined: no phenotype has been shown to depend on KDX1 with SLT2 intact. |
| Ketone-body uptake and oxidation | module_node | — | BIOLOGY + CURATION | — | 0 | The physiologically dominant KT2440 enzyme for terminal acetoacetyl-CoA thiolysis has not been established among its thiolase paralogs. |
| Ketone-body uptake and oxidation | module_node | — | BIOLOGY | — | 0 | It is unresolved whether KT2440 primarily receives D-3-hydroxybutyrate by BhbP-mediated uptake or from an intracellular storage-polymer-derived source, and whether HbdH and Aacs dominate the corresponding reactions in vivo. |
| KIAA1614 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 3 | KIAA1614 has no established direct molecular mechanism or validated functional partner set. |
| KIAA1614 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 2 | The distribution, dynamics and functional relevance of KIAA1614 cellular pools remain incompletely characterized. |
| KIAA1614 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 2 | KIAA1614 has no validated pathway or biological-process assignment. |
| Kit signaling pathway module | module | OPEN | BIOLOGY + CURATION | — | 0 | Whether STAT activation downstream of ligand-stimulated wild-type KIT proceeds mainly by direct receptor phosphorylation, by Src-family kinases, or by JAK2 is not settled; the GO_REF/IMP evidence for GO:0046427 on human KIT comes from on… |
| KLB | gene | OPEN | BIOLOGY | MF_DARK | 1 | The endogenous stoichiometry and ligand-dependent assembly sequence of KLB-FGFR complexes in human target tissues remain incompletely resolved. |
| KLB | gene | OPEN | BIOLOGY | MF_DARK | 1 | It is unknown whether either KLB GH-like domain retains any physiologically relevant residual chemistry despite loss of an essential catalytic glutamate. |
| klp-11 | gene | — | BIOLOGY | MF_DARK | 1 | No KLP-11 subunit-resolved in vivo molecular function is established independently of its partners: all motility, IFT and localization data are for the intact KLP-11/KLP-20/KAP-1 heterotrimer (or the KLP-11/KLP-20 heterodimer), and KLP-1… |
| klp-11 | gene | — | BIOLOGY | BP_DARK | 1 | The identity of the IFT cargo(es) directly engaged by KLP-11-containing kinesin-II via KAP-1 in C. elegans, and how cargo loading/unloading is regulated along the middle segment, are not resolved by the primary literature reviewed here. |
| klp-11 | gene | — | BIOLOGY | MF_DARK | 1 | The atomic structure of the fully assembled C. elegans kinesin-II heterotrimer and the structural basis of KLP-11-mediated asymmetric autoregulation of motor activity are unsolved. |
| klp-20 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Within the klp-11/klp-20 heterodimer it is not resolved which subunit is the "unprocessive" motor domain and which is the processive one — i.e. whether klp-20 itself is the processive or the autoinhibited/unprocessive head, and the resid… |
| klp-20 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 1 | The direct, klp-20-motor-selected ciliary cargo repertoire is not enumerated: what cargoes the klp-20-containing kinesin-II specifically delivers is inferred through the IFT-A/IFT-B particle rather than measured for the motor itself. |
| knh4 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular activity of Knh4 is unknown. It is undetermined whether Knh4 binds, cross-links, transports, or otherwise scaffolds cell-wall beta-glucan; no catalytic activity, ligand, or biochemical partner has been demonstrated, and the… |
| knh4 | gene | OPEN | BIOLOGY | BP_DARK | 1 | Knh4's specific biological role and its contribution relative to the essential Kre9 ortholog and the other non-essential Kre9/Knh1 paralogs in S. pombe are undetermined. Whether knh4 acts redundantly, in a specialized condition, or in a … |
| L-arginine biosynthesis via acetylated ornithine | module_node | — | BIOLOGY + CURATION | — | 0 | Organisms can encode more than one valid implementation of glutamate acetylation, ArgC reduction, or ornithine release. |
| L-arginine biosynthesis via acetylated ornithine | module_node | — | BIOLOGY + CURATION | — | 0 | KT2440 retains arginine prototrophy after individual disruption of argD/astC PP_4481, argE, or argJ. |
| L-aspartate de novo and selected salvage routes to NAD+ | module_node | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | In Pseudomonas putida KT2440, the molecular activity, substrate specificity, and physiological role of the second compact CinA-C/PncC-family protein PP_3298/Q88HQ5 remain unknown. |
| L-histidine biosynthesis | module_node | — | BIOLOGY + CURATION | — | 0 | KT2440 contains two unrelated candidates for histidinol-phosphate phosphatase activity. PP_3157/Q88I44 has a HisN-family assignment, whereas PP_5147/Q88CN3 has only generic HAD-family support. Neither protein has been assayed directly in… |
| LEE1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular function of LEE1 beyond metal (zinc) coordination is unknown. No catalytic activity or specific binding activity has been demonstrated experimentally. In particular, whether the two CCCH zinc fingers bind nucleic acid — and… |
| LEE1 | gene | OPEN | BIOLOGY | MF_DARK | 0 | Whether LEE1 has any role in protein ubiquitination is unresolved. The makorin-family (PTHR11224 / MKRN-like) ubiquitin-ligase annotations are propagated from RING-domain-containing metazoan makorins, but LEE1 lacks the catalytic RING do… |
| LEE1 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 0 | The biological process(es) in which LEE1 acts are unknown. Reported deletion and overexpression phenotypes (altered chemical resistance/accumulation, decreased competitive fitness, increased sporulation efficiency, altered invasive/veget… |
| LIH1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The actual catalytic activity of the LIH1 protein is undetermined. Although LIH1 retains an intact serine-hydrolase catalytic triad (Ser181/Asp253/His315) and the GHSLG nucleophile-elbow motif, it has never been expressed, purified, or a… |
| LIH1 | gene | OPEN | BIOLOGY | CC_DARK | 0 | The subcellular localization of LIH1 is unknown. It is not established whether LIH1 is secreted (as many fungal lipases of this family are), retained intracellularly, or membrane-associated. |
| LIH1 | gene | OPEN | BIOLOGY | BP_DARK | 0 | The biological process and physiological role of LIH1 are unknown. No loss-of-function phenotype has been reported, the conditions (if any) under which LIH1 is required or induced are undefined, and the assignment to "lipid metabolic pro… |
| LMTK1 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 0 | The human construct used for the direct kinase work in PMID:35902728 has not been mapped unambiguously to a current Q6ZMQ8 isoform. |
| LMTK1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | Conservation of the LMTK1-TBC1D9B-Rab11A pathway in endogenous human neurons is untested. |
| LMTK1 | gene | OPEN | BIOLOGY | MF_DARK | 0 | The direct neuronal substrate connecting LMTK1 kinase activity to TBC1D9B and Rab11A regulation is unknown. |
| LMTK1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | Reproducible intrinsic tyrosine kinase activity of human LMTK1 remains unresolved. |
| LMTK1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether recurrent human PP1 interactions represent a physiological PP1-STK39 scaffold is unknown, and the species of the PMID:17267545 AATYK1 construct is not stated in the cached abstract. |
| LMTK2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The mechanism that targets newly synthesized LMTK2 from the endoplasmic reticulum specifically to early and recycling endosome membranes remains unknown. |
| LMTK2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The direct effector mechanism by which the LMTK2-MYO6 module drives endosomal tubule formation and broad cargo movement is unresolved; MYO6 binding is proven, but MYO6 has not been shown to be an LMTK2 substrate, and known PP1C and CFTR … |
| LMTK3 | gene | OPEN | BIOLOGY | MF_DARK | 0 | Whether current-sequence human LMTK3 has intrinsic protein tyrosine kinase activity remains unresolved. |
| LMTK3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | Directness and site resolution remain incomplete for several proposed human LMTK3 substrates. |
| LMTK3 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 0 | Endogenous human LMTK3 topology and localization outside cancer-cell models are incompletely established. |
| LMTK3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The breadth and kinase dependence of LMTK3's PP1-targeting scaffold function remain unresolved. |
| LMTK3 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 0 | Biologically relevant alternative human LMTK3 protein products have not been established. |
| LMTK3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The physiological scope of the RAB7A-dependent multivesicular-body and extracellular-vesicle phenotype is unknown. |
| LMX1B | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The endogenous LMX1B target genes that are necessary and sufficient for human podocyte differentiation and adult maintenance remain unresolved; in particular, COL4A3, COL4A4, NPHS2, and CD2AP should not be treated as a universal direct L… |
| LMX1B | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | It is not known which ATG8-family paralogs are endogenous LMX1B cofactors in human midbrain dopaminergic neurons, how their contributions differ between basal nuclear and starvation-induced cytosolic binding, or what interaction stoichio… |
| LMX1B | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether the three annotated human LMX1B splice isoforms differ in regulatory-DNA selection, coregulator binding, ATG8 binding, localization, or tissue-specific biological output has not been established. |
| LNP1 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 1 | The normal physiological process and cellular phenotype controlled by wild-type LNP1 are unknown. |
| LNP1 | gene | NARROWING | BIOLOGY | MF_DARK | 2 | It is unknown whether LNP1 binds 14-3-3 proteins directly, which phosphosite controls the association, and what the association does in cells. |
| LNP1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The physiological significance of the LNP1-LYN interaction and whether LYN phosphorylates LNP1 are unknown. |
| LNP1 | gene | OPEN | BIOLOGY | CC_DARK | 1 | The endogenous subcellular localization and trafficking behavior of LNP1 are unresolved. |
| LNPEP | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The molecular mechanism by which the LNPEP cytosolic and transmembrane regions control GLUT4 sorting, and the degree to which this mechanism operates in human adipocytes in vivo, remain unresolved. |
| LNPEP | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 3 | The peptide-import route, TAP contribution, substrate repertoire, and human dendritic-cell states that make LNPEP-dependent cross-presentation essential are not fully defined. |
| LNPEP | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Functional differences among the three annotated human LNPEP splice isoforms, and the protease and signals that generate the circulating pregnancy-serum ectodomain, remain poorly resolved. |
| LNPK | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 1 | Whether LNPK itself has physiologically relevant ubiquitin-protein ligase activity, and any endogenous substrate of that proposed activity, remain unresolved. |
| LNPK | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The causal steps connecting LNPK-mediated ER-junction stabilization to selective secretome-mRNA initiation and to corpus-callosum development are not known. |
| LNPK | gene | OPEN | ONTOLOGY | CC_DARK | 1 | GO lacks a cellular-component term for the ER three-way junction membrane, so LNPK's defining active subcompartment can currently be represented only by the broader ER tubular-network membrane term. |
| LNX1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The endogenous, tissue-specific substrate hierarchy of LNX1p80 and the rules determining whether a recruited substrate undergoes degradative polyubiquitination, regulatory monoubiquitination, or another ubiquitin outcome remain unresolved. |
| LNX1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The identity of the E3 ligase or ligases recruited by RING-less LNX1p70, the ligand contexts in which recruitment occurs, and whether this indirect ubiquitination mechanism operates at endogenous abundance in vivo are unknown. |
| LNX1 | gene | OPEN | BIOLOGY | CC_DARK | 0 | Endogenous expression, localization, and partner occupancy of LNX1p80 versus LNX1p70 across human tissues and cell states are insufficiently resolved. |
| LNX2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The physiological substrate hierarchy of human LNX2 is unresolved: NUMB is a direct substrate in a purified assay, but the dominant endogenous substrates and relevant cell types have not been established. |
| LNX2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | How the NPXY motif, four PDZ domains, and self-association cooperate with the Zn-RING-Zn catalytic module to select substrates and control LNX2 localization is not known at endogenous expression levels. |
| LNX2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The ubiquitin-chain architectures and downstream fates generated by LNX2 on physiological substrates in cells remain unresolved. |
| LOC117183218 (core function) | core_function | — | BIOLOGY | — | 0 | Whether this predicted truncated isoform (PE 4) lacking the HECT catalytic domain is expressed as a functional protein or represents a computational gene prediction artifact is unknown. |
| LOC117183218 (core function) | core_function | — | BIOLOGY | — | 0 | Whether the isolated RCC1-like domain from this truncated isoform retains any independent protein binding or substrate recognition capability outside the context of a full-length HERC3 is unknown. |
| lolD | gene | OPEN | BIOLOGY | — | 0 | ATPase kinetics and subunit coupling have not been measured for the KT2440 LolCDE complex. |
| lolD | gene | OPEN | ONTOLOGY | MF_DARK | 0 | GO has an ATP hydrolysis molecular-function term for LolD but no molecular-function term for the ATP-coupled lipoprotein-extraction activity of the assembled LolCDE complex. |
| lolE | gene | OPEN | BIOLOGY | — | 0 | The distinct LolE cargo-contacting role relative to LolC has not been tested in KT2440. |
| LONP1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular features and regulatory states that direct a LONP1-bound client toward productive folding rather than ATP-coupled degradation are unknown. |
| LONP1 | gene | OPEN | BIOLOGY | BP_DARK | 0 | The causal physiological role of LONP1 binding to single-stranded mtDNA, promoter sequences, G-quadruplex-prone DNA, and GU-rich RNA remains unresolved. |
| LONP1 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 0 | The subcellular localization, processing, oligomerization, and catalytic competence of LONP1 isoforms 2 and 3 are unknown. |
| LONRF1 | gene | OPEN | BIOLOGY | MF_DARK | 0 | Direct ubiquitin ligase activity by LONRF1 and its E2 requirements, chain products, and physiological substrates have not been established. |
| LONRF1 | gene | OPEN | BIOLOGY | BP_DARK | 0 | The biological process in which LONRF1-mediated ubiquitination acts is unknown. |
| LONRF1 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 0 | The native subcellular location and any stable macromolecular complex of LONRF1 are unknown. |
| LONRF1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | Whether the canonical product and isoform 2 differ in activity, stability, localization, or partner selection is unknown. |
| LONRF2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The E2 enzyme requirements, ubiquitin-chain architecture, and immediate degradation machinery used by LONRF2 remain unresolved in the locally available evidence. |
| LONRF2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether the N-terminal InterPro RING-like region at residues 143-193 is an intact zinc-coordinating RING or an atypical or degenerate remnant is unresolved. |
| LONRF2 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The physiological substrate spectrum of LONRF2 and the extent to which the ALDOA axis operates outside endometrial-cancer models are unknown. |
| LONRF2 | gene | OPEN | BIOLOGY | CC_DARK | 1 | The native subcellular site of LONRF2 activity and any regulated cofactor assembly are not established. |
| LONRF2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether isoforms 1 and 2 differ in substrate recognition, ubiquitin-ligase activity, localization, or neuronal function is unknown, and the isoform tested in each direct study is not identified in the cached abstracts. |
| LONRF3 | gene | OPEN | BIOLOGY | MF_DARK | 2 | Intrinsic ubiquitin protein ligase activity by LONRF3 has not been demonstrated, and its E2 requirements, active RING region or regions, and ubiquitin-chain products are unknown. |
| LONRF3 | gene | OPEN | BIOLOGY | BP_DARK | 1 | No physiological LONRF3 substrate or biological process has been established. |
| LONRF3 | gene | OPEN | BIOLOGY | CC_DARK | 1 | The native subcellular location of active LONRF3 and any regulated cofactor assembly are unknown. |
| LONRF3 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether the three annotated LONRF3 isoforms differ in ligase activity, substrate selection, localization, or stability is unknown, and the isoform used for each interaction-screen edge is not established in the cached main texts. |
| LORICRIN | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The extent and molecular composition of compensation for LORICRIN loss in human epidermis are unknown, including whether compensation preserves mechanical strength across body sites as effectively as it preserves permeability. |
| LORICRIN | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 1 | The physiological significance of the reported nucleoplasmic localization of wild-type loricrin is unresolved; no normal nuclear molecular function has been established. |
| LOX | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The quantitative substrate partitioning of endogenous human LOX among collagen types, elastin, and the corresponding LOXL-family enzymes in the aortic wall is unresolved. |
| LOX | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | How BMP1 cleavage, downstream ADAMTS2/14 cleavage, tyrosine sulfation, and propeptide-mediated recruitment are coordinated to partition LOX between collagen and elastin substrates in native human tissues is not known. |
| LOX | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The physiological functions of released LOX-PP, and whether endogenous mature LOX has any normal intracellular or nuclear activity, remain unresolved. |
| LOXHD1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular activity by which LOXHD1 maintains TMC1 at the lower tip-link site is unknown; available co-immunoprecipitation establishes association under heterologous overexpression conditions but not a direct interface, stoichiometry,… |
| LOXHD1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Which of the four annotated human LOXHD1 splice isoforms are translated and required in cochlear hair cells is unknown. |
| LOXHD1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The conserved TMC1-positioning and mechanotransduction mechanism has not been demonstrated directly in human cochlear hair cells. |
| LOXL1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The catalytic efficiency and native substrate-site spectrum of purified human LOXL1 have not been established directly, including how its contribution to elastin cross-linking differs from its contribution to collagen cross-linking and f… |
| LOXL1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Which extracellular human LOXL1 cleavage products are catalytically active, and how BMP1 and ADAMTS14 processing regulates activity, stability, and substrate targeting, remains unresolved. |
| LOXL1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The in-vivo mechanism and specificity by which fibulin-5 and other matrix partners target human LOXL1 to elastogenic sites are not known, nor is it clear which LOXL1 precursor or processed form mediates each interaction. |
| LOXL2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The endogenous human collagen and elastin lysine/hydroxylysine sites modified specifically by LOXL2, rather than another LOX-family enzyme, and their tissue-specific partitioning are unresolved. |
| LOXL2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The physiological purpose and tissue regulation of LOXL2 cleavage between SRCR2 and SRCR3 remain unknown, including whether processing changes substrate choice, extracellular retention, or SRCR-dependent scaffolding without activating ca… |
| LOXL2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular architecture, stoichiometry, and dynamics by which LOXL2 SRCR domains organize collagen IV and fibronectin deposition are not known. |
| LOXL2 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | Whether endogenous LOXL2 has a reproducible normal intracellular catalytic substrate and how any intracellular pool bypasses or exits the secretory pathway remain unresolved. |
| LOXL3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The physiological human protein substrates and isoform-specific substrate preferences of LOXL3 are not established in vivo. |
| LOXL3 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | Whether human LOXL3 undergoes a required extracellular proteolytic activation step, including cleavage by BMP1-family proteases, is unknown. |
| LOXL3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The biochemical reproducibility, physiological scope, and isoform dependence of the reported nuclear STAT3 deacetylation/deacetylimination activity remain unresolved. |
| LOXL3 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 2 | The endogenous expression, secretion, localization, and exact database mapping of all reported human LOXL3 transcript forms are incompletely resolved. |
| LOXL4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The endogenous human protein substrates and modified lysine sites of LOXL4 are unknown, including whether collagen and elastin are direct physiological substrates. |
| LOXL4 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 1 | Whether endogenous human LOXL4 is proteolytically processed after secretion, and whether any such cleavage regulates activity, substrate choice, or matrix retention, remains unresolved. |
| LOXL4 | gene | OPEN | BIOLOGY | CC_DARK | 1 | The extracellular compartment in which endogenous human LOXL4 performs its main catalytic function, and the extent to which it resides in matrix, elastic fibers, or extracellular vesicles, are not directly resolved. |
| LOXL4 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 0 | The physiological relevance, compartmental compatibility, and directness of the reported high-throughput LOXL4 interaction partners and signaling-receptor-complex association are unresolved. |
| LPA | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether apo(a) ever acquires intrinsic serine-endopeptidase activity in a physiological context remains unresolved. |
| LPA | gene | OPEN | BIOLOGY | — | 0 | The relative physiological contributions of individual apo(a) kringle interactions to Lp(a) deposition and antifibrinolytic activity are not defined across the natural range of KIV-2 copy-number alleles. |
| LPA | gene | OPEN | BIOLOGY | — | 0 | The biological consequence of the directly observed apo(a)-APOH interaction is unknown. |
| LPAL2 | gene | OPEN | BIOLOGY | MF_DARK | 2 | It is unknown whether any LPAL2 transcript produces a stable endogenous polypeptide corresponding to Q16609 or another open reading frame. |
| LPAL2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The direct molecular mechanism by which LPAL2 RNA alters MMP9 transcription and hepatocellular-carcinoma phenotypes is unknown. |
| LPAL2 | gene | OPEN | BIOLOGY | — | 0 | The transcript isoform and structural RNA elements responsible for the reported lncRNA activity have not been resolved. |
| LPAR1 | gene | OPEN | BIOLOGY | — | 1 | Functional differences between Q92633-1 and Q92633-2 have not been established. |
| LPAR1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The quantitative contributions of Gi/Go, Gq/11, and G12/13 to native human LPAR1 signaling remain incompletely resolved across cell types and ligand concentrations. |
| LPAR1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The physiological effects of LPAR1 interactions with RAMP1, RAMP2, and RAMP3 are unknown. |
| LPAR1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Which PDZ-domain interactions occur with full-length endogenous LPAR1 and materially regulate receptor trafficking or signaling is unresolved. |
| LPAR2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The quantitative Gi/Go, Gq, and G12/13 coupling preferences of endogenous human LPAR2 remain unresolved across physiological cell types and LPA molecular species. |
| LPAR2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | How the terminal DSTL motif partitions LPAR2 among NHERF2/PLCB3, MAGI3, and other PDZ scaffolds in native human tissues is unknown. |
| LPAR2 | gene | OPEN | BIOLOGY | — | 0 | The endogenous regulatory roles of TRIP6, RalA, and GRK2 around LPAR2 are not fully separated from cell-model-specific signaling and trafficking effects. |
| LPAR2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The physiological consequences of screen-detected LPAR2 interactions with LGALS3 and RAMP1-3 are unknown. |
| LPAR3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The quantitative Gq/11, Gi/o, and other coupling profile of endogenous human LPAR3 is unresolved across native cell types. |
| LPAR3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | Native LPAR3 ligand preferences across physiological LPA molecular species are incompletely defined. |
| LPAR3 | gene | OPEN | BIOLOGY + CURATION | — | 1 | The relationship between the historical HOFNH30 sequence and current human LPAR3 transcripts and proteins remains unresolved. |
| LPAR3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The physiological settings and consequences of LPAR3 phosphorylation, beta-arrestin recruitment, and internalization are not established in native human tissues. |
| LPAR3 | gene | OPEN | BIOLOGY | — | 0 | The physiological relevance of the 53 HuRI binary interaction partners is unknown. |
| LPAR3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether the uterine implantation and embryo-spacing functions established for mouse Lpar3 are conserved as LPAR3-dependent physiology in humans is unresolved. |
| LPAR4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The quantitative Gq/11, G12/13, Gs, Gi/o, and beta-arrestin coupling profile of endogenous human LPAR4 is unresolved across native cell types. |
| LPAR4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | Native LPAR4 affinity and efficacy across physiological LPA molecular species remain incompletely defined. |
| LPAR4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | Why LPAR4 suppresses motility in some cancer-cell models but promotes invadopodia, invasion, and metastasis in fibrosarcoma is unresolved. |
| LPAR4 | gene | OPEN | BIOLOGY | — | 0 | The extent to which mouse Lpar4 and stem-cell-culture developmental phenotypes predict normal human tissue functions remains unclear. |
| LPAR4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The physiological consequences of screen-detected LPAR4 interactions with RAMP1, RAMP2, and RAMP3 are unknown. |
| LPAR4 | gene | OPEN | BIOLOGY + CURATION | — | 0 | LPAR4 structural determinants, receptor-specific trafficking regulation, and possible endogenous proteoform variation remain largely uncharacterized. |
| LPAR5 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The quantitative Gq/11, G12/13, Gs, Gi/o, and beta-arrestin coupling profile of endogenous human LPAR5 is unresolved across native cell types and ligands. |
| LPAR5 | gene | OPEN | BIOLOGY | — | 0 | The physiological competition and relative importance of LPA, FPP, NAG, and alkyl glycerol phosphate as endogenous LPAR5 agonists are unknown. |
| LPAR5 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The endogenous mechanism and consequences of LPA-induced LPAR5 internalization are unresolved. |
| LPAR5 | gene | OPEN | BIOLOGY | — | 0 | The conservation and human relevance of Lpar5-dependent neuropathic-pain physiology remain uncertain. |
| LPAR5 | gene | OPEN | BIOLOGY | — | 0 | The native roles of LPAR5 in human platelet-lineage, intestinal immune, plaque, and cancer contexts require further separation. |
| LPAR5 | gene | OPEN | BIOLOGY + CURATION | — | 0 | Whether LPAR5 has functionally distinct endogenous protein isoforms or stable receptor-specific partners is unknown. |
| LPAR6 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The quantitative G12/13, Gq, Gi/o, and beta-arrestin coupling profile of endogenous human LPAR6 is unresolved across native cell types. |
| LPAR6 | gene | OPEN | BIOLOGY | — | 0 | The endogenous LPA molecular species that occupy LPAR6 in human tissues and the physiological significance of its reported 2-acyl-LPA preference are unknown. |
| LPAR6 | gene | OPEN | BIOLOGY | — | 0 | The proximal LPAR6 signaling branch and downstream effectors that maintain human hair-shaft growth and texture are not defined. |
| LPAR6 | gene | OPEN | BIOLOGY | — | 0 | Why different disease-associated LPAR6 missense variants cause trafficking failure versus surface-expressed signaling failure, and which defects are pharmacologically rescuable, remains incompletely resolved. |
| LPAR6 | gene | OPEN | BIOLOGY + CURATION | — | 0 | Functionally distinct endogenous LPAR6 protein isoforms and stable receptor-specific interaction partners have not been established. |
| LPCAT4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The endogenous acceptor and acyl-CoA usage of human LPCAT4 is not quantitatively resolved across native tissues and cell types. |
| LPCAT4 | gene | OPEN | BIOLOGY + CURATION | — | 0 | The physiological extent of LPCAT4-dependent 1-acyl LPG acylation and phosphatidylglycerol remodeling is unresolved. |
| LPCAT4 | gene | OPEN | BIOLOGY | — | 0 | The biological roles of LPCAT4-generated phospholipids carrying unsaturated fatty acids at sn-1 are unknown in human cells. |
| LPCAT4 | gene | OPEN | BIOLOGY | — | 0 | The membrane orientation and structure-based determinants of LPCAT4 acceptor position, phospholipid headgroup, and acyl-CoA selectivity are not established. |
| LPCAT4 | gene | OPEN | BIOLOGY | — | 0 | The physiological relevance of reported liver-endocrine and hepatocellular-carcinoma phenotypes to endogenous human LPCAT4 activity remains uncertain. |
| LPCAT4 | gene | OPEN | BIOLOGY + CURATION | — | 0 | Functionally distinct endogenous LPCAT4 protein isoforms and stable LPCAT4-containing complexes have not been demonstrated. |
| LPGAT1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The contribution of lysosome-to-ER phospholipid salvage to endogenous LPGAT1 activity in intact human tissues is unknown. |
| LPGAT1 | gene | OPEN | BIOLOGY | — | 0 | The quantitative acceptor and acyl-donor specificity of endogenous human LPGAT1 across PC, PE, and PS is incompletely resolved. |
| LPGAT1 | gene | OPEN | BIOLOGY + CURATION | — | 0 | Whether human LPGAT1 has physiologically meaningful LPG acyltransferase or PG remodeling activity remains disputed. |
| LPGAT1 | gene | OPEN | BIOLOGY + CURATION | — | 0 | The reported monoacylglycerol acyltransferase activity and triglyceride-synthesis role have not been established as direct human LPGAT1 functions. |
| LPGAT1 | gene | OPEN | BIOLOGY | — | 0 | The mechanism linking LPGAT1-dependent membrane regeneration to mitochondrial dysfunction, hepatopathy, and survival phenotypes is unresolved. |
| LPGAT1 | gene | OPEN | BIOLOGY + CURATION | — | 0 | Functionally distinct endogenous LPGAT1 protein isoforms, membrane topology, and constitutive protein-complex membership are not established. |
| LPIN2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The quantitative contribution of LPIN2 to PA-to-DAG flux in native human tissues is unresolved because LPIN1 and LPIN3 can compensate in a tissue- and state- dependent manner. |
| LPIN2 | gene | OPEN | BIOLOGY | — | 0 | The membrane-recruitment mechanism, exact ER topology, and in-vivo regulation of human LPIN2 catalytic activity are incompletely defined. |
| LPIN2 | gene | OPEN | BIOLOGY + CURATION | — | 0 | Endogenous human LPIN2 transcriptional coactivator partners, genomic targets, and dependence on catalytic state remain insufficiently established. |
| LPIN2 | gene | OPEN | BIOLOGY | — | 0 | The causal pathway from LPIN2 loss to the bone inflammation, dyserythropoietic anemia, and dermatosis of Majeed syndrome is unresolved. |
| LPIN2 | gene | OPEN | BIOLOGY | — | 0 | The extent to which LPIN2 directly restrains human macrophage inflammation versus indirectly changing membrane lipid composition remains uncertain. |
| LPIN2 | gene | OPEN | BIOLOGY + CURATION | — | 0 | Functionally distinct endogenous LPIN2 protein isoforms and obligatory stable LPIN2-containing complexes have not been established. |
| LPIN3 | gene | — | — | — | 0 | The quantitative contribution of endogenous human LPIN3 to phosphatidate-to-DAG flux relative to LPIN1 and LPIN2 is unknown across tissues. Recombinant activity is direct, but human adipocyte experiments reveal substantial paralog compen… |
| LPIN3 | gene | — | — | — | 0 | Native human LPIN3 membrane recruitment, residence time, and organelle specificity are unresolved. Cytosolic localization is observed and ER catalysis is modeled, but stable endogenous LPIN3 association with the ER has not been directly … |
| LPIN3 | gene | — | — | — | 0 | Lipin-3 phosphoregulation has been characterized in vitro, but the signals that control endogenous LPIN3 abundance, phosphatidate access, and catalytic output in human cells remain poorly defined and should not be inferred from LPIN1 ins… |
| LPIN3 | gene | — | — | — | 0 | LPIN3-specific contributions to human gastrointestinal lipid handling, adipogenesis, and lipoprotein production remain unresolved. Current physiology is derived mainly from mouse double-mutant or cooperative-paralog experiments. |
| LPIN3 | gene | — | — | — | 0 | A direct transcriptional coactivator function has not been shown for LPIN3. The conserved LXXIL motif and nuclear localization are suggestive, but available direct family experiments establish coactivation for LPIN1 and LPIN2. |
| LPIN3 | gene | — | — | — | 0 | No study has compared Q9BQK8-1 with the one-residue-insertion isoform Q9BQK8-2 for catalytic activity, localization, regulation, tissue expression, or partner binding. |
| LPIN3 | gene | — | — | — | 0 | The stoichiometry, tissue distribution, and functional effect of endogenous LPIN3 oligomerization are unknown. Experimental LPIN1-LPIN3 association does not establish a constitutive stable human complex. |
| LPL | gene | — | — | — | 0 | The distribution of active monomeric and dimeric LPL in native human capillaries, and whether oligomeric state changes with GPIHBP1, APOC2, particle binding, or ANGPTL exposure, remain unresolved. |
| LPL | gene | — | — | — | 0 | The quantitative contributions of catalytic TAG hydrolysis versus noncatalytic GPIHBP1-dependent particle margination and receptor/proteoglycan bridging to tissue-specific lipid uptake have not been separated in humans. |
| LPL | gene | — | — | — | 0 | How LPL moves from parenchymal-cell secretion sites through interstitial HSPGs to endothelial GPIHBP1 in different human tissues is incompletely defined, including the kinetics and regulation of each transfer step. |
| LPL | gene | — | — | — | 0 | The relative effects of ANGPTL3, ANGPTL4, and ANGPTL3-ANGPTL8 complexes on GPIHBP1-bound human LPL across adipose, muscle, cardiac, and fasting/fed contexts remain uncertain; several decisive physiological studies are mouse-based. |
| LPL | gene | — | — | — | 0 | The physiological contribution of LPL phospholipase A1 activity relative to its dominant triacylglycerol lipase activity is unknown, including which particle phospholipids are hydrolyzed in vivo. |
| LPL | gene | — | — | — | 0 | Many reported LPL interaction partners come from high-throughput screens. Which interactions form reproducible, stoichiometric, and functionally consequential assemblies at endogenous abundance remains unresolved. |
| LPL | gene | — | — | — | 0 | Variant studies distinguish defects in folding, secretion, GPIHBP1 or HSPG binding, particle recognition, and catalysis, but a systematic human genotype-to- biochemical-mechanism map is incomplete. |
| LPO | gene | — | — | — | 0 | The occupancy, covalent attachment, and maturation pathway of heme in endogenous human LPO have not been established directly; key mechanistic and structural assignments derive from recombinant or non-human LPO. |
| LPO | gene | — | — | — | 0 | The abundance and processing of canonical LPO, incompletely processed LPO, and UniProt isoform 2 across saliva, milk, and airway secretions are unknown. Isoform 2 deletes residues 26-108, extending beyond the annotated propeptide into th… |
| LPO | gene | — | — | — | 0 | Physiological partitioning among thiocyanate, iodide, bromide, urate, and other donors remains incompletely quantified under the pH, peroxide flux, and substrate concentrations found in different human secretions. |
| LPO | gene | — | — | — | 0 | The tissue-specific peroxide sources and physical or functional coupling of LPO to DUOX-family oxidases in salivary, mammary, and airway epithelia remain incompletely resolved. |
| LPO | gene | — | — | — | 0 | The biological effects of propeptide removal or retention on LPO folding, secretion, stability, and antimicrobial activity are not known. |
| LPO | gene | — | — | — | 0 | Human salivary preparations contain monomeric and reversibly aggregated LPO, but the native oligomeric state and physiological significance of this behavior in intact secretions are unresolved. |
| LPP | gene | — | — | — | 0 | The endogenous composition, stoichiometry, and exchange kinetics of LPP- organized adhesion assemblies are unknown, including whether VASP, ACTN1, palladin, and SCRIB bind simultaneously or in mutually exclusive contexts. |
| LPP | gene | — | — | — | 0 | The mechanism that imports intact LPP into the nucleus, the signals that regulate import versus CRM1-dependent export, and any endogenous nuclear binding partners or transcriptional targets remain unresolved. |
| LPP | gene | — | — | — | 0 | It is unclear how force, matrix stiffness, phosphorylation, or other modifications change the accessibility and partner preferences of LPP's proline-rich region, LIM domains, and terminal PDZ-binding sequence. |
| LPP | gene | — | — | — | 0 | Human physiological requirements for LPP in vascular smooth muscle and other normal tissues remain incompletely defined; pressure-dependent vascular phenotypes currently rely substantially on mouse knockout evidence. |
| LPP | gene | — | — | — | 0 | An intronic promoter produces smooth-muscle-enriched LPP transcripts, but it is unknown whether these transcripts alter the protein product, translation, localization, or molecular function. |
| LPX2 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | The direct molecular function and physiological substrate of LPX2 are unknown. The "peroxisomal lipase" designation rests on gene-deletion lipidomics plus a literature attribution of lipase activity (Ploier et al. 2013) that is actually … |
| LPX2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | LPX2's family placement conflicts with its proposed function: its only recognized sequence family is EIS1/Eisosome1 (a plasma-membrane eisosome protein family), yet it localizes to the peroxisomal matrix and is proposed to act in lipid m… |
| LPX2 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The in-vivo biological role of LPX2 is undefined beyond a lipidomic association. No growth phenotype, defined pathway placement, or contribution to peroxisomal fatty-acid metabolism has been demonstrated specifically for LPX2; the model … |
| LPX2 (core function) | core_function | OPEN | BIOLOGY + CURATION | MF_DARK | 1 | The molecular function of LPX2 is not experimentally established. It is proposed to be a peroxisomal lipase ("Lipase of Peroxisomes 2"), but no reproducible enzymatic activity, catalytic mechanism, or physiological substrate has been dem… |
| LPXN | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The endogenous composition, stoichiometry, and temporal order of LPXN-bound PYK2/PTK2B or FAK1/PTK2, Src-family kinases, PTP-PEST, and p95PKL at adhesion structures are unresolved. |
| LPXN | gene | OPEN | BIOLOGY | BP_DARK | 0 | Whether LPXN is required for podosome organization and bone resorption in human osteoclasts is unknown. |
| LPXN | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The relative abundance, localization, partner selection, and activity of the two human LPXN protein isoforms have not been established. |
| LPXN | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The mechanism and physiological scope of LPXN nuclear import and its choice among androgen receptor, SRF, and beta-catenin transcriptional programs are unresolved. |
| LRATD1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular activity of LRATD1 is unknown, including whether its LRAT-like domain has any catalytic or noncatalytic ligand-binding function. |
| LRATD1 | gene | OPEN | BIOLOGY | BP_DARK | 0 | The normal human physiological process controlled by LRATD1 is unknown. |
| LRATD1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The functional consequence and endogenous prevalence of LRATD1 N-myristoylation are unknown. |
| LRATD1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The expression, localization, molecular activity, and biological effects of LRATD1 isoform 2 are unknown. |
| LRATD1 | gene | OPEN | BIOLOGY | MF_DARK | 0 | No endogenous molecular partner has been validated for LRATD1. |
| LRATD2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The direct molecular activity by which LRATD2 selects or advances EGFR cargo is unknown, including whether it binds EGFR, a cargo receptor, a coat component, or a regulatory GTPase directly. |
| LRATD2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The endogenous composition, stoichiometry, and lifetime of LRATD2-containing trafficking assemblies are unknown. |
| LRATD2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The endogenous occupancy and trafficking consequence of LRATD2 N-myristoylation are unknown. |
| LRATD2 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The normal tissue-level physiological role of LRATD2 and the relationship between its trafficking function and tumor-associated phenotypes remain unresolved. |
| LRATD2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The structural function of the catalytically divergent LRAT-like region is unknown. |
| LRBA | gene | OPEN | BIOLOGY | MF_DARK | 1 | The direct molecular contacts by which LRBA selects CTLA4 and enables its entry into Rab11-dependent recycling are unknown. |
| LRBA | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular basis for LRBA-mediated endolysosome homeostasis beyond CTLA4 cargo is unresolved, including the relevant cargo spectrum and membrane-remodeling step. |
| LRBA | gene | OPEN | BIOLOGY | MF_DARK | 1 | LRBA's direct role in ATG9A-vesicle capture, movement, or fusion at damaged mitochondria and the phagophore assembly site is unknown. |
| LRBA | gene | OPEN | BIOLOGY | BP_DARK | 1 | The physiological outputs and spatial organization of LRBA-dependent PKA RII anchoring in primary B cells are unknown. |
| LRBA | gene | OPEN | BIOLOGY | BP_DARK | 0 | Functional differences between the two reviewed LRBA protein isoforms have not been established. |
| LRCH1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The structural interface by which the LRCH1 leucine-rich-repeat region occludes Cdc42 binding to the DOCK8 DHR-2 domain has not been resolved, and the residues that determine inhibition are unknown. |
| LRCH1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | LRCH1 co-immunoprecipitates with DOCK7, but it is unknown whether LRCH1 inhibits DOCK7 nucleotide-exchange activity or whether this association has a distinct cellular consequence. |
| LRCH1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Direct actin binding by the calponin-homology domain of human LRCH1 has not been demonstrated, and the cortical function reported for the single Drosophila LRCH protein has not been resolved among the four human paralogues. |
| LRCH1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The endogenous expression, localization, and partner specificity of the three LRCH1 splice isoforms have not been compared in immune cells. |
| LRCH1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | It remains unclear whether the DOCK8 and LAT mechanisms operate in the same endogenous human T-cell state and whether the Src/Lck and inflammatory phenotypes observed in other immune contexts reflect the same proximal LRCH1 activity. |
| LRCH2 | gene | OPEN | BIOLOGY | MF_DARK | 0 | It is unknown whether LRCH2 changes the guanyl-nucleotide exchange activity, substrate selection, or signaling output of DOCK8 rather than only recruiting expressed DOCK8 toward the cell periphery. |
| LRCH2 | gene | OPEN | BIOLOGY | MF_DARK | 0 | Direct binding of human LRCH2 to actin has not been demonstrated, and the contribution of its calponin-homology domain to endogenous localization and function is unknown. |
| LRCH2 | gene | OPEN | BIOLOGY | BP_DARK | 0 | The native cell types, subcellular sites, and physiological processes that use the LRCH2-DOCK8 association have not been established with endogenous proteins. |
| LRCH2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The expression, localization, and partner specificity of LRCH2 isoforms 1 and 2 have not been compared in endogenous human tissues. |
| LRCH2 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The effect of the reported p.Lys258Glu leucine-rich-repeat substitution on LRCH2 folding, DOCK8 recruitment, cellular behavior, and human disease risk is unknown. |
| LRCH3 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The abundance, dynamics, and cellular contexts of endogenous LRCH3 association with MYO6 and DOCK7 have not been established, and it is unknown whether all three proteins occupy one module simultaneously in unmodified human cells. |
| LRCH3 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular relationship between LRCH3 and septins remains unresolved because septins were not recovered in LRCH3 immunoprecipitates despite proximity and calponin-homology-region-dependent relocalization evidence. |
| LRCH3 | gene | OPEN | BIOLOGY | MF_DARK | 0 | It is unknown whether LRCH3 changes DOCK7 guanine-nucleotide exchange activity, substrate choice, or spatial signaling toward RAC1 and CDC42 during septin remodeling. |
| LRCH3 | gene | OPEN | BIOLOGY | MF_DARK | 0 | Direct binding of LRCH3 to F-actin has not been demonstrated, and the actin structure or subcellular site at which endogenous septin remodeling occurs is not defined. |
| LRCH3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The expression, localization, and partner specificity of the four LRCH3 splice isoforms have not been compared in endogenous human tissues. |
| LRCH4 | gene | OPEN | BIOLOGY | MF_DARK | 0 | The molecular activity by which LRCH4 augments Toll-like-receptor signaling is unknown: it has not been established whether LRCH4 binds LPS directly, changes membrane-lipid organization, controls CD14 trafficking, or acts through another… |
| LRCH4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | It is unknown whether LRCH4 is required for Toll-like-receptor responses in native primary human immune cells and whether the ligand range observed in mouse systems is conserved in humans. |
| LRCH4 | gene | OPEN | BIOLOGY | CC_DARK | 0 | The endogenous subcellular distribution, membrane orientation, and trafficking itinerary of human LRCH4 are unknown. |
| LRCH4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The physiological significance of LRCH4 binding to DOCK6, DOCK7, and DOCK8 is unknown, including which Rho GTPase output is affected and whether the interaction contributes to Toll-like-receptor or membrane-raft phenotypes. |
| LRFN1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Which LAR-family receptor phosphatase interactions are physiologically occupied by endogenous human LRFN1, whether they occur predominantly in trans or can also occur in cis, and how each interaction contributes to human postsynaptic mat… |
| LRFN1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The endogenous human-neuronal requirement for the LRFN1 ESTV motif, the identity and stoichiometry of its occupied PDZ-scaffold partners, and the mechanism by which those interactions organize receptor nanodomains are not established. |
| LRFN1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The physiological role, if any, of LRFN1-containing cis homo- and heteromeric SALM complexes in postsynaptic assembly or neurite development is unknown. |
| LRFN2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The endogenous scaffold, glutamate-receptor, and trafficking partners occupied by LRFN2 at human pre- and postsynaptic membranes, and the requirement for its terminal ESTV motif in human neurons, remain unknown. |
| LRFN2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | How presynaptic SALM1 couples CASK and its juxtamembrane basic region to F-actin/PIP2-dependent neurexin cis clustering is unresolved, including whether the relevant interactions are simultaneous, transient, or indirect. |
| LRFN2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The direction and cellular basis of Lrfn2-dependent synaptic plasticity are not settled, and the relative contributions of excitatory versus inhibitory synapses differ between mouse models and brain regions. |
| LRFN2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The physiological role of SALM1-containing cis homo- and heteromeric SALM assemblies is unknown, as is whether they regulate trafficking, membrane avidity, or synaptic partner selection. |
| LRFN4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The endogenous human-neuronal requirement for each SALM3-LAR-RPTP pair, the presynaptic splice isoforms that engage LRFN4, and the relative contribution of PTPRF, PTPRD and PTPRS to excitatory versus inhibitory presynapse assembly are un… |
| LRFN4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The architecture and conformational dynamics of full-length human LRFN4 alone and in a membrane-spanning LRFN4-LAR-RPTP adhesion complex have not been determined. |
| LRFN4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 3 | Which of the demonstrated DLG1, DLG2, DLG3 and DLG4 partners, or other PDZ proteins, occupy endogenous LRFN4 in human neurons, and how that interaction module coordinates postsynaptic-density assembly with extracellular LAR-RPTP adhesion… |
| LRFN4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The extracellular ligand or activating condition for LRFN4 signaling in human monocytes and the mechanism linking its cytoplasmic region to 14-3-3, NCK1 and Rac1 are not established. |
| LRFN5 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Which LAR-RPTP splice forms bind endogenous full-length LRFN5 at synapses is unresolved, especially because cell-aggregation assays and purified-protein measurements report opposite effects of mini-exon B. |
| LRFN5 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The stoichiometry, membrane directionality, and partner hierarchy of endogenous full-length human LRFN5 complexes at excitatory and inhibitory synapses are not established. |
| LRFN5 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Whether LRFN5-HVEM signaling suppresses macrophage or microglial activation in human CNS tissue, and which cell type and signaling direction are essential, remain unknown. |
| LRG1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The structure, stoichiometry, and cell-context determinants of the LRG1-TGF-beta receptor assembly are unresolved, including how endoglin and ligand exposure govern conditional ALK1 association and selection between ALK1-SMAD1/5 and ALK5… |
| LRG1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The physiological source, tissue distribution, and abundance of LPHN2-activating deglycosylated LRG1 in humans are unknown, as is the precise structural basis for LPHN2 selectivity over LPHN1 and LPHN3. |
| LRG1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | It is unknown whether human LRG1 binds human extracellular cytochrome c with physiologically relevant affinity and neutralizes cytochrome-c activity in vivo. |
| LRGUK | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 1 | The biochemical activity of the human LRGUK GUK-like domain is unresolved: partner binding is demonstrated in mouse LRGUK1, but nucleotide binding, phosphotransfer and ATPase activity have not been established, so neither a guanylate kin… |
| LRGUK | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The endogenous human LRGUK interaction complex and the causal contribution of each partner to sperm assembly remain unresolved; the direct human HOOK2 observation is a binary-interactome result, whereas the broader HOOK1-3/RIMBP3/KLC3 co… |
| LRGUK | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 1 | The precise placement and molecular role of LRGUK within the mammalian sperm C1b/C1f central-apparatus region, and any role in non-sperm cilia, remain unresolved despite patient sperm abnormalities and ciliate comparative evidence. |
| LRIF1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The structural organization of the LRIF1-HP1-SMCHD1 assembly is unknown. No experimentally determined LRIF1 structure exists, and the direct HP1-binding motif is known without a mapped structural mechanism for how LRIF1 engages SMCHD1 or… |
| LRIF1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The cellular functions of the short LRIF1 isoform remain untested. Its sequence lacks residues 1-536 but retains the HP1-binding motif, both nuclear-localization signals, and the coiled coil; retention of these features alone does not es… |
| LRIF1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | How LRIF1 and SMCHD1 repress D4Z4 after somatic recruitment remains unresolved, including whether LRIF1 is recruited through H3K9me3/HP1 or another chromatin factor and whether the auxiliary pathway acts by higher-order compaction. |
| LRIG1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The E3 ligase and degradation machinery that execute basal, c-CBL-independent LRIG1-mediated MET destabilization are unresolved, and it is not known whether the SAIT301-induced HRS/USP8 pathway is used during unperturbed MET regulation. |
| LRIG1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The direct structural interface, affinity and stoichiometry of full-length LRIG1 with its receptor targets remain unresolved, and positive cell-based association results have not been reconciled with failure to detect EGFR binding in pur… |
| LRIG1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The physiological protease, cleavage site and direct signaling target of the shed LRIG1 ectodomain are unknown, as is whether the two curated human isoforms differ in production or activity of the soluble product. |
| LRIG2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The endogenous receptor partners and direction of LRIG2-mediated signaling regulation in normal human tissues are unknown. |
| LRIG2 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The cellular mechanism that releases the soluble LRIG2 ectodomain is unknown. |
| LRIG2 | gene | OPEN | BIOLOGY | BP_DARK | 1 | How LRIG2 loss causes urofacial syndrome type 2 at the molecular and circuit levels remains unresolved. |
| LRIG2 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 1 | It is unknown whether the mouse Lrig2-Neogenin shedding mechanism and auditory role are conserved in human LRIG2. |
| LRIG3 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The endogenous human receptor partners, binding interfaces, and direction of LRIG3-mediated receptor regulation remain incompletely defined. |
| LRIG3 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The extent to which the mouse Lrig3-Ntn1 inner-ear mechanism is conserved in human otic development is unknown. |
| LRIG3 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The physiological source, protease, and normal target tissues of soluble LRIG3 are unresolved. |
| LRIG3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The localization and functions of the two curated LRIG3 isoforms have not been compared. |
| LRIT1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The normal expression, localization, molecular partners, and physiological role of endogenous human LRIT1 in retinal neurons have not been established. |
| LRIT1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The stoichiometry, orientation, and binding interfaces of the LRIT1-mGluR6-FRMPD2 assembly are unknown. |
| LRIT1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | How LRIT1 modulates cone synaptic gain and background adaptation is unresolved. |
| LRIT1 | gene | OPEN | BIOLOGY | CC_DARK | 2 | The relationship between LRIT1's synaptic pool, rat outer-segment disk localization, and heterologous ER accumulation is not understood. |
| LRIT2 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 0 | The molecular activity and endogenous interaction partners of human LRIT2 are unknown. |
| LRIT2 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 1 | The cell types, subcellular sites, and physiological role of endogenous human LRIT2 in the eye have not been established. |
| LRIT2 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 0 | Whether LRIT2 associates with LRIT1 endogenously, and whether that association has a conserved retinal consequence, remains unresolved. |
| LRIT2 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 0 | The expression, localization, and partner specificity of LRIT2 isoforms 1 and 2 have not been compared. |
| LRIT3 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The direct extracellular binding interface by which LRIT3 organizes nyctalopin, TRPM1, and the depolarizing-bipolar-cell signalplex is unresolved. |
| LRIT3 | gene | OPEN | BIOLOGY | CC_DARK | 2 | The exact cell-side distribution and molecular partners of endogenous human LRIT3 at rod and cone synapses remain unresolved. |
| LRIT3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The expression, trafficking, and function of human LRIT3 isoform 2 are unknown. |
| LRIT3 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The endogenous physiological relevance of LRIT3-dependent FGFR1 maturation and signaling outside the overexpression assay is unknown. |
| LRMDA | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The relative expression and functional equivalence of the reviewed 198-residue Q9H2I8 protein and the 226-residue A0A087WWI0 proteoform are unknown. |
| LRMDA | gene | OPEN | BIOLOGY | BP_DARK | 1 | The cargo and trafficking steps through which RAB32-LRMDA-Commander control PMEL processing, melanosome fibrillation, and lumen pH remain unresolved. |
| LRMDA | gene | OPEN | BIOLOGY | BP_DARK | 1 | How the melanosome-biogenesis mechanism relates to LRMDA's developmental role in melanocyte differentiation is unknown. |
| LRMDA | gene | OPEN | BIOLOGY | CC_DARK | 1 | The endogenous composition, stoichiometry, and lifetime of the RAB32-LRMDA-Commander assembly on human melanosomes are unknown. |
| LRP10 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The physiological human cargo repertoire of LRP10, including whether it directly internalizes apoE-rich beta-VLDL in relevant human cell types, is unresolved. |
| LRP10 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | How SORL1 participates in LRP10-dependent sorting, and whether either receptor recruits the other or a shared trafficking complex, has not been established. |
| LRP10 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The cellular itinerary, cargo selectivity, and physiological consequences of LRP10 isoform 2 are unknown. |
| LRP10 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The causal route from disease-associated LRP10 loss or mislocalization to Lewy-body disease phenotypes remains unresolved, and the reported alpha-synuclein effects have not been established as a universal normal function of LRP10. |
| LRP11 (core function) | core_function | NARROWING | BIOLOGY | MF_DARK | 1 | Whether human LRP11 binds native LDL directly, with what affinity and particle specificity, and whether it internalizes LDL rather than only signaling in response to it remain unknown. |
| LRP11 (core function) | core_function | OPEN | BIOLOGY | CC_DARK | 1 | The endogenous protein expression, localization and biological activity of human LRP11 isoform 2 have not been established. |
| LRP11 (core function) | core_function | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 1 | LRP11's proposed beta-arrestin interaction, phosphoprotein-binding specificity and the quantitative distribution between plasma and intracellular membranes remain unresolved. |
| LRP11 (core function) | core_function | NARROWING | BIOLOGY | BP_DARK | 1 | The normal human physiological context of LRP11 signaling remains unknown outside cancer-cell and experimental T-cell systems. |
| LRP12 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 1 | The species and constructs used for the α4-integrin molecular assays, and independent curated experimental confirmation on human LRP12, remain unresolved from the accessible evidence. |
| LRP12 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The physiological extracellular ligand and any cargo-internalization function of LRP12 remain unknown. |
| LRP12 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Functional differences between the two curated human LRP12 isoforms are unresolved. |
| LRP12 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The mechanism connecting Lrp12 to neuronal arborization, migration, and cortical lamination is not defined and has not been tested directly in human neural cells. |
| LRP12 | gene | OPEN | BIOLOGY | — | 1 | No experimental structure defines full-length LRP12 or its complex with α4 integrin. |
| LRP1B | gene | OPEN | BIOLOGY | MF_DARK | 1 | The endogenous full-length human LRP1B ligand repertoire, adaptor usage, and tissue-specific internalization kinetics are not established. |
| LRP1B | gene | OPEN | BIOLOGY | BP_DARK | 1 | The normal physiological roles of LRP1B in its restricted human tissue-expression domains, including the importance of lipoprotein uptake, remain unresolved. |
| LRP1B | gene | OPEN | BIOLOGY | BP_DARK | 1 | The molecular connection between LRP1B cargo trafficking and suppression of cancer-cell proliferation is unknown. |
| LRP1B | gene | OPEN | BIOLOGY | CC_DARK | 1 | Full-length human LRP1B processing, higher-order structure, and possible stable receptor-complex membership are unresolved. |
| LRP1B | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | Whether human LRP1B produces functional alternative protein isoforms is unknown. |
| LRP2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The endogenous human LRP2 cargo repertoire and quantitative uptake contribution in each expressing tissue are incompletely defined. |
| LRP2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Ligand-specific interfaces and the complete adaptor architecture of full-length human LRP2 during its endocytic conformational cycle remain unresolved. |
| LRP2 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The cargo-specific mechanisms linking LRP2 loss to the pleiotropic features of Donnai-Barrow/facio-oculo-acoustico-renal syndrome are not established. |
| LRP2 | gene | OPEN | BIOLOGY | CC_DARK | 0 | Proteolytic processing, soluble-receptor release, and nuclear-tail signaling by endogenous human LRP2 remain insufficiently characterized. |
| LRP2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | It is unknown whether any human LRP2 splice transcripts produce stable functional protein isoforms with distinct trafficking or cargo specificity. |
| LRP2BP | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 1 | The endogenous molecular consequence of the LRP2BP-LRP2 association is unknown. |
| LRP2BP | gene | OPEN | BIOLOGY | MF_DARK | 1 | The LRP2BP-side interaction interface and endogenous complex composition are unresolved. |
| LRP2BP | gene | OPEN | BIOLOGY | CC_DARK | 0 | The identity and dynamics of the LRP2BP-positive cytoplasmic vesicles are unknown. |
| LRP2BP | gene | OPEN | BIOLOGY | BP_DARK | 0 | The biological significance of LRP2BP isoform 2 is unknown. |
| LRP3 | gene | OPEN | BIOLOGY | MF_DARK | 3 | The direct molecular activity and physiological extracellular ligand of LRP3 are unknown. |
| LRP3 | gene | OPEN | BIOLOGY | MF_DARK | 2 | It is unknown whether the cytoplasmic tyrosine-based signal mediates LRP3 endocytosis, which adaptors it recruits, and whether any physiological cargo is internalized. |
| LRP3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The proximal pathway connecting LRP3 to osteogenic-versus-adipogenic fate and the generality of this phenotype beyond immortalized human stromal-cell clones are unknown. |
| LRP4 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The architecture and signaling behavior of full-length membrane-embedded human LRP4 in the AGRIN-LRP4-MuSK complex remain unresolved. |
| LRP4 | gene | OPEN | BIOLOGY | BP_DARK | 0 | Direct endogenous human-neuromuscular evidence for LRP4 complex dynamics and signaling is limited. |
| LRP4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The molecular basis for pathway-selective effects of LRP4 beta-propeller variants is incomplete. |
| LRP4 | gene | OPEN | BIOLOGY | MF_DARK | 0 | The physiological LRP4 cytoplasmic-tail interactome and its contribution to either core pathway are unknown. |
| LRP5 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The molecular features that make a ligand-receptor complex prefer LRP5 rather than the closely related LRP6, and the extent to which the two coreceptors are interchangeable in human osteoblasts, remain unresolved. |
| LRP5 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Direct assembly, stoichiometry, and coreceptor selectivity of a human Norrin-FZD4-LRP5 signaling complex have not been established biochemically or structurally. |
| LRP5 | gene | OPEN | BIOLOGY | — | 0 | It is unknown whether the 1,034-residue RefSeq isoform 2 is translated and produces a stable membrane protein with any signaling activity. |
| LRP5 | gene | OPEN | BIOLOGY | BP_DARK | 1 | Whether LRP5 has a direct, cell-autonomous role in glucose or lipid metabolism, distinct from secondary effects of skeletal and canonical Wnt signaling, remains unresolved. |
| LRP5L | gene | OPEN | BIOLOGY + CURATION | WHOLLY_DARK | 4 | Whether the human LRP5L locus produces a stable endogenous polypeptide is unknown, and the transcript(s), translation start site, and isoform(s) that could generate such a product have not been reconciled with the current pseudogene model. |
| LRP5L | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular mechanism connecting LRP5L perturbation or the P36R construct to laminin gamma-1 and c-MAF expression is unknown, including whether the reported effects are direct, require an endogenous translated product, or are specific … |
| LRP6 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 0 | It is unknown whether the additional NCBI RefSeq LRP6 transcript/protein models designated a-j produce stable products with functions that differ from the UniProtKB O75581/RefSeq isoform-b model reviewed here. |
| LRP6 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The architecture and conformational transitions of full-length, membrane-embedded human LRP6 in an activated Wnt-Frizzled signalosome remain unresolved. |
| LRP6 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The relative contribution of direct GSK3 inhibition by phosphorylated LRP6 motifs versus recruitment and sequestration of AXIN-GSK3 in endogenous human signalosomes is not quantitatively resolved. |
| LRP6 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 0 | The tissue-specific division of labor between human LRP6 and LRP5, and the mechanistic effects of many LRP6 disease variants, remain incompletely resolved. |
| LRP8 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The extent to which endogenous human LRP8 couples Reelin binding to DAB1-dependent developmental and synaptic outputs in defined neural cell types remains unresolved. |
| LRP8 | gene | OPEN | BIOLOGY | — | 0 | Endogenous functions of the five curated human LRP8 splice isoforms are not resolved at protein, tissue, or signaling level. |
| LRP8 | gene | OPEN | BIOLOGY | — | 0 | The architecture and stoichiometry of full-length LRP8 ligand complexes in a membrane remain unknown. |
| LRP8 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The physiological importance and tissue range of LRP8-mediated viral entry in humans remain incompletely defined. |
| lys-1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | It is not known whether LYS-1 has any muramidase / lysozyme (peptidoglycan-hydrolysing) enzymatic activity. All functional evidence is genetic (infection-inducible expression, RNAi, overexpression); the protein has never been purified or… |
| lys-1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular substrate or microbial target of LYS-1 is undefined: it is unknown which bacterial surface molecule(s) LYS-1 acts on, and whether its antibacterial spectrum extends beyond S. marcescens, S. aureus and B. thuringiensis. |
| lys-1 | gene | OPEN | BIOLOGY | BP_DARK | 2 | Whether lys-1 is individually necessary in vivo or is functionally redundant within the 15-member C. elegans lysozyme family is unresolved. The defense phenotypes rest on RNAi knockdown and overexpression rather than a characterized sing… |
| lysA-I | gene | — | BIOLOGY | — | 1 | The relative in-vivo flux, conditional expression, and redundancy of the Q88L58 LysA-I and Q88CF4 LysA-II paralogs are unresolved. |
| lysA-II | gene | — | BIOLOGY | — | 1 | The relative in-vivo flux, conditional expression, and redundancy of the Q88CF4 LysA-II and Q88L58 LysA-I paralogs are unresolved. |
| LYZ (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The functional consequence of the sanguivore-specific positively selected substitutions in vampire bat lysozyme is undetermined: no muramidase or bacteriolytic assay has been performed on the D. rotundus enzyme, so it is unknown whether … |
| LYZ (core function) | core_function | OPEN | BIOLOGY | BP_DARK | 1 | It is undetermined whether vampire bat lysozyme has a digestive role on the ingested blood meal in addition to its antimicrobial role. |
| MAL33 | gene | OPEN | BIOLOGY | BP_DARK | 1 | Whether the MAL33 allele of the S. cerevisiae S288C reference strain is a functional MAL-activator at all is the central unknown: it is reported to be non-functional, so its capacity to activate maltose-inducible transcription of the MAL… |
| MAL33 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The functional relationship of MAL33 to the other MAL-activator paralogs is uncharacterized: whether MAL33 is redundant with, distinct from, or (in S288C) simply a degenerate copy of the functional activators (Mal63p and relatives), and … |
| Mammalian GABA shunt (glutamate to GABA to succinate) | module_node | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The mitochondrial GABA-import step is not represented by a confidently assigned participant in this module. |
| Mammalian proline-P5C biosynthesis and catabolism | module_node | — | CURATION | — | 0 | This module does not represent bacterial ProB-ProA-ProC or fused PutA architectures. |
| MCH2 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 3 | The transported substrate, transport direction (uniport/symport/antiport), driving force (proton-coupled vs. facilitated diffusion), and physiological/biological role of MCH2 are all undetermined. It is one of the "dark" conserved yeast … |
| MCH2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether MCH2 contributes to the mch1-5 quintuple-mutant chemostat biomass phenotype, and whether the five MCH paralogs (and JEN1) act redundantly, is unresolved. No mch2-single phenotype has been established. |
| MCH2 (core function) | core_function | OPEN | BIOLOGY | BP_DARK | 2 | The direct transported substrate of MCH2 is unknown, and consequently no molecular function more specific than the generic "transmembrane transporter activity" can be assigned. Monocarboxylic acids (lactate, pyruvate, acetate) are experi… |
| MCO14 | gene | OPEN | BIOLOGY | BP_DARK | 0 | The biological process in which MCO14 participates in yeast mitochondria is unknown. The family-derived tetrahydrobiopterin pathway is largely absent from S. cerevisiae, so the process the protein actually serves (metabolic, structural, … |
| MCO14 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 0 | The composition of the high-molecular-weight, membrane-potential-dependent complex that Mco14 assembles into is unknown; no specific interaction partner has been curated. |
| MCO14 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 0 | Whether MCO14 is a catalytically active dehydratase in yeast, and if so its true physiological substrate, is undetermined; the annotated 4a-carbinolamine dehydratase activity is a family/motif-based prediction (UniProt "Putative") with n… |
| mcs6 (core function) | core_function | — | — | — | 0 | Whether the ~5% of transcripts that are acutely Mcs6-dependent (the Sep1/Ace2 cell-separation program) reflect a promoter-specific requirement for Ser5 phosphorylation, for Cdk9/Pcm1 recruitment and capping, or for another TFIIH-linked s… |
| mcs6 (core function) | core_function | — | — | — | 0 | The division of labour between Mcs6 and Csk1 in activating Cdc2 bound to different cyclins (Cig2 at G1/S versus Cdc13 at G2/M), and whether specific Cdc2 subpopulations depend on the Mcs6 complex, remain unsettled; whether the free trime… |
| MEP isoprenoid precursor biosynthesis | module_node | OPEN | BIOLOGY + CURATION | — | 1 | IspG and IspH electron-delivery systems vary across lineages, and family membership alone does not identify the physiological carrier. |
| mex-6 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The non-redundant, MEX-6-specific contribution to embryonic polarity is undefined. It is unknown whether MEX-6 has any private target mRNA, tissue, developmental timing, or molecular activity distinct from its near-identical paralog MEX-… |
| mex-6 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The direct mRNA targets of MEX-6 and its RNA-binding specificity have not been determined for MEX-6 itself. All biochemical RNA-recognition data (poly-U tract, high affinity, low specificity, discriminator residue) come from the paralog … |
| mex-6 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether MEX-6 RNA binding is required for its function in anterior-posterior polarity is untested for MEX-6. It is unknown whether zinc-finger/RNA-binding-dead MEX-6 can still form an anterior gradient, dock PLK-1/PLK-2, and support dete… |
| mff-1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The specific molecular activity of C. elegans MFF-1 is uncharacterized: whether worm MFF-1 physically binds DRP-1 (and via which surface), whether it acts as a receptor/adaptor that recruits DRP-1 as in mammals, and whether it has any ac… |
| mff-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The division of labor between mff-1 and mff-2 is unresolved: which paralog dominates, whether they are functionally interchangeable, whether they act in different tissues or at different targets (mitochondria vs peroxisomes), and whether… |
| MIM1 | gene | NARROWING | BIOLOGY | MF_DARK | 2 | The mechanism by which Mim1 integrates an alpha-helical transmembrane anchor is undetermined. It is not established whether the substrate helix passes through a proteinaceous conduit formed by the Mim1 oligomer, is handed to the lipid ph… |
| MIM1 | gene | OPEN | BIOLOGY | BP_DARK | 2 | What determines whether a given alpha-helically anchored outer-membrane protein requires the MIM complex is unknown. There is no sequence or biophysical rule that predicts MIM dependence, and no substrate-recognition determinant on eithe… |
| MIM1 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | Why the Neurospora crassa orthologue only partially complements yeast mim1-delta, while the more distant Schizosaccharomyces pombe orthologue complements fully, is unexplained. It is therefore not established that MIM function is uniform… |
| MIM1 (core function) | core_function | OPEN | ONTOLOGY | CC_DARK | 1 | No ontology term can express what MIM does at the lipid droplet. GO has GO:0160259 for the ER-lipid droplet contact site and GO:0170007 for the corresponding tether activity, and GO:0044233 for the ER-mitochondrion apposition, but nothin… |
| MIM1 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | Which partner supplies the lipid droplet-facing determinant of the tether is undetermined, so it is not established whether Mim1 enables the tethering activity or merely contributes the mitochondrial anchor while Ayr1 does the recognising. |
| Mitochondrial respiratory Complex V (F1Fo ATP synthase) — subunits and F1 assembly; ATP5F1A/ATP5F1B/ATP5F1D/ATP5F1E/ATP5PO/ATP5MC3/ATP5MD + ATPAF2/TMEM70 | module | OPEN | BIOLOGY + CURATION + ONTOLOGY | WHOLLY_DARK | 4 | Whether the LINC00528 locus (UniProtKB:Q8N1L1 / C22orf37) is protein-coding at all is unresolved, so the reported 170-aa microprotein "ATHENA" cannot yet be admitted as a Complex V assembly factor. The prior question is not what ATHENA d… |
| mks-2 | gene | OPEN | ONTOLOGY + CURATION | MF_DARK | 1 | MKS-2 has no assigned molecular function and there is no GO term to express one. Its role is to be a structural/diffusion-barrier scaffold subunit of the ciliary transition-zone MKS module, but GO has no molecular-function term such as "… |
| mks-2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The specific, non-redundant molecular contribution of MKS-2/TMEM216 within the MKS module is undetermined: its direct binding partners in the worm transition zone are not mapped, and it is unknown whether MKS-2 provides a discrete sub-fu… |
| mksr-1 | gene | OPEN | ONTOLOGY + CURATION | MF_DARK | 1 | MKSR-1 has no assigned molecular function and there is no GO term to express one. Its role is to be a structural/diffusion-barrier scaffold subunit of the ciliary transition-zone MKS module, but GO has no molecular-function term such as … |
| mksr-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The specific, non-redundant molecular contribution of MKSR-1/B9D1 within the MKS module is undetermined: whether its predicted C2/B9 Ca2+/lipid-binding activity is real, its direct binding partners in the worm TZ beyond MKSR-2/B9D2, and … |
| mlaD | gene | OPEN | BIOLOGY | — | 0 | The physiologically dominant net direction of the KT2440 Mla system has not been established directly. |
| mlaD | gene | OPEN | BIOLOGY | — | 0 | PP_0960 has not been tested directly by biochemical or loss-of-function experiments in KT2440. |
| mlaE | gene | OPEN | BIOLOGY | — | 0 | The physiologically dominant net direction and substrate spectrum of KT2440 MlaFEDB have not been established directly. |
| mlaE | gene | OPEN | BIOLOGY | — | 0 | Q88P93 has not been tested directly in a purified KT2440 complex or a KT2440 loss-of-function strain. |
| mlaF | gene | OPEN | BIOLOGY | — | 0 | The coupling between KT2440 MlaF ATP hydrolysis and net phospholipid-transfer direction has not been established directly. |
| mlaF | gene | OPEN | BIOLOGY | — | 0 | Q88P94 has not been tested directly in purified KT2440 MlaFEDB or by a KT2440 loss-of-function study. |
| mmf2 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 2 | The specific in-vivo enamine/imine substrate deaminated by fission-yeast mmf2 (e.g. 2-aminoacrylate vs 2-iminobutanoate vs a broader set) has not been experimentally determined; the activity is inferred from RidA-family membership and th… |
| mmf2 (core function) | core_function | OPEN | BIOLOGY | BP_DARK | 1 | No physiological role or loss-of-function phenotype has been characterized for mmf2 in S. pombe; whether it maintains mitochondrial DNA / protects mitochondrial PLP enzymes (as its S. cerevisiae ortholog Mmf1p does) is unknown. PomBase r… |
| mmf2 (core function) | core_function | OPEN | BIOLOGY + CURATION | CC_DARK | 4 | The mitochondrial-matrix localization of mmf2 has not been directly demonstrated in S. pombe; it rests on an ISO transfer from S. cerevisiae Mmf1p and a predicted transit peptide, while its PANTHER subfamily is named PROTEIN HMF1-RELATED… |
| MNN14 | gene | NARROWING | BIOLOGY | RESIDUAL_SUBGAP | 3 | The in-vivo division of labour between MNN14 and its paralog MNN4 is unresolved. MNN14 has intrinsic mannosylphosphate transferase activity in vitro, yet MNN4 is curated as a positive regulator (enzyme activator) of the Mnn6/Ktr6 mannosy… |
| MNN14 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The acceptor-position specificity of MNN14 in vivo is unknown: which mannose residues/positions on N-linked (and possibly O-linked) glycans MNN14 phosphorylates in the cell, and whether MNN4 and MNN14 act on the same or different positions. |
| MNN14 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The basis of the functional redundancy between MNN14 and MNN4, and any distinct or condition-specific role of MNN14, are unknown. There is no described standalone loss-of-function phenotype for an mnn14 single mutant beyond the residual … |
| MNT4 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | The acceptor substrate and demonstrated catalytic activity of MNT4 are unknown: no enzyme assay, donor/acceptor pair, or reaction product has been reported for the protein. |
| MNT4 (core function) | core_function | OPEN | BIOLOGY | BP_DARK | 1 | The in-vivo biological role and deletion phenotype of MNT4 are unknown, and the family default role (protein O-linked glycosylation) is specifically excluded for MNT4. |
| MNT4 (core function) | core_function | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | The subcellular compartment in which MNT4 acts is uncertain. |
| MOH1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | The molecular activity of Moh1 is undetermined. Beyond structural zinc binding by the Yippee domain, it is not known what Moh1 binds (protein? nucleic acid?) or what biochemical output, if any, the cradle-shaped Yippee pocket produces. N… |
| MOH1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | No functionally validated direct physical partner or substrate of Moh1 is known. CCT2/CCT3 and multiple core GID-complex subunits are now the strongest co-purification candidates, but the Drosophila Yippee-Hemolin interaction has no esta… |
| MOH1 | gene | NARROWING | BIOLOGY | BP_DARK | 3 | The mechanism by which Moh1 shapes stress tolerance and quiescence is unknown. It is unexplained why loss of Moh1 increases acute resistance to several lethal stresses yet decreases long-term stationary-phase/chronological survival, and … |
| MOH1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | Whether "apoptotic process"/regulated cell death is the correct biological-process framing for Moh1 is unresolved. The label derives from a single heterologous complementation study interpreted within the contested yeast programmed-cell-… |
| MOH1 | gene | OPEN | BIOLOGY | CC_DARK | 0 | The subcellular site of Moh1 action is unknown; no reliable localization is curated, and the GOA cellular_component annotation is ND. |
| MPDU1 (core function) | core_function | — | — | — | 0 | The precise molecular mechanism by which MPDU1 promotes utilization of Dol-P-Man and Dol-P-Glc is undetermined: it lacks any defined catalytic activity and no informative molecular-function GO term is assigned. It may reorient (flip) the… |
| MPDU1 (core function) | core_function | — | — | — | 0 | Whether a distinct Dol-P-Glc-selective utilization factor also exists is unresolved, as the SL15/Lec35 product was reported to be selective for MPD over GPD, implying an additional GPD-selective gene product remains to be identified. |
| MRX20 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The physiological substrate transported by MRX20 is unknown. It has the mitochondrial-carrier fold and the conserved carrier signature residues, but its specific solute (whether a tricarboxylate/citrate as in related family members, anot… |
| MRX20 | gene | OPEN | BIOLOGY | BP_DARK | 1 | Whether MRX20 has any direct role in mitochondrial gene expression is unknown. The "Mrx" name reflects only proteomic co-purification with mitochondrial-ribosome (MIOREX) complexes, and no experiment has shown that MRX20 participates in … |
| MRX20 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biological process MRX20 serves and the basis of its loss-of-function phenotypes are unknown. The deletion is viable with only weak, pleiotropic high-throughput phenotypes, none of which points to a specific pathway. |
| MTCH2 | gene | OPEN | BIOLOGY | MF_DARK | 2 | The molecular function through which MTCH2 promotes BAX and BAK higher-order self-assembly and apoptotic pore growth is undetermined. It is not the insertase activity, and no alternative activity - lipid scramblase, lipid transfer, or di… |
| MTCH2 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | No substrate transported by MTCH2 has ever been identified, and it is not established whether the ancestral SLC25 transport activity was lost outright or has simply never been assayed for MTCH2 under conditions that would detect it. |
| mtl3 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 1 | mtl3 has no experimentally established molecular function, no identified binding partner or ligand, and no directly demonstrated biological process. Its assignment to the Mid2-like cell-wall stress-sensor family and its inferred role in … |
| mtl3 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | The molecular function of mtl3 is undetermined: it is unknown what (if any) cell-wall or membrane cue it senses, what its direct binding partner or signaling output is, and whether it acts as a bona fide stress sensor/receptor, a purely … |
| mug151 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The direct molecular function of S. pombe mug151 is undetermined: no catalytic, binding, or other biochemical activity has been experimentally assayed for the protein, and its assignment to the SAP30BP/HCNGP family is purely by sequence … |
| mug151 | gene | OPEN | BIOLOGY | BP_DARK | 1 | It is unknown whether mug151 has a genuine, specific meiotic function or whether its classification as a "meiotically up-regulated gene" reflects only transcriptional induction of a broadly-acting nuclear protein. |
| Musm1 (core function) | core_function | — | BIOLOGY + CURATION | — | 1 | Whether this MUP allergen has any genuine endocrine/metabolic function (as ISS-propagated from MUP metabolic studies) is unresolved and probably spurious for this protein. |
| nce101 | gene | OPEN | BIOLOGY | MF_DARK | 0 | The molecular function of nce101 is undetermined: no biochemical activity, ligand, substrate, catalytic residue, or diagnostic sequence motif has been identified for the protein or the NCE101 family. |
| nce101 | gene | OPEN | BIOLOGY | BP_DARK | 0 | The biological process in which nce101 participates in S. pombe is unknown, and it has not been shown that fission yeast operates a non-classical protein export pathway through nce101. |
| nce101 | gene | OPEN | BIOLOGY | CC_DARK | 0 | The subcellular localization and membrane topology of Nce101 are experimentally undetermined: it is unclear whether the protein is stably membrane-integral, which membrane it occupies, and in what orientation (N-in versus N-out, signal-a… |
| nce101 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 0 | No loss-of-function phenotype isolates a specific molecular or cellular role, and no interacting partners, complex membership, or regulatory context are known; it is also unresolved whether nce101 is functionally redundant with other sma… |
| Neurotransmitter loading into synaptic vesicles | module | OPEN | BIOLOGY | — | 0 | The molecular function of SV2A/B/C, the most abundant transporter-like proteins of the synaptic vesicle, is unresolved; they are not modeled as a loading step. |
| Neurotransmitter loading into synaptic vesicles | module | OPEN | BIOLOGY | — | 0 | The contribution of the intrinsic VGLUT chloride conductance, and of vesicular Cl-, to the balance between delta-pH and delta-psi during glutamate loading is not modeled. |
| Neurotransmitter loading into synaptic vesicles | module | OPEN | CURATION | — | 0 | Zinc co-loading by ZnT3 into a subset of glutamatergic vesicles is left out pending a decision on whether ion co-loading belongs in this module. |
| nhr-47 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether NHR-47 binds an endogenous small-molecule ligand — and, if so, its chemical identity — is unknown. It is classified as an orphan receptor, and as a member of the HNF4-derived supplementary nuclear receptors it may have lost or su… |
| nhr-47 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 1 | The direct transcriptional targets and the DNA response element bound by NHR-47 in vivo are undetermined, and it is unknown whether NHR-47 acts as an activator or a repressor. No ChIP, reporter, or motif data define its regulon; the down… |
| nhr-47 | gene | OPEN | BIOLOGY | BP_DARK | 2 | The endogenous physiological role and definitive loss-of-function phenotype of nhr-47 are unresolved. Its only reported phenotypes are germline RNAi effects that modulate susceptibility to environmental toxicants (polystyrene nanoparticl… |
| nirB (core function) | core_function | — | — | — | 0 | Q88M69 preference for NADH versus NADPH has not been measured directly. |
| nirD (core function) | core_function | — | — | — | 0 | The electron-transfer contribution of Q88M68 to Q88M69 has not been reconstituted directly. |
| NIT1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | The physiological substrate and catalytic activity of NIT1 (YIL164C) are unknown. It has never been shown to hydrolyze a nitrile or any amide/other C-N bond in vitro or in vivo, and it is unresolved whether the protein is catalytically a… |
| NIT1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | It is unresolved whether YIL164C is a functional gene or a truncated/pseudogene fragment, and whether YIL164C and YIL165C are translated as one protein in S. cerevisiae S288C. |
| NIT1 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 1 | The biological process and subcellular localization of NIT1 are unknown; its high-throughput deletion phenotypes have no established mechanistic link to a molecular function. |
| nlp-29 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 1 | Whether the mature amidated NLP-29 peptides themselves directly kill or inhibit microbes, and by what mechanism (membrane permeabilization, DNA binding as reported for the paralog NLP-31, or another target), has not been demonstrated. Ev… |
| nlp-29 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The specific contribution of nlp-29 alone to pathogen resistance and survival is undetermined: the nlp-29(tm1931) null shows no marked change in resistance to D. coniospora, consistent with functional redundancy within the nlp-27 to nlp-… |
| nlp-29 | gene | OPEN | BIOLOGY | MF_DARK | 1 | It is unknown which of the several distinct amidated peptides cleaved from the NLP-29 precursor mediate antimicrobial activity versus which engage NPR-12, and the predicted proprotein processing and C-terminal amidation have not been dir… |
| nlp-29 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether NLP-29's antimicrobial action is receptor-mediated or a direct physicochemical effect on microbes is unresolved. NPR-12 is the only demonstrated receptor and mediates host neuroimmune signaling (sleep, dendrite degeneration), not… |
| nphp-2 | gene | OPEN | ONTOLOGY + CURATION | MF_DARK | 1 | NPHP-2 has no assigned molecular function and no adequate GO molecular-function term to express one. It is a non-catalytic ankyrin-repeat protein whose role is to organize the ciliary inversin compartment and anchor proximal-ciliary sign… |
| nphp-2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | How the ciliary inversin compartment is initially established and maintained, and which direct molecular partners recruit and retain NPHP-2 there, is unknown. NPHP-2 reaches and is restricted to the InvC independently of transition-zone,… |
| nphp-2 | gene | OPEN | BIOLOGY | MF_DARK | 2 | Whether the NPHP-2 EF-hand actually binds calcium and, if so, whether the calcium signal specifies NPHP-2 localization, modulates its activity, or both, is undetermined. The EF-hand is only a predicted calcium-binding motif; it is requir… |
| nphp-2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The relationship between the ciliary NPHP-2/Y32G9A.6 and the canonical vertebrate-style Inversin complex is unresolved. In C. elegans the classical Inversin complex is built from MLT-4 (INVS), NEKL-2 (NEK8) and MLT-2 (ANKS6) and function… |
| nspC | gene | OPEN | BIOLOGY | — | 1 | NspC has not been tested biochemically or genetically in KT2440, so its in vivo substrate partition and contribution to spermidine production remain unconfirmed. |
| NVJ3 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The direct molecular/biochemical activity of Nvj3 is undetermined: it is unknown whether Nvj3 binds or transfers a specific lipid, senses a lipid, or acts purely as a scaffold/adaptor recruited by Mdm1. Its only recognizable domain is th… |
| NVJ3 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether Nvj3 itself possesses membrane-tethering activity, or is only a passenger recruited to Mdm1-formed ER-vacuole contacts, is unresolved. |
| NVJ3 | gene | NARROWING | BIOLOGY | BP_DARK | 1 | The specific molecular step by which Nvj3 influences triacylglycerol synthesis and lipid-droplet packaging is unknown, as is the physiological consequence of its loss beyond a mild neutral-lipid imbalance. |
| OCA6 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | Whether OCA6 is a catalytically active phosphatase at all is undetermined. It carries the PFA-DSP/PTP fold and a predicted active-site cysteine, but its CX5R catalytic loop is degenerate (the invariant phosphate-binding arginine is missi… |
| OCA6 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | The physiological substrate of OCA6 is unknown. Even if it retains activity, whether it acts on a phosphoprotein (as the "protein tyrosine phosphatase" name implies), on inositol pyrophosphates (as the active family member Siw14/Oca3 doe… |
| OCA6 (core function) | core_function | OPEN | BIOLOGY | BP_DARK | 1 | OCA6's specific role within the OCA family / OCA complex and in the oxidative-stress response is unresolved — whether it is a catalytic subunit, a regulatory/scaffolding subunit, or functionally redundant with its paralogs, and how it co… |
| odr-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The activating ligand and the in vivo mechanism that regulates ODR-1's cyclase output are unknown. No peptide or small-molecule ligand has been identified for its extracellular periplasmic-binding-protein-like domain, and it is undetermi… |
| odr-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether ODR-1's guanylate cyclase domain is catalytically active on its own (a functional cyclase) versus a regulatory subunit that must partner with another guanylyl cyclase (e.g. DAF-11) to form an active enzyme has not been directly t… |
| orf30 | gene | OPEN | ONTOLOGY | — | 1 | GO has no molecular-function term for mimicry-based competitive inhibition, so the activity that defines the AcrF2 family cannot be asserted with an existing identifier. |
| orf30 | gene | OPEN | BIOLOGY | — | 1 | It is undetermined whether a single copy of gp30 is sufficient to disable a Csy complex, or whether inhibition requires occupancy of more than one site, and consequently what intracellular concentration the phage must reach for the mecha… |
| osm-6 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 1 | The specific intra-complex protein contacts of OSM-6/IFT52 within the C. elegans IFT-B particle have not been experimentally mapped. In other organisms IFT52 bridges the IFT-B1 core (contacting IFT88, IFT70 and IFT46) and links the core … |
| osm-6 | gene | OPEN | BIOLOGY | MF_DARK | 1 | No independent biochemical or enzymatic activity has been demonstrated for OSM-6/IFT52, and although its N-terminal domain adopts a class-I glutamine-amidotransferase-like (GIFT) fold, whether this fold has any residual ligand-binding or… |
| Osmoregulated periplasmic glucan biosynthesis | module_node | — | BIOLOGY + CURATION | — | 0 | The exact KT2440 biochemical roles of OpgH and OpgG, including donor, acceptor, linkage, chain-length, and branching effects, have not been resolved in this first pass. |
| pbpG | gene | OPEN | BIOLOGY + CURATION | — | 0 | Q88GD0 endopeptidase substrate specificity and any secondary carboxypeptidase activity have not been assayed directly. |
| pbpG | gene | OPEN | BIOLOGY | — | 0 | Whether KT2440 PbpG localizes at division sites or influences divisome assembly as reported for a close ortholog has not been tested. |
| Peptidoglycan precursor biosynthesis and lipid II export | module_node | OPEN | BIOLOGY | — | 9 | How flux through the shared UDP-GlcNAc pool is partitioned between MurA (peptidoglycan) and LpxA (lipid A) is undetermined. Escherichia coli MurA is a direct binding partner of the LapB scaffold and of LpxA, LpxC, LpxD, and FabZ, but no … |
| Phagophore assembly site (PAS) | module | — | ONTOLOGY + CURATION | CC_DARK | 2 | GO:0034045 "phagophore assembly site membrane" does not pick out a unique structure. Its definition ("a cellular membrane associated with the phagophore assembly site") is satisfied by at least three distinct membranes - the phagophore i… |
| Phagophore assembly site (PAS) | module | — | BIOLOGY | CC_DARK | 1 | How much of the phagophore membrane originates from membrane already resident at the PAS is unquantified: the number of Atg9 vesicles consumed per autophagosome is small, but the fraction of final autophagosomal surface they contribute, … |
| Phagophore assembly site (PAS) | module | — | BIOLOGY + CURATION | CC_DARK | 1 | Whether mammalian cells have a structure equivalent to the yeast PAS is unsettled, yet GO:0000407 - whose definition is drawn from the yeast punctum - is applied to mammalian proteins. |
| Phagophore-organelle membrane contact site | module | — | ONTOLOGY | CC_DARK | 1 | The Gene Ontology has no cellular-component term for the ER-phagophore membrane contact site, so the compartment in which ATG2, WIPI4, and ATG9 act cannot be annotated as the contact site itself. |
| Phagophore-organelle membrane contact site | module | — | BIOLOGY | BP_DARK | 2 | How the contact site is taken apart is not established: the trigger that releases ATG2, WIPI4, and ATG9 from the rim, and whether release precedes, accompanies, or follows ESCRT-dependent sealing, are undetermined. |
| Phagophore-organelle membrane contact site | module | — | ONTOLOGY + BIOLOGY | BP_DARK | 1 | GO has no biological-process term for phagophore closure, the sealing event that terminates the contact site. |
| phb-1 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 2 | The molecular mechanism of the mitochondrial prohibitin complex is unresolved. It is not established whether the complex acts primarily as a membrane-bound chaperone/holdase for newly synthesized mitochondrial-encoded proteins, as a scaf… |
| phb-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The mechanistic basis by which the SAME reduction of the prohibitin complex produces OPPOSITE ageing outcomes is unknown - prohibitin deficiency shortens the lifespan of otherwise wild-type animals yet extends the lifespan of diapause (d… |
| phb-2 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 2 | The molecular mechanism of the mitochondrial prohibitin complex is unresolved. It is not established whether the complex acts primarily as a membrane-bound chaperone/holdase for newly synthesized mitochondrial-encoded proteins, as a scaf… |
| phb-2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | How phb-2's mitophagy-receptor activity is molecularly integrated with, and separated from, its obligate structural role in the same protein is not resolved in C. elegans. It is unknown whether the worm phb-2 uses a defined LC3/LGG-famil… |
| phb-2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The mechanistic basis by which the SAME reduction of the prohibitin complex produces OPPOSITE ageing outcomes is unknown - prohibitin deficiency shortens the lifespan of otherwise wild-type animals yet extends the lifespan of diapause (d… |
| PHGDH | gene | OPEN | BIOLOGY | — | 3 | Whether PHGDH has any physiological non-enzymatic function is undetermined. Two enzyme-independent activities have been claimed - a nuclear DNA-binding transcriptional-regulator role and a sequence-specific mRNA 3'UTR-binding role - but … |
| PhnWX 2-aminoethylphosphonate degradation | module | OPEN | BIOLOGY | — | 1 | The KT2440 PhnW and PhnX proteins have not been directly assayed for the two reactions represented here. |
| PhnWX 2-aminoethylphosphonate degradation | module | OPEN | BIOLOGY + CURATION | — | 1 | The transporter responsible for 2-aminoethylphosphonate uptake in KT2440 is unresolved. |
| PhnWX 2-aminoethylphosphonate degradation | module | OPEN | BIOLOGY + CURATION | — | 1 | PP_2210 is only a candidate AepR-like regulator of the adjacent KT2440 phnWX genes. |
| PI15 | gene | OPEN | BIOLOGY | MF_DARK | 1 | PI15's physiological human protease substrates, target specificity, inhibitory constants, and molecular inhibition mechanism are unknown. |
| PI15 | gene | OPEN | BIOLOGY | BP_DARK | 1 | PI15's normal physiological biological process and organismal phenotype are unknown. |
| PI15 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | It is unclear whether PI15 is a true exosome/prostasome cargo or a soluble protein that co-purifies with extracellular vesicles. |
| PI16 | gene | OPEN | BIOLOGY | MF_DARK | 2 | The physiological protease-target spectrum and structural inhibition mechanism of human PI16 are incompletely defined. |
| PI16 | gene | OPEN | BIOLOGY | — | 2 | The relationship between GPI-anchored and soluble human PI16 pools is unknown. |
| PI16 | gene | OPEN | BIOLOGY | — | 2 | The human physiological relevance of PI16-dependent chemerin processing, cardiomyocyte growth control, and neuropathic-pain signaling is not established. |
| pop2 (core function) | core_function | — | BIOLOGY | BP_DARK | 2 | The substrates of the Pop1-independent, partly cytoplasmic SCF(Pop2) complex are unknown; its in vitro ubiquitin ligase activity was demonstrated only in a substrate-independent autoubiquitylation assay. |
| PP_0312 (core function) | core_function | — | — | — | 0 | Direct electron transfer from reduced KT2440 DgcB to PP_0312/PP_0313 has not been reconstituted. |
| PP_0313 (core function) | core_function | — | — | — | 0 | Direct electron transfer from reduced KT2440 DgcB to PP_0312/PP_0313 has not been reconstituted. |
| PP_1451 | gene | OPEN | BIOLOGY + CURATION | — | 0 | PP_1451 tether-hydrolase activity and substrate specificity have not been tested directly in KT2440. |
| PP_1451 | gene | RESOLVED | BIOLOGY + CURATION | — | 0 | The pathway-level report classified PP_1451 as an uncertain release candidate, while the PP_2320 gene-level report instead called PP_1451 a short LdtPae1-clade crosslinking candidate; both conclusions relied on short-range sequence compa… |
| PP_1451 | gene | OPEN | BIOLOGY | — | 0 | KT2440 may lack a dedicated 3-to-3 peptidoglycan-crosslinking L,D-transpeptidase if PP_2320 anchors OprI and PP_1451 releases the tether. |
| PP_1703 (core function) | core_function | — | — | — | 0 | Q88M71 electron donor, physiological substrate, and cellular localization have not been tested directly. |
| PP_2320 | gene | OPEN | BIOLOGY + CURATION | — | 0 | PP_2320 substrate specificity and physiological importance have not been tested directly in KT2440. |
| PP_2928 | gene | OPEN | BIOLOGY | — | 1 | PP_2928 has not been tested biochemically or genetically in KT2440, so its substrate preference and contribution to cellular spermidine production remain unconfirmed. |
| PP_3117 (core function) | core_function | — | — | — | 0 | The direct molecular partners and biochemical activity of Q88I84 have not been established. |
| PP_3195 | gene | OPEN | BIOLOGY + CURATION | — | 1 | No FdeB-family protein has been assayed directly with the R13077 lactone, and PP_3195 has not been tested genetically in KT2440. |
| PP_3197 | gene | OPEN | BIOLOGY + CURATION | — | 1 | PP_3197's exact physiological substrate, ring-cleavage product, and catalytic metal have not been measured in KT2440. |
| PP_3197 | gene | OPEN | BIOLOGY | — | 1 | The electron-transfer relationship between PP_3198/FdeD and the upstream monooxygenase candidate PP_3199/FdeE remains untested in KT2440. |
| PP_3198 | gene | OPEN | BIOLOGY + CURATION | — | 1 | The electron donor and physiological electron acceptor of PP_3198 are unknown. |
| PP_3199 | gene | OPEN | BIOLOGY + CURATION | — | 1 | PP_3199's physiological substrate range, hydroxylation position, and NADH-versus-NADPH preference have not been measured directly in KT2440. |
| PP_3204 | gene | OPEN | BIOLOGY + CURATION | — | 1 | FdeH's biochemical contribution to the shared R13075 step is unknown. |
| PP_3205 | gene | OPEN | BIOLOGY + CURATION | — | 1 | Neither R13078 nor R13079 has been demonstrated for PP_3205 or Hsero_1011. |
| PP_3206 | gene | OPEN | BIOLOGY + CURATION | — | 1 | No FdeJ-family protein has been shown biochemically to catalyze R13076, and PP_3206 has not been tested genetically in KT2440. |
| PP_3298 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | The molecular activity, substrate specificity, and physiological role of PP_3298/Q88HQ5 are unknown. CinA-C/PncC-family domain assignments do not establish that this paralog deamidates NMN. |
| PP_4677 (core function) | core_function | — | — | — | 0 | Direct biochemical activity and the relative in-vivo contributions of Q88DZ1 and Q88GQ4 have not been measured in KT2440. |
| ppgn-1 | gene | OPEN | BIOLOGY | WHOLLY_DARK | 1 | ppgn-1 has no experimental functional characterization in C. elegans: no loss-of-function (mutant or RNAi) phenotype, no localization, and no biochemical assay has been reported for this gene. Every GO annotation is phylogenetic (IBA) or… |
| ppgn-1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The endogenous substrate(s) of ppgn-1 in C. elegans are unidentified. It is unknown whether the worm protease matures a functional homolog of MrpL32 (regulated processing) and/or which misfolded inner-membrane proteins it degrades (quali… |
| ppgn-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The oligomeric composition of the C. elegans m-AAA complex containing ppgn-1 is undetermined: whether ppgn-1 forms a homo-oligomer, assembles into a hetero-oligomer with the AFG3L2-type subunit spg-7, and whether the two worm subunits ar… |
| ppgn-1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | Whether ppgn-1 (as opposed to its paralog spg-7) contributes to any organismal process in C. elegans - the mitochondrial unfolded-protein response, respiration, mitochondrial dynamics, fertility, longevity, or stress/pathogen resistance … |
| PRM5 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular function of PRM5 is entirely unknown. No catalytic activity, ligand/partner binding, transport, or scaffolding role has been demonstrated or can be inferred from sequence, and no informative GO molecular-function term is su… |
| PRM5 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biological process PRM5 participates in is unknown. It is transcriptionally induced by mating pheromone and by the cell wall integrity (Mpk1–Rlm1) pathway, but it has not been shown to function in mating, cell fusion, cell-wall bioge… |
| PRM5 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 0 | PRM5's own subcellular localization has not been directly determined. Its current fungal-type-vacuole and bud-neck component annotations are phylogenetic (IBA) propagations from experimentally localized paralogs (CSI2, YNL058C), not dire… |
| Prokaryotic molybdenum cofactor biosynthesis from GTP to Mo-molybdopterin and optional dinucleotide variants | module | OPEN | BIOLOGY + CURATION | — | 1 | Catalytic MPT adenylyltransferase competence is lineage-dependent among prokaryotic MoaB-family proteins, and sequence-family membership alone does not reliably distinguish active enzymes from MPT-binding noncatalytic proteins. |
| Prokaryotic molybdenum cofactor biosynthesis from GTP to Mo-molybdopterin and optional dinucleotide variants | module | OPEN | BIOLOGY + CURATION | — | 1 | Broad MobA-like/PTHR43777 family assignments do not by themselves resolve whether an uncharacterized protein uses GTP to make MGD, CTP to make MCD, or another nucleotide and acceptor. |
| PSEN1 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | The complete normal in-vivo substrate scope of PSEN1-containing gamma-secretase across tissues is unresolved. APP and Notch are established substrates, but which additional candidate substrates or interactors should be treated as evolved… |
| PSEN1 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 2 | The physiological scope of PSEN1-mediated ER calcium leak/homeostasis is unresolved. It is not yet clear which calcium-homeostasis annotations reflect a conserved normal presenilin function in vivo versus phenotypes of familial-Alzheimer… |
| PSEN1 | gene | OPEN | CURATION | CC_DARK | 1 | The compartment-specific map of endogenous active PSEN1/gamma-secretase is incomplete. Many location annotations refer to membranes compatible with PSEN1 trafficking, but unusual or low-specificity locations still need to be separated fr… |
| Pseudomonad CbrA/CbrB carbon catabolite control | module_node | — | CURATION | — | 0 | The CbrA sensor kinase and the Crc co-repressor have no gene reviews in this repository. |
| Pseudomonad CbrA/CbrB carbon catabolite control | module_node | — | BIOLOGY | — | 0 | The proximal carbon signal that CbrA senses is not established. |
| Pseudomonad CbrA/CbrB carbon catabolite control | module_node | — | ONTOLOGY | — | 0 | The crcZ and crcY decoy small RNAs are mechanistically central but are non-coding, so the module has no participant slot for them. |
| Pseudomonad GacS/GacA lifestyle-control phosphorelay | module_node | — | BIOLOGY | — | 0 | The proximal stimulus sensed by GacS, and the mechanism by which RetS opposes the relay, are not established for Pseudomonas putida KT2440. |
| Pseudomonad GacS/GacA lifestyle-control phosphorelay | module_node | — | CURATION | — | 0 | The post-transcriptional arm that carries the Gac signal in other pseudomonads (RsmA/RsmE repressors and their decoy small RNAs) has no reviewed gene grounding in this repository. |
| Pseudomonad lanthanide-switch PQQ alcohol oxidation | module_node | — | BIOLOGY | — | 0 | The specific physiological cytochrome c electron-transfer partner for PedE and PedH in KT2440 has not been directly demonstrated. |
| Pseudomonad lanthanide-switch PQQ alcohol oxidation | module_node | — | BIOLOGY | — | 0 | The direct lanthanide-sensing input to PedS2 and the mechanism by which PedH protein feeds back on pedE/pedH transcription are unresolved. |
| Pseudomonad lanthanide-switch PQQ alcohol oxidation | module_node | — | BIOLOGY | — | 0 | The range of lanthanides that support PedH catalysis and switch behavior depends on element identity, concentration, and growth conditions. |
| Pseudomonas 2-ketogluconate loop | module_node | — | BIOLOGY | — | 0 | The biochemical reaction of conserved KguE remains unknown. |
| Pseudomonas 2-ketogluconate loop | module_node | — | BIOLOGY + CURATION | — | 0 | Purified Q88HI1 target-protein biochemistry has not directly confirmed the KguD reaction or excluded weak side activities. |
| Pseudomonas 2-ketogluconate loop | module_node | — | CURATION | — | 0 | GO lacks terms specific for 2-dehydro-D-gluconate transport and catabolism. |
| Pseudomonas pyoverdine non-proteinogenic precursor supply | module_node | — | BIOLOGY | — | 0 | Characterized KT2440 pyoverdine contains a cyclic N5-hydroxyornithine rather than an identified N5-acylated hydroxyornithine residue, so it is unresolved whether any KT2440 product depends on PvdY-mediated acetylation. PP_4245 has also n… |
| Pseudomonas pyoverdine non-proteinogenic precursor supply | module_node | — | CURATION | — | 0 | PP_2800 shares a broad diaminobutyrate-transaminase family assignment with PvdH but lies outside the pyoverdine locus. |
| PSY / plastoglobule | annotation | — | — | — | 2 | The sub-plastid compartment in which Arabidopsis PSY is catalytically active (plastoglobule, envelope membrane, or thylakoid-associated membrane) has not been resolved by fractionation of native, untagged protein. |
| PTM1 | gene | OPEN | BIOLOGY | MF_DARK | 3 | The molecular function of PTM1 is unknown: no enzymatic activity, transported substrate, bound ligand, or channel/receptor activity has been demonstrated, and it is not known whether PTM1 acts as a cargo-binding trafficking chaperone (th… |
| PTM1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The physiological cargo(es) or interacting client(s) of PTM1 that would define its trafficking role are unidentified; it is unknown which membrane proteins or lipids, if any, depend on PTM1 for their transport, sorting, or retention with… |
| PTM1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biological process PTM1 participates in, and its loss-of-function phenotype, are undefined. No clear phenotype has been reported for the ptm1Δ single mutant, and it is unknown whether the whole-genome-duplication paralog YHL017W prov… |
| PTTG1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular basis and timing of PTTG1's separase-activating/chaperone function are less resolved than its pseudosubstrate-inhibitory mechanism. |
| PTTG1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The direct requirement for PTTG1 in human spermatogenesis and meiotic cohesion has not been established by the locally accessible evidence. |
| pydX (core function) | core_function | — | — | — | 0 | Direct cofactor analysis has not resolved whether KT2440 PydX binds FAD or the FMN assigned by UniProt. |
| Pyrimidine-intermediate dephosphorylation | module_node | — | BIOLOGY + CURATION | — | 0 | The protein responsible for GO:0043726 activity in Pseudomonas putida KT2440 has not been assigned. |
| Pyrroloquinoline quinone biosynthesis | module_node | OPEN | BIOLOGY + CURATION | — | 1 | The division of labor between multiple PqqD paralogs is not generally established and may differ among organisms. |
| Pyrroloquinoline quinone biosynthesis | module_node | OPEN | BIOLOGY + ONTOLOGY | — | 1 | The native PqqB substrate, product, and placement relative to proteolytic processing remain incompletely defined. |
| Pyrroloquinoline quinone biosynthesis | module_node | OPEN | BIOLOGY + CURATION | — | 3 | The name PqqG covers non-equivalent pathway-associated proteins. The KT2440 candidate PP_0375 is an S9 serine peptidase co-transcribed with pqqCDE, whereas the biochemically characterized PqqF/PqqG complex in Methylorubrum uses an M16B p… |
| Q2U1U6 (core function) | core_function | — | BIOLOGY | MF_DARK | 0 | The catalytic activity and substrate specificity of Q2U1U6 have not been experimentally validated; it is unknown whether the protein acts on chondroitin sulfate, dermatan sulfate, hyaluronic acid, alginate, or another acidic polysaccharide. |
| Q2U1U6 (core function) | core_function | — | BIOLOGY | CC_DARK | 0 | It is unknown whether Q2U1U6 is secreted. Signal peptide prediction and localization have not been performed; at 134 aa the protein is unusually small for a secreted polysaccharide lyase, raising the question of whether it is a functiona… |
| R3HDML | gene | OPEN | BIOLOGY | MF_DARK | 1 | The direct molecular activity, receptor, substrate, and extracellular binding partner of mature R3HDML are unknown. |
| R3HDML | gene | OPEN | BIOLOGY | BP_DARK | 1 | Conservation of the mouse skeletal-muscle developmental and regenerative role in human R3HDML has not been demonstrated. |
| RAB9A / GTPase activity | annotation | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The specific GEF that activates RAB9A on late endosomes and the GAP that inactivates it have not been definitively identified, so how the RAB9A nucleotide switch is spatially and temporally controlled is unresolved. |
| Ratn1 (core function) | core_function | — | BIOLOGY + CURATION | — | 1 | Whether this MUP allergen has any genuine endocrine/metabolic function (as ISS-propagated from MUP metabolic studies) is unresolved and probably spurious for this protein. |
| rde-2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Beyond acting as a passive structural bridge between MUT-7 and MUT-16, it is unknown whether the intrinsically disordered regions of RDE-2/MUT-8 have any additional molecular activity (e.g. RNA binding, condensate nucleation, or alloster… |
| rde-2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The complete set of RDE-2 direct binding partners within the Mutator complex is unresolved. Direct interactions are established only with MUT-7 (CTD-CTD) and MUT-16 (via the RDE-2 N-terminal region); whether RDE-2 directly contacts other… |
| rde-2 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 1 | How RDE-2 mechanistically contributes to the secondary siRNA (22G-RNA) amplification reaction itself is unknown. It is established that rde-2 loss abolishes RdRP-dependent secondary siRNA accumulation, but whether RDE-2's only role is to… |
| Reductive pyrimidine degradation | module_node | — | CURATION | — | 0 | Direct biochemical discrimination of beta-ureidopropionate, allantoate, and N-carbamoyl-L-amino-acid turnover by PSEPK Q88FQ3 is unavailable. |
| Reductive pyrimidine degradation | module_node | — | CURATION | — | 0 | PP_0614/Q88Q81 carries the same dual EC assignment as Q88FQ3 and has not been compared experimentally with it. |
| RELN | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether human reelin has an intrinsic serine peptidase activity remains unresolved. |
| RELN | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The cellular mechanics and cohort scope of RELN-dependent Purkinje-layer formation in humans are not established. |
| RFT1 | gene | NARROWING | BIOLOGY | MF_DARK | 4 | It is not established which molecular activity of RFT1 is the one the protein evolved to perform and that is required for cell viability. The reconstituted M5-DLO scramblase activity may be a moonlighting capacity of a substrate-binding … |
| RFT1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | The identity of the ER protein(s) responsible for the Rft1-independent M5-DLO flippase activity detected in microsomes and in reconstituted vesicles is unknown. |
| Rice momilactone A biosynthesis | module | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The precise native order of C3 and C20 tailoring, and the relative contribution of CYP701A8 versus SDR activity to the C3 ketone, remain unresolved by complete heterologous pathway reconstruction. |
| RidA reactive enamine/imine detoxification | module_node | — | BIOLOGY | — | 0 | The E. coli physiological exposure regimes that activate RidA's separate N-chlorination-dependent holdase function remain unresolved. |
| ROF1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The direct in vivo target genes of Rof1 in S. cerevisiae are undetermined. No genome-wide Rof1 ChIP dataset has been reported (unlike its paralog Mit1); the available data are downstream expression changes from overexpression, not direct… |
| ROF1 | gene | OPEN | BIOLOGY | MF_DARK | 2 | Whether Rof1 functions as a transcriptional activator or repressor of its direct targets in S. cerevisiae is unresolved. GO annotations encode positive regulation (transferred from the C. albicans activator Wor1), yet the budding-yeast p… |
| ROF1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | Rof1 has no penetrant, condition-independent loss-of-function phenotype, and the physiological signal or condition that activates it is unknown. Single-deletion effects on colony morphology are strain-background dependent and conflicting… |
| rosetteless (core function) | core_function | — | — | — | 0 | The structural-constituent molecular function is inferred from the protein's extracellular location and the loss-of-function phenotype; no biochemical activity has been measured. Whether the two C-type lectin-like domains bind carbohydra… |
| RPL36A | gene | OPEN | BIOLOGY | BP_DARK | 1 | The relative incorporation and tissue distribution of RPL36A versus its close paralog RPL36AL in native human ribosomes are unresolved. |
| RPL36A | gene | OPEN | BIOLOGY | CC_DARK | 1 | The HPA endoplasmic-reticulum signal has not been separated from localization of rough-ER-bound translating ribosomes. |
| rrg8 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular function of rrg8 is unknown. No biochemical activity, catalytic residue, or recognizable domain/family match has been identified for the fission-yeast protein; the budding-yeast ortholog carries PF17068/IPR031415 but also l… |
| rrg8 | gene | OPEN | BIOLOGY + ONTOLOGY | RESIDUAL_SUBGAP | 1 | Whether rrg8 is a stable subunit of mitochondrial RNase P, a transient assembly/maturation factor for the enzyme, or acts on tRNA processing indirectly is unresolved. The mechanism by which it promotes 5' pre-tRNA cleavage is not defined. |
| rrg8 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | The direct role of the S. pombe protein itself has not been measured. All functional annotations (mitochondrion, mitochondrial tRNA 5'-end processing) are transferred by orthology from S. cerevisiae; there is no fission-yeast biochemistr… |
| Scgb1a1 (core function) | core_function | — | BIOLOGY | — | 1 | The direct molecular receptor and signal-transduction route by which secreted CC10 enters or signals to T cells to destabilize GATA-3 mRNA and suppress Th2 cytokines is not defined. |
| Scgb1a1 (core function) | core_function | — | BIOLOGY | — | 1 | Whether progesterone/steroid binding is a physiologically relevant function of mouse uteroglobin is doubtful. |
| SCGB1C1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 3 | The direct ligand-binding specificity of human SCGB1C1 is unresolved. GOA now carries odorant binding based on olfactory/Bowman's gland localization and secretoglobin-family inference, but the actual human ligands, binding affinities, an… |
| SCGB1C1 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | The receptor or signaling mechanism behind SCGB1C1 immunomodulation is unknown. Mouse asthma experiments support an anti-inflammatory/Treg-expanding phenotype, and human airway tissue shows cytokine-responsive SCGB1C1 expression, but the… |
| SCGB1C1 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | Human disease-context roles for SCGB1C1 remain mostly expression-level or biomarker-level. SCGB1C1 is altered in chronic rhinosinusitis with nasal polyps, upper-respiratory infection susceptibility studies, ovarian carcinoma expression s… |
| SCP2D1 | gene | OPEN | BIOLOGY + ONTOLOGY | RESIDUAL_SUBGAP | 3 | SCP2D1's exact lipid-binding and transfer biochemistry remains unresolved. Current evidence supports multi-class lipid binding, but binding constants, transfer rates, lipid preferences, membrane-donor/ acceptor requirements, and whether … |
| SCP2D1 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 2 | SCP2D1's direct subcellular localization and site of lipid action remain underdetermined. Cytosolic localization is currently inferred, while peroxisomal localization from SCP2/SCPX cannot be transferred to SCP2D1 and no endogenous SCP2D… |
| SCP2D1 | gene | OPEN | BIOLOGY | BP_DARK | 3 | The cellular and physiological pathway for SCP2D1 remains unknown: siRNA knockdown alters cholesterol staining and LDL uptake, and expression is enriched in testis and reactivated in some cancers, but it is unresolved whether these obser… |
| SDD3 | gene | OPEN | BIOLOGY | MF_DARK | 1 | SDD3 has no experimentally demonstrated molecular function. Its assignment as a zinc metalloendopeptidase rests entirely on the presence of the M16 family fold and the intact HxxEH zincin motif plus a computational zinc-proteome predicti… |
| SDD3 | gene | OPEN | BIOLOGY | BP_DARK | 1 | It is unknown whether SDD3's recovery as an overexpression suppressor of mitochondria-mediated cell death reflects a genuine endogenous role in cytosolic proteostasis / clearance of over-accumulated mitochondrial precursors, or an indire… |
| SDD3 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | Whether SDD3 is a catalytically active zinc metalloendopeptidase, and if so what peptide/protein substrate(s) it cleaves and with what specificity, is unknown; the only evidence for an activity is the presence of the M16 zincin fold and … |
| SDD3 / biological_process | annotation | OPEN | BIOLOGY | BP_DARK | 1 | The normal (loss-of-function) biological process in which SDD3 participates is unknown; no SDD3 deletion phenotype has been reported that would assign it to a specific pathway. |
| sel0 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether sel0 (SPAC20G4.05c) actually possesses AMPylase (protein adenylyltransferase) activity has not been tested in S. pombe; the activity is inferred entirely from orthologs. No in vitro assay or in vivo AMPylation readout has been re… |
| sel0 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The in vivo substrate(s) of sel0 in S. pombe are unknown. It is undetermined which fission-yeast proteins (e.g. redox enzymes such as glutaredoxins, or mitochondrial metabolic enzymes) are AMPylated by sel0. |
| sel0 | gene | OPEN | BIOLOGY | BP_DARK | 1 | It is unknown whether sel0 functions in oxidant detoxification / the oxidative- stress response in S. pombe. The GO cellular oxidant detoxification annotation is a curator inference from orthologs, not a fission-yeast phenotype. |
| selA (core function) | core_function | — | — | — | 0 | No direct biochemical or structural study of Q88QJ8 was found. |
| SERINC1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Direct endogenous human evidence for SERINC1 adaptor and enzyme-activator activity is lacking. |
| SERINC1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The extent of functional redundancy among human SERINC paralogs is unresolved. |
| SERINC1 | gene | OPEN | BIOLOGY | CC_DARK | 1 | Whether endogenous human SERINC1 has a functional plasma-membrane pool is uncertain. |
| SERINC3 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The normal non-viral physiological consequences and regulation of SERINC3 phospholipid scrambling in human plasma and Golgi membranes are unclear. |
| SERINC3 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The functional differences between Q13530-1 and the N-terminally truncated Q13530-2 isoform are unknown. |
| SERINC5 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The molecular mechanism by which virion-incorporated SERINC5 restricts entry remains unresolved. |
| SERINC5 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The physiological regulation and non-viral cellular consequences of SERINC5 scrambling are unknown. |
| SERINC5 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Functional differences among the four human SERINC5 isoforms are not established. |
| SET6 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The protein substrate of SET6 is unknown: no methylation site on any histone or non-histone protein has ever been attributed to SET6, so the specific methyl-acceptor it acts on is undetermined. |
| SET6 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether SET6 actually catalyzes methyl transfer in vitro or in vivo has never been demonstrated; its catalytic competence is inferred solely from conserved active-site residues. |
| SET6 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The biological role and subcellular localization of SET6 are unknown: deletion produces no standalone growth phenotype, and where in the cell SET6 acts has not been measured. |
| SFT2D3 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 3 | The direct molecular activity of human SFT2D3 is unresolved. It is not known whether SFT2D3 directly binds SNAREs, acts through GARP/COG/golgin-associated tethering machinery, regulates SNARE localization indirectly, or has a distinct ca… |
| SFT2D3 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 3 | The endogenous subcellular location and trafficking itinerary of human SFT2D3 remain incompletely mapped. It is unclear which Golgi subcompartment(s), endosomal populations, or stress-induced vesicle intermediates contain active SFT2D3, … |
| SFT2D3 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | The physiological and disease-relevant role of SFT2D3 is unresolved. It is not known which endogenous cargoes, cell types, stress conditions, or disease contexts require SFT2D3 specifically, as opposed to redundant or compensatory activi… |
| she-1 (core function) | core_function | — | BIOLOGY | — | 0 | The direct ubiquitylation substrate(s) presented by SHE-1 to its SCF complex, and the specific Skp1/Cullin partners forming that complex, are undetermined. |
| SIA1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | SIA1's molecular activity is undetermined. Although it has a calcineurin-like metallophosphatase fold and carries a family-level IBA "phosphoprotein phosphatase activity" annotation, no catalytic activity or substrate has ever been demon… |
| SIA1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The mechanism linking SIA1 to glucose activation of Pma1 is unknown - whether SIA1 acts directly on the pump or through an intermediate signalling/lipid step, and which of the "at least two independent mechanisms" of Pma1 glucose activat… |
| SIA1 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | SIA1's direct physical partners and its subcellular localization are unknown. No validated Pma1 physical interaction is curated, and there is no experimentally determined localization despite a predicted N-terminal signal peptide. |
| SIA1 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 2 | The molecular mechanism by which SIA1 promotes glucose activation of Pma1 is unknown: it is not established whether SIA1 acts directly on Pma1 (e.g. as an activator or scaffold) or indirectly (e.g. via a signalling relay, a kinase/phosph… |
| sil1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether Sil1 nucleotide-exchange activity is individually required in S. pombe, or is functionally redundant with the fission-yeast Hsp110/Grp170-type NEF (the Lhs1/Grp170 class), is undetermined; the phenotypic consequence of losing sil… |
| sil1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The in-vivo biological roles and physiological clients of sil1 in S. pombe are unknown; the only pombe phenotypes are scattered drug/stress sensitivities and a cell-fusion morphology defect drawn from genome-wide screens, none mechanisti… |
| sil1 | gene | OPEN | BIOLOGY | CC_DARK | 0 | The membrane topology and ER-retention mechanism of pombe Sil1 are unresolved: the protein is annotated as a single-pass membrane protein from one predicted TM helix, yet SIL1-family orthologs are ER-lumenal, and no canonical HDEL/KDEL r… |
| sil1 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | It has not been shown biochemically that S. pombe Sil1 binds fission-yeast BiP and stimulates its nucleotide (ADP/ATP) exchange; the direct BiP partner and the NEF activity are inferred from orthology, not measured in this species. |
| SLC3A1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The relative physiological contributions of SLC7A9 and SLC7A13 as SLC3A1 partners along distinct human proximal-tubule segments are unresolved. |
| SLC3A1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The physiological function of the large extracellular glycosidase-like domain, beyond structural stabilization and oligomerization, remains incompletely defined. |
| SlyD-assisted nickel insertion for E. coli NiFe hydrogenases | module_node | — | BIOLOGY | — | 0 | The physical handoff route from the SlyD metal-binding tail through HypB to a hydrogenase large subunit has not been resolved. |
| SNO2 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The SNO2-specific in-vivo physiological role and its required condition are undetermined. SNO2 is dispensable for vitamin B6-limited growth, and it is unresolved whether its native function is in pyridoxal 5'-phosphate (B6) biosynthesis,… |
| SNO2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The degree and direction of functional redundancy among the three yeast SNO paralogs (SNO1/SNO2/SNO3) is unresolved: it is unknown whether SNO2 can substitute for SNO1 in B6 biosynthesis, whether SNO2 and SNO3 are interchangeable, and wh… |
| SNO2 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | The glutaminase and PLP-synthase activities of the SNO2 protein have never been directly demonstrated: it is unknown whether purified SNO2, alone or reconstituted with a SNZ subunit, is catalytically active, and its kinetic parameters ar… |
| sod-2 | gene | NARROWING | BIOLOGY | BP_DARK | 4 | How loss of the primary mitochondrial superoxide dismutase SOD-2 extends C. elegans lifespan is only partly resolved. A specific mechanism has been proposed — a RAS-dependent ROS-signalling (RDRS) pathway in which elevated mitochondrial … |
| sod-2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The functional division of labour between the two nearly identical mitochondrial manganese superoxide dismutases, SOD-2 and SOD-3, is undefined. It is unknown why C. elegans maintains both, what distinguishes their substrates or sub-mito… |
| sod-2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether SOD-2's association with respiratory supercomplex I:III:IV reflects only local superoxide scavenging at the site of ROS production, or whether SOD-2 also acts as a direct structural stabilizer of the supercomplex independent of i… |
| sod-3 | gene | OPEN | BIOLOGY | BP_DARK | 2 | The functional division of labour between the two nearly identical mitochondrial manganese superoxide dismutases, SOD-3 and SOD-2, is undefined. It is unknown why C. elegans maintains a low-basal, DAF-16-inducible MnSOD (sod-3) alongside… |
| sod-3 | gene | OPEN | BIOLOGY | BP_DARK | 2 | Whether the DAF-16-driven induction of sod-3 is causally protective (increasing oxidative-stress resistance or extending lifespan) or is primarily a transcriptional readout of DAF-16 activity is unresolved. It is also unknown whether the… |
| sod-3 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | Whether SOD-3's association with the respiratory supercomplex I:III:IV reflects only local superoxide scavenging at the site of ROS production, or whether SOD-3 can also act as a catalysis-independent structural stabilizer of the superco… |
| spa1 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 1 | The subcellular localization of spa1 in S. pombe is undetermined; no microscopy or fractionation has placed the protein in a compartment. |
| spa1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether S. pombe spa1 promotes ubiquitin-independent proteasomal degradation of ODC (the mammalian antizyme mechanism), or only sterically inhibits ODC dimer assembly, has not been tested in fission yeast. |
| spa1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The physiological purpose of the deeply conserved antizyme/frameshift feedback circuit is unknown, given that spa1 is dispensable for growth and its loss produces only condition-dependent polyamine accumulation and stress phenotypes. |
| speA (core function) | core_function | — | — | — | 0 | Q88QC7 has not been biochemically or genetically tested in KT2440. |
| speB (core function) | core_function | — | — | — | 0 | Q88KU3 substrate specificity has not been measured directly. |
| speC (core function) | core_function | — | — | — | 0 | Q88PI6 has not been biochemically or genetically tested in KT2440. |
| SPG21 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 3 | Whether maspardin is a pseudoenzyme is asserted but not demonstrated. No hydrolase, esterase, lipase or any other catalytic assay has ever been performed on maspardin, in twenty-two years. Every statement that it lacks enzymatic activity… |
| SPG21 (core function) | core_function | NARROWING | BIOLOGY | MF_DARK | 2 | What maspardin does to RAB7A once bound is unknown. Binding the GTP-loaded GTPase is established, and the downstream consequences of losing maspardin are well characterised, but the effector output itself - the mechanism by which maspard… |
| SRP40 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 2 | The specific molecular activity of Srp40p and the precise step in ribosome biogenesis at which it acts are unknown. Whether it directly chaperones/assembles snoRNPs, stabilizes box H/ACA snoRNAs, or contributes indirectly (e.g. through i… |
| SRP40 (core function) | core_function | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 1 | The molecular activity that underlies this core function is undefined: whether Srp40p's contribution to ribosome biogenesis is a bona fide RNA/snoRNP-chaperone activity, an assembly/stabilization scaffold role, or an indirect phospho- an… |
| SrSeptin2 (core function) | core_function | — | — | — | 0 | No loss-of-function, biochemical or interaction data exist for SrSeptin2. GTP binding and hydrolysis, filament assembly with other S. rosetta septins, and any requirement for rosette development or cell division are all untested. |
| SrSeptin6 (core function) | core_function | — | — | — | 0 | No loss-of-function, biochemical or interaction data exist for SrSeptin6. Whether it binds or hydrolyses GTP, which septins it pairs with in a filament, and whether it is needed for rosette development are untested. |
| SULT1A1 | gene | — | BIOLOGY + CURATION | BP_DARK | 2 | The site at which the gut-microbial metabolite 4-ethylphenol is sulfated to 4-EPS in vivo, and whether SULT1A1 is the enzyme that does it, are unknown - the attribution rests on in vitro biochemistry with recombinant enzyme. |
| SULT1A1 | gene | NARROWING | BIOLOGY | MF_DARK | 4 | No endogenous metabolite has been shown to depend on SULT1A1 in vivo, and a comparative-evolution test now argues that the original framing of this gap was wrong: the acceptor pocket shows no sign of being tuned to a dedicated endogenous… |
| SULT1A1 (core function) | core_function | — | BIOLOGY | BP_DARK | 2 | It is not established which sulfotransferase carries out the bulk of thyroid hormone sulfation in human liver and kidney in vivo, so SULT1A1's quantitative contribution to thyroid hormone disposal is unknown. |
| SULT1A1 / thyroid hormone metabolic process | annotation | — | BIOLOGY | BP_DARK | 1 | Whether SULT1A1 is the enzyme that actually performs the bulk of thyroid hormone sulfation in vivo is undetermined; its dominance in vitro rests on affinity measurements with recombinant enzyme, not on flux measurements or loss-of-functi… |
| Synaptic vesicle cycle (umbrella) | module | OPEN | BIOLOGY | — | 0 | The molecular steps of synaptic vesicle maturation (how a regenerated vesicle re-acquires its full protein complement and release competence) are poorly defined beyond synaptophysin-assisted VAMP2 sorting, and the function of the abundan… |
| Synaptic vesicle cycle (umbrella) | module | OPEN | BIOLOGY | — | 1 | Whether synapsin-driven liquid-liquid phase separation, rather than actin tethering, is the dominant mechanism maintaining the reserve pool in vivo has not been settled. |
| Synaptic vesicle endocytosis and vesicle regeneration | module | OPEN | BIOLOGY | — | 1 | The relative contribution of direct clathrin-mediated endocytosis versus ultrafast/bulk retrieval followed by endosomal regeneration varies with temperature, stimulation strength and synapse type and is still contested. |
| Synaptic vesicle endocytosis and vesicle regeneration | module | OPEN | CURATION | — | 0 | The actin and formin machinery required for ultrafast endocytosis is not modeled here. |
| Synaptic vesicle endocytosis and vesicle regeneration | module | OPEN | CURATION | — | 0 | Rab5, Rab35 and other endosomal sorting factors acting during vesicle regeneration from the synaptic endosome are not modeled. |
| Synaptic vesicle exocytosis (docking, priming, Ca2+-triggered fusion) | module | OPEN | BIOLOGY | — | 1 | The identity of the Ca2+ sensor(s) for spontaneous release remains debated, so no spontaneous-release variant is asserted alongside the synchronous and asynchronous variants. |
| Synaptic vesicle exocytosis (docking, priming, Ca2+-triggered fusion) | module | OPEN | BIOLOGY | — | 0 | Whether Munc13 acts mainly as a vesicle tether/docking factor, as a syntaxin-1 opener, or as both at a given synapse is still being resolved. |
| Synaptic vesicle exocytosis (docking, priming, Ca2+-triggered fusion) | module | OPEN | CURATION | — | 0 | Bassoon, piccolo and liprin-alpha contribute to active-zone assembly and vesicle recruitment but are not modeled as parts of this module. |
| SYNPR | gene | OPEN | BIOLOGY | MF_DARK | 1 | The direct molecular mechanism by which SYNPR and related tetraspanins determine synaptic-vesicle shape and size is unknown. |
| SYNPR | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 1 | Whether SYNPR has any autonomous ion-channel or solute-channel activity remains unestablished. |
| SYPL1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The direct molecular activity by which SYPL1 cooperates with VAMP3 to produce, shape, sequester, or load cytoplasmic-droplet saccules is unknown. |
| SYPL1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | Whether SYPL1 is functionally required for constitutive transport-vesicle organization in human somatic cells remains unestablished. |
| Tac1 (core function) | core_function | OPEN | BIOLOGY | — | 2 | Whether mature, amidated substance P is actually produced from this precursor in the naked mole rat has never been measured. Every naked mole-rat observation of the peptide is immunohistochemical, so the conserved amidation and dibasic c… |
| Tac1 (core function) | core_function | OPEN | BIOLOGY | — | 2 | The neurokinin A arm of this gene is entirely uncharacterised in Heterocephalus glaber. Neurokinin A has never been detected in this species, no naked mole-rat TACR2 pharmacology exists, and it is unknown whether the visceral peptidergic… |
| tam14 | gene | OPEN | BIOLOGY | BP_DARK | 3 | No biological process has been established for tam14 in S. pombe. Despite its name (altered transcripts in meiosis), no meiotic — or any other — function has been demonstrated: tam14 was excluded from the deletion-phenotyping set in its … |
| tam14 / molecular_function | annotation | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 2 | The molecular function of tam14 in S. pombe is undetermined. Whether it acts, like its RAMP4/SERP1 orthologs, as an accessory subunit of the Sec61 translocon that contacts translocating nascent chains and stabilizes newly synthesized mem… |
| TAS1R1 (core function) | core_function | — | — | — | 1 | Whether Oreotrochilus melanogaster TAS1R1-TAS1R3 actually detects carbohydrates (versus retaining or partially retaining amino-acid/umami sensitivity) has not been directly tested; the carbohydrate-receptor model is extrapolated from Cal… |
| TAS1R3 | gene | — | BIOLOGY | MF_DARK | 1 | No experimental data (expression, receptor pharmacology, or behavior) exist for TAS1R3 in Oreotrochilus melanogaster specifically, or for this exact UniProt accession (A0A7L3N407); functional inference is drawn entirely from a different … |
| TAS1R3 | gene | — | CURATION | MF_DARK | 0 | Whether the deposited fragmentary sequence (Flags: Fragment; non-terminal at both position 1 and 832) captures the complete, functionally critical regions of the receptor - including the full Venus-flytrap domain and the hummingbird-line… |
| TAS2R38 | gene | — | BIOLOGY | MF_DARK | 1 | The complete, native-cell functional consequence of the western-chimpanzee start-codon-loss (ATG->AGG) TAS2R38 allele -- surface trafficking, ligand binding, and downstream Ca2+ signaling in actual taste receptor cells rather than a hete… |
| TAS2R38 | gene | — | BIOLOGY | RESIDUAL_SUBGAP | 1 | The ecologically relevant natural agonist spectrum of chimpanzee TAS2R38 is unresolved; PTC itself is an experimental probe rather than a demonstrated dietary ligand. |
| TAS2R38 | gene | — | BIOLOGY | — | 1 | No experimentally solved structure of TAS2R38 exists. The proposed PTC/PROP binding pocket (residues including N103, F197, W201, F264) rests entirely on homology modeling validated by site-directed mutagenesis and calcium-imaging respons… |
| TAS2R38 | gene | — | BIOLOGY | — | 1 | Whether TAS2R38 itself is directly activated by bacterial quorum-sensing metabolites (e.g. Pseudomonas acyl-homoserine lactones) proposed to drive sinonasal innate-defense signaling is unresolved at the receptor-ligand level; pathway-lev… |
| tax-2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | How the TAX-2 beta subunit mechanistically modulates the channel — lowering cGMP sensitivity ~25-fold and changing divalent-cation block and single-channel behavior relative to the TAX-4 homomer — and whether this tuning is uniform acros… |
| tax-2 | gene | OPEN | BIOLOGY | MF_DARK | 1 | Whether the TAX-2 cyclic-nucleotide-binding domain itself binds cGMP and whether that binding is functional (vs. a modulatory/non-canonical CNBD as in vertebrate CNGB beta subunits) is unknown. |
| tax-2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The endogenous TAX-4:TAX-2 subunit stoichiometry and whether channel composition varies between neuron types or between ciliary subcompartments of a single neuron is inferred, not measured. |
| tax-2 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether TAX-2 has roles independent of TAX-4 — for example partnering other CNG alpha subunits, or non-conducting structural/trafficking roles — is unresolved. |
| tax-4 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The in vivo subunit stoichiometry and arrangement of the native sensory CNG channel (the TAX-4:TAX-2 ratio in the tetramer, and whether it varies between neurons or even between ciliary subcompartments of one neuron) is not established. |
| tax-4 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Which channel form (the ~25-fold more cGMP-sensitive TAX-4 homomer versus the less-sensitive TAX-4/TAX-2 heteromer) operates in which neuron in vivo, and how the TAX-2 beta subunit tunes ligand sensitivity and selectivity in the physiolo… |
| tax-4 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether TAX-4's in vitro cAMP responsiveness is ever used physiologically, and what sets the in vivo cGMP-versus-cAMP ligand tuning of the native channel, is unknown. |
| TBCK (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | What the pseudokinase domain does is entirely unknown. It is now established to be catalytically dead and to bind no nucleotide, which removes the only function ever ascribed to it, and nothing has replaced that function: no ligand, no b… |
| tgt (core function) | core_function | — | — | — | 0 | GO:0008479 formally defines free-queuine insertion, while InterPro2GO IPR004803 and UniRule MF_00168 apply it to bacterial preQ1-inserting Tgt. |
| tgt (core function) | core_function | — | — | — | 0 | No direct biochemical or genetic characterization of Q88PL7 in P. putida was found. |
| THI22 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 2 | Whether THI22 has any catalytic activity in vivo — HMP kinase (EC 2.7.1.49), HMP-P kinase (EC 2.7.4.7), or thiaminase II (EC 3.5.99.2) — is undetermined. The single direct enzymatic test of the family that included THI22 detected no HMP-… |
| THI22 (core function) | core_function | OPEN | BIOLOGY | CC_DARK | 0 | The true subcellular localization of THI22 is unresolved. UniProt annotates it as Secreted based on a predicted N-terminal signal peptide, whereas phylogenetic annotation and the cytosolic biochemistry of the paralogs place the family in… |
| THI22 (core function) | core_function | OPEN | BIOLOGY | BP_DARK | 1 | Why S. cerevisiae retains a third, apparently redundant and enzymatically undemonstrated paralog is unknown. Its selective advantage — conditional/stress-specific function, gene-dosage buffering of thiamine metabolism, or ongoing pseudog… |
| Thiamine diphosphate biosynthesis | module_node | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 1 | In P. putida KT2440, the physiological enzyme for the ThiF-type ThiS C-terminal adenylylation step is unresolved: no dedicated thiF is annotated, and MoeB/PP_0735 is only an uncertain substitute candidate. |
| Three-subunit bacterial urease biogenesis and urea hydrolysis | module | — | BIOLOGY | BP_DARK | 0 | Has urease activity or UreDEFG-dependent metallocenter assembly been measured directly for the PP_2842-PP_2849 locus in Pseudomonas putida KT2440? |
| TIAL1 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The two current human TIAL1 isoforms have not been functionally resolved, particularly the effect of the isoform-2 insertion within RRM1. |
| TIAL1 | gene | OPEN | BIOLOGY | BP_DARK | 1 | TIAL1's independent requirement for stress-granule assembly is unresolved because TIA1 and G3BP-family proteins provide partly redundant nucleation activities. |
| TIAL1 | gene | OPEN | BIOLOGY | CC_DARK | 1 | The physiological relevance of cytolytic-granule localization and nucleolytic activity remains uncertain. |
| TIMMDC1 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 2 | The molecular function of TIMMDC1 is undetermined: it is unresolved whether it possesses genuine protein/membrane-insertase catalytic activity (as its Tim17/Tim22/Tim23 fold might suggest) or acts purely as a membrane scaffold that posit… |
| tin-44 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | The molecular activity of C. elegans TIN-44 has never been directly measured. Its recruitment/tethering of mitochondrial HSP70 (HSP-6), its role as the scaffold that organizes the PAM import motor, and the coupling of mtHsp70 ATPase cycl… |
| tin-44 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The molecular consequences and essentiality of tin-44 loss in C. elegans have not been directly characterized. The only worm loss-of-function data are indirect: tin-44/T09B4.9 RNAi behaves as a mitochondrial-import knockdown that activat… |
| tin-44 / mitochondrial inner membrane | annotation | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The submitochondrial topology of C. elegans TIN-44 is unverified. It is assigned to the mitochondrial inner membrane by ortholog/subcellular-mapping inference, but whether the worm protein is an integral inner-membrane protein, a periphe… |
| TLN (core function) | core_function | — | — | — | 0 | Shown only with a 24-residue synthetic peptide. Whether full-length TLN binds VIN1, whether its vinculin-binding sites are cryptic and force-exposed as in vertebrate talin, and how many functional sites the rod carries are unknown. |
| TLN (core function) | core_function | — | — | — | 0 | None of these activities or the focal adhesion location has been tested for O. pearsei talin; the role of the extra PTB domain is unknown. |
| TMEM106A | gene | OPEN | BIOLOGY | MF_DARK | 0 | The molecular activity of the canonical TMEM106A protein at the plasma membrane is undefined: it is not established whether it acts as a receptor, co-receptor, signaling adaptor, or transporter, and no physiological ligand or validated b… |
| TMEM106A | gene | OPEN | BIOLOGY | BP_DARK | 1 | It is unknown whether the human TMEM106A locus participates in a GSDMD:TMEM106A trans-spliced chimeric mRNA. The chimera, and the out-of-frame C-terminal peptide it contributes, were characterized only in mouse; the existence, regulation… |
| TMEM187 (core function) | core_function | NARROWING | BIOLOGY | MF_DARK | 3 | The molecular activity of TMEM187 is undetermined. Binding to RAB11A is established; what TMEM187 does to RAB11A, or to anything else, is not. Specifically: it has not been shown to inhibit GRAB-catalysed nucleotide exchange in a reconst… |
| TMEM187 (core function) | core_function | OPEN | BIOLOGY | BP_DARK | 1 | Whether TMEM187 has a role outside erythropoiesis is unknown. It is ubiquitously expressed and X-linked, but every functional observation comes from erythroid or erythroid-induced systems, and the mouse lineage has lost the gene entirely… |
| TMEM70 | gene | NARROWING | BIOLOGY + CURATION | MF_DARK | 2 | The structural mechanism by which TMEM70 promotes subunit-c membrane insertion, c-ring nucleation, and handoff to TMEM242 remains unresolved. |
| TMEM70 | gene | OPEN | BIOLOGY + CURATION + ONTOLOGY | BP_DARK | 2 | TMEM70's reported contribution to respiratory-chain complex I assembly or stability remains difficult to distinguish from secondary effects of complex V failure and cristae disruption. |
| TMEM70 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | The basis for tissue-specific severity and variable clinical outcome in TMEM70 deficiency remains incompletely understood. |
| tomm-22 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 2 | The biochemical activity of C. elegans TOMM-22 itself has never been directly measured. Its presequence-binding (cis/trans receptor) function, its chaperone-like activity, and its preprotein substrate-class specificity are all inferred f… |
| tomm-22 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether tomm-22 is essential in C. elegans is unresolved. Only partial-knockdown (RNAi) data exist, and no null/deletion allele has been characterized, so it is unknown whether complete loss of TOMM-22 is lethal (as for TOM22 in mouse) o… |
| tomm-22 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 1 | The existence, expression, and function of the shorter tomm-22 isoform b (O17287-2), which lacks residues 1-94 and therefore essentially the entire cytosolic receptor domain and transmembrane anchor, are uncharacterized. |
| TopAI-YjhQ toxin-antitoxin neutralization | module_node | — | BIOLOGY | — | 0 | The substrate of YjhQ's predicted GNAT-family N-acetyltransferase fold and its relationship to TopAI neutralization are unknown. |
| TreS-Mak-GlgE branched alpha-glucan biosynthesis | module_node | — | ONTOLOGY | — | 0 | GO lacks a substrate-specific molecular-function term for maltokinase activity (EC 2.7.1.175). |
| TreS-Mak-GlgE branched alpha-glucan biosynthesis | module_node | — | ONTOLOGY | — | 0 | GO lacks a substrate-specific molecular-function term for the GlgE alpha-1,4-glucan:maltose-1-phosphate maltosyltransferase reaction (EC 2.4.99.16). |
| treSA (core function) | core_function | — | — | — | 0 | The physiological direction and quantitative contribution of TreSA in native KT2440 trehalose metabolism have not been established. |
| treSB (core function) | core_function | — | — | — | 0 | The TreS reaction has not been biochemically characterized for Q88FN0. |
| treSB (core function) | core_function | — | — | — | 0 | The maltokinase reaction has not been biochemically characterized for Q88FN0. |
| Tricarboxylic acid cycle | module_node | — | BIOLOGY | — | 0 | The physiological division of labor among bacterial paralogs at the aconitase, isocitrate-dehydrogenase, fumarase, and malate-oxidation steps is often condition dependent. |
| Tricarboxylic acid cycle | module_node | — | BIOLOGY | — | 0 | Shared Lpd-family E3 enzymes can serve several lipoyl-dependent complexes, and the physiological E3 partner of a particular bacterial 2-oxoglutarate dehydrogenase may not be established. |
| TRMT6 | gene | OPEN | CURATION + ONTOLOGY | MF_DARK | 2 | TRMT6's molecular function is understood structurally but is not represented in its annotations. Its entire GOA molecular-function coverage is six rows of GO:0005515 protein binding plus one high-throughput GO:0003723 RNA binding, none o… |
| TRMT61A | gene | NARROWING | BIOLOGY | RESIDUAL_SUBGAP | 3 | It is undetermined whether the TRMT6-TRMT61A complex has a genuine, physiologically meaningful mRNA substrate class, or whether cytosolic mRNA m1A is confined to a handful of T-loop-like sites at stoichiometries too low to regulate anyth… |
| ttg2D | gene | OPEN | BIOLOGY | — | 0 | Binding stoichiometry and phospholipid-class preferences have not been measured directly for Q88P91. |
| ttg2E | gene | OPEN | BIOLOGY | — | 0 | The exact effect of KT2440 Ttg2E on MlaFEDB assembly, stability, and MlaF ATPase activity is untested. |
| ttg2E | gene | OPEN | BIOLOGY | — | 0 | Ttg2E has not been individually tested for solvent tolerance or envelope phenotypes in KT2440. |
| Tus-dependent bacterial MnmA tRNA wobble-uridine thiolation | module_node | — | BIOLOGY | — | 0 | Direct biochemical reconstitution of the complete KT2440 IscS-TusA- TusBCD-TusE-MnmA relay was not identified in the initial local evidence. |
| TXNDC16 | gene | OPEN | BIOLOGY + ONTOLOGY | MF_DARK | 2 | It is unresolved whether TXNDC16/ERp90 is a purely non-catalytic PDI-family scaffold/adaptor or whether it performs a CXXC-independent redox activity using conserved noncanonical cysteines. |
| TXNDC16 | gene | OPEN | BIOLOGY | BP_DARK | 2 | The ERAD substrate set and pathway step that depend on TXNDC16 remain unknown. ERp90 is proposed to help ERFAD recruit or deliver substrates to the retrotranslocation machinery, but no endogenous substrates or loss-of-function ERAD defec… |
| TXNDC16 | gene | OPEN | BIOLOGY + CURATION | RESIDUAL_SUBGAP | 3 | The biological significance of TXNDC16 secretion and meningioma-associated autoantibodies is unclear. TXNDC16 is secreted because its ER-retrieval motif is masked, and antibodies can distinguish meningioma sera, but it is not known wheth… |
| Ubiquinone biosynthesis | module_node | — | BIOLOGY + CURATION | — | 0 | Oxygen-independent UbiT/UbiU/UbiV hydroxylation reaches the same ubiquinone product but uses distinct machinery and incompletely resolved chemistry. |
| Ubiquinone biosynthesis | module_node | — | BIOLOGY | — | 0 | Exact reaction order and intermediate nomenclature for the three ring hydroxylations varies across bacterial lineages. |
| Ubiquinone biosynthesis | module_node | — | BIOLOGY + CURATION | — | 0 | UbiB is a conserved kinase-like ATP-dependent accessory factor, but the direct molecular output of bacterial UbiB proteins remains less certain than their pathway requirement. |
| UBP11 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 2 | The physiological substrate(s), ubiquitin-linkage specificity, biological process, and non-redundant in vivo role of UBP11 are unknown. It is established that Ubp11p is a catalytically competent deubiquitinase, but not what it deubiquiti… |
| UMAD1 | gene | OPEN | BIOLOGY + CURATION | MF_DARK | 3 | It is unresolved whether endogenous UMAD1 assembles into a stable human ESCRT-I complex, and if so which TSG101/VPS28/VPS37-containing complex it joins and what molecular role its UMA domain performs. |
| UMAD1 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | The biological process in which UMAD1 acts is unresolved. Cytokinetic abscission is proposed by an uncached 2023 primary study summarized in Falcon deep research, while endosomal sorting, autophagosome closure, membrane repair, and viral… |
| UMAD1 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 3 | The compartment where UMAD1 acts is unresolved. Midbody localization is asserted in the unverified cytokinesis model, while endosomal localization is inferred from ESCRT-I family context; neither compartment is established from locally r… |
| VAM10 | gene | OPEN | BIOLOGY | MF_DARK | 1 | The mechanism of the Sec18p-independent priming step defined by Vam10p is unknown: what change in the vacuolar membrane or its protein/lipid composition Vam10p produces to license subsequent Ypt7p-dependent tethering has not been determi… |
| VAM10 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 0 | Whether Vam10p has orthologs with a conserved function beyond Saccharomyces (in other fungi or in higher eukaryotes) is uncharacterized, so it is unknown whether the Sec18p-independent priming role is a general feature of membrane fusion… |
| VAM10 (core function) | core_function | OPEN | BIOLOGY | MF_DARK | 1 | The molecular activity of Vam10p is undetermined. It is not known whether Vam10p is an enzyme, a lipid- or membrane-binding protein, a protein adaptor/tether, or a regulator that modifies another priming factor; no biochemical activity h… |
| VAM10 (core function) | core_function | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The direct molecular partner(s) of Vam10p are unknown. It is unresolved whether Vam10p acts on the Rab GTPase Ypt7p, on the HOPS tethering complex, on a vacuolar SNARE, or on a membrane lipid to enable the Ypt7p-dependent tethering it is… |
| VIN1 (core function) | core_function | — | — | — | 0 | Activation was shown only with a synthetic talin peptide and heterologous (rabbit muscle) actin. Whether VIN1 is activated by other partners at sponge cell-cell contacts (for example O. pearsei alpha-catenin under tension) is unknown. |
| Viral factory (virus-induced replication microcompartment) | module | OPEN | ONTOLOGY + CURATION | CC_DARK | 2 | No GO term denotes a proteinaceous (non-membrane, non-condensate) viral replication compartment such as the chimallin-bounded phage nucleus, and no term expresses the structural role of its shell subunits. |
| Viral factory (virus-induced replication microcompartment) | module | OPEN | CURATION | CC_DARK | 1 | GO's viral-factory compartment terms are essentially uncurated for the phase-separated factories, even where the scaffold protein and the LLPS mechanism are established. |
| Viral factory (virus-induced replication microcompartment) | module | OPEN | BIOLOGY | MF_DARK | 2 | The viral factor(s) that recruit host mitochondria to the factory periphery, and the mechanism by which the Marseilleviridae virion transiently recruits host nuclear transcription machinery to a cytoplasmic factory, are both unidentified. |
| Viral factory (virus-induced replication microcompartment) | module | OPEN | ONTOLOGY | BP_DARK | 1 | GO has no term for evading a host CRISPR-Cas system, only one for suppressing it, so the best-characterised case of compartmentalisation defeating host immunity cannot be annotated with the mechanism it demonstrates. |
| VOPP1 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 4 | The mechanism connecting vesicle-associated VOPP1 to NF-kappaB-dependent transcription and survival signaling remains unresolved. VOPP1/ECOP can modulate NF-kappaB activity in glioma models, but the direct molecular path from endolysosom… |
| VOPP1 | gene | OPEN | BIOLOGY + CURATION | CC_DARK | 3 | The compartment-specific architecture of VOPP1 scaffolding remains incompletely defined. VOPP1 is clearly vesicular/endolysosomal and binds WWOX through a PPPY-WW interface, but the structural features beyond the PPPY motif, the high-res… |
| VOPP1 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | The extent to which VOPP1's cancer-associated expression and pathway dependencies represent generalizable human disease mechanisms remains open. Glioma, breast cancer, and HCC studies support pro-survival/tumorigenic roles, but the valid… |
| wago-4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | Whether WAGO-4 has any catalytic (slicer/endonuclease) activity is undetermined. It is inferred to be a non-catalytic, siRNA-guided mRNA-binding effector, but no biochemical assay has directly tested WAGO-4 for target cleavage. |
| wago-4 | gene | OPEN | BIOLOGY | BP_DARK | 1 | The direct molecular consequence of WAGO-4 engaging a target mRNA, and how the shared 22G-RNA target space with CSR-1 yields opposite (silencing versus licensing) outcomes, is unresolved. The full endogenous target-mRNA repertoire that W… |
| wago-4 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 2 | The mechanism by which WAGO-4 (with ZNFX-1 in the Z granule) transports and transmits 22G-RNA/mRNA silencing information across generations is unknown, including how material is handed between P granules, Z granules, and Mutator foci. |
| WDR6 | gene | NARROWING | BIOLOGY + CURATION | MF_DARK | 2 | The structural basis by which human WDR6 selects and positions position-34 tRNA substrates for FTSJ1 remains incompletely resolved. |
| WDR6 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 2 | The relationship between WDR6's core tRNA-modification role and its reported LKB1, insulin signaling, lipogenesis, viral restriction, autophagy, and ubiquitin-ligase-associated phenotypes remains unresolved. |
| WDR6 | gene | OPEN | BIOLOGY + CURATION | BP_DARK | 3 | WDR6's tissue-specific and disease-relevant functions remain poorly defined, especially for brain, liver, cancer, and variant-associated phenotypes. |
| Wzy-dependent O-antigen chain-length control | module_node | — | BIOLOGY | — | 0 | FepE's direct effect on an active E. coli K-12 O16 O-antigen pathway should be tested with a restored, non-polar O-antigen background. |
| xbx-1 | gene | OPEN | BIOLOGY | RESIDUAL_SUBGAP | 1 | The specific molecular contribution of the XBX-1 light intermediate chain to dynein-2 function in C. elegans is undetermined: whether it is chiefly required for dynein-2 complex assembly/stability, for coupling the motor to IFT trains as… |
| xbx-1 | gene | OPEN | ONTOLOGY | CC_DARK | 0 | No GO cellular-component term expresses the cytoplasmic dynein-2 (IFT-dynein) complex distinctly from cytoplasmic dynein-1, so XBX-1's actual complex membership can only be annotated with the conflated parent term GO:0005868. |
| YET2 | gene | OPEN | BIOLOGY | MF_DARK | 2 | The specific molecular function (molecular activity) of Yet2p is undetermined. Yet2p has no catalytic domain and SGD annotates its molecular_function as ND. PAINT now places protein translocation chaperone activity at the BAP29/BAP31 anc… |
| YET2 | gene | OPEN | BIOLOGY | MF_DARK | 3 | The physiological cargo and interaction partners of Yet2p are unidentified. Unlike its paralogs Yet1p and Yet3p, which form a stable Yet1p-Yet3p complex that associates with the Sec translocation apparatus, Yet2p is not a stable member o… |
| YET2 | gene | OPEN | BIOLOGY | BP_DARK | 2 | The biological role of Yet2p and its degree of functional redundancy with YET1 and YET3 are unknown. SGD annotates its biological_process as ND. Single yet2 deletion has no strong reported phenotype; the only phenotypic signal is a genet… |
| YFH7 | gene | OPEN | BIOLOGY | BP_DARK | 2 | The physiological phosphoacceptor substrate of YFH7 is unknown. It is established as an ATP-dependent small-molecule kinase, but what small molecule it phosphorylates — and therefore the metabolic pathway and biological process it serves… |
| YrhB ATP-independent chaperone-like refolding | module_node | — | BIOLOGY | — | 0 | YrhB's native K-12 clients and the physiological conditions that require its chaperone-like activity remain unknown. |