View original ARBA rule on UniProt
Aggregated ARBA localization rule that asserts the UniProt SUBCELLULAR LOCATION "Mitochondrion" (SL-0173) for eukaryotic proteins matching any of 1,490 OR-ed condition sets built from CATH FunFam, InterPro and PANTHER signatures. Via the UniProtKB-SubCell -> GO mapping (GO_REF:0000044) the assertion is propagated to GO:0005739 (mitochondrion) with evidence IEA / ECO:0007322. The rule currently annotates 536,854 unreviewed (TrEMBL) proteins and 0 reviewed proteins. It is not a single-family rule but an umbrella aggregating hundreds of independent branch-level classifiers of very uneven quality, ranging from canonical mitochondrial families (MIC60, TOM40, TIM/Tim10-like, cytochrome c oxidase subunits, sideroflexins) to bare single unlabeled FunFams and clade-overfitted singletons.
Condition-set counts describe the sets recorded in this review, which may omit the full rule.
ARBA00004173 is not one rule but an umbrella of 1,490 independent, OR-ed branch-level classifiers that all emit the same UniProt SUBCELLULAR LOCATION value (Mitochondrion, SL-0173), which GO_REF:0000044 converts to GO:0005739 (IEA/ECO:0007322) on 536,854 unreviewed proteins with zero reviewed proteins acting as controls. The rule is genuinely heterogeneous rather than uniformly bad. Many branches are unimpeachable - MIC60 (CS15), TOM40 (CS74), Tim10-like translocase subunits (CS23), mitochondrially encoded cytochrome b (CS1), cytochrome c oxidase subunits, sideroflexins (CS38) - and for these GO:0005739 is correct, if often underspecified relative to available submitochondrial child terms. The GO curator complaint (geneontology/go-annotation#6412, @hattrill, about Drosophila ScpX / Q9VJ43) exposes a specific and structural defect rather than a one-off mistake. The branch whose signature pair matches Q9VJ43's architecture is CS779 (FunFam 3.30.1050.10:FF:000001 AND FunFam 3.40.47.10:FF:000016 AND NOT Bacteria/Archaea/Viruses), i.e. it requires the N-terminal thiolase domain in addition to the C-terminal SCP2 domain. But in the mouse orthologue P32020 the mitochondrion assertion is scoped by UniProt to "Isoform SCP2" (P32020-2), the short alternative-initiation product that LACKS the thiolase domain, while the comment scoped to "Isoform SCPx" (P32020-1, the full-length architecture CS779 actually detects) lists Peroxisome only. ARBA has evidently learned the SUBCELLULAR LOCATION comment while discarding its `molecule:` (isoform) qualifier, so the branch selects exactly the isoform that is not annotated mitochondrial. The curator's diagnosis ("only the short isoform P32020_2 is potentially mitochondrial") is correct and, on the UniProt record, even understated. The same SCPx architecture simultaneously fires ARBA00004496 (Cytoplasm; CS2894 is the identical FunFam pair) and ARBA00004275 (Peroxisome; CS80 is 3.40.47.10:FF:000016 alone), so the three sibling location rules jointly reproduce the union of the two isoforms' recorded locations, of which only Peroxisome is right for SCPx. How far this generalizes is not established here: 139/1,490 (9.3%) of this rule's condition sets have a signature set that also appears verbatim in the Cytoplasm rule and 19/1,490 (1.3%) in the Peroxisome rule (3 in both), but co-annotation to mitochondrion plus cytoplasm or peroxisome is routine and often correct (fumarase, aconitase, several aminoacyl-tRNA synthetases, beta-oxidation enzymes), so these counts are an UPPER BOUND on candidate sets for per-set triage, not by themselves evidence of collapse. Distinguishing genuine dual localization from isoform collapse requires inspecting each set - or a baseline measuring how often reviewed proteins matching those signatures legitimately carry both SL values - and neither was done. The isoform-collapse mechanism itself is verified for exactly one orthologue, mouse P32020; human P22307 and rat P11915 were not checked, and ARBA's actual training provenance for CS779 was not established. Independently of scale, the literature actively argues against mitochondrial residence for this family: Li, Fan & Papadopoulos (PMID:26901662) showed by live-cell confocal imaging that the N-terminal presequence of SCPX/SCP2 is not sufficient to direct the proteins to mitochondria, and that PTS1-mediated peroxisomal targeting dominates. Structurally the rule is far outside any parsimony envelope: 693 sets (46.5%) are a single FunFam plus taxon (240 with no resolved label at all), 1,303 (87%) have no positive taxon condition beyond NOT(Bacteria/Archaea/Viruses), only 422 (28%) contain any signature whose label mentions "mitochondri*" (a weak proxy), and of the 885 distinct InterPro entries used, 493 have some InterPro2GO mapping but only 35 are mapped to GO:0005739 by InterPro curators. That last figure is a weak proxy too and is NOT evidence that InterPro curators rejected a mitochondrial location: InterPro2GO maps a term only where it holds for every match, its CC coverage is deliberately sparse, and - decisively - this rule's condition sets are conjunctive, so for the 131 InterPro+InterPro+PANTHER, 99 InterPro x3, 99 InterPro+PANTHER and 67 InterPro x2 sets no individual entry need imply mitochondrion for the set to. Only the 81 single-InterPro sets permit a like-for-like comparison, and that restricted statistic was not computed. Recommended action is MODIFY rather than DEPRECATE: the biologically sound branches are numerous and valuable, and wholesale retirement would lose a large amount of correct annotation. The deeper fix is SPLIT into per-family rules, mirroring the falcon report's framing that the rule should survive only "as a container for branch-level classifiers". Caveats on this review: `just analyze-rule ARBA00004173` refuses to run on rules with more than 12 condition sets, so no pairwise overlap statistics, heatmap or `entries` view could be generated, and `sync-rule-review-single` / `render-rule` are not runnable. Only one deep-research provider succeeded (falcon); the perplexity run failed with HTTP 401 (quota exhausted). Twelve illustrative condition sets are enumerated above with their true 1-based numbers; the other 1,478 have not been individually adjudicated.
MODIFY, not DEPRECATE. Unlike a rule that is wrong throughout, ARBA00004173 contains a large core of correct branches keyed on whole-protein mitochondrial families (MIC60, TOM40, Tim chaperones, COX subunits, sideroflexins, MT-encoded OXPHOS subunits) for which GO:0005739 is exactly the right assertion; deleting the rule would discard correct annotation on a large fraction of 536,854 proteins. The defect the GO curators reported is specific, mechanistically identifiable, and fixable: ARBA is learning UniProt SUBCELLULAR LOCATION comments without honouring their `molecule:` (isoform) scoping, so an architecture-specific signature (thiolase + SCP2 FunFam pair, CS779) inherits a location that UniProt records only for a different, domain-deficient isoform (P32020-2). Because the failure is a property of the training procedure rather than of one hand-written branch, it warrants a targeted engineering fix plus branch pruning rather than either blanket acceptance or blanket removal. Its prevalence is unquantified: 139 of this rule's condition sets share a signature set with the Cytoplasm rule ARBA00004496 and 19 with the Peroxisome rule ARBA00004275, but genuine dual localization produces the same signal, so those counts bound the triage list from above rather than counting defects, and the mechanism is confirmed only for mouse P32020. A secondary, independent problem is the very large tail of low-information branches (693 single-FunFam sets, 240 unlabeled) and 140 singleton positive taxon clades that look like training-set residue. If UniProt is unwilling to make ARBA isoform-aware, the fallback should be SPLIT into per-family rules so that each branch can be accepted, audited or retired on its own evidence.
Sound. Mitochondrially encoded cytochrome b (MT-CYB and orthologues) is a bona fide mitochondrial inner-membrane protein, so GO:0005739 is correct (arguably underspecified relative to mitochondrial respiratory chain complex III / inner membrane). I specifically checked the plant chloroplast cytochrome b6f false-positive risk and it does not materialise: Arabidopsis cytochrome b6 (P56773) carries IPR005797 (N-terminal), not IPR005798, and plant petD (e.g. P56774, P05643, Q332U6) carries IPR005798 but not IPR027387, so the two-InterPro conjunction excludes the plastid subunits. This is an example of the rule's good branches.
Biologically correct target (COX2 is mitochondrially encoded and resides in the mitochondrial inner membrane) but the positive taxon condition is an artefact: COX2 is pan-eukaryotic, yet this branch is confined to Euarchontoglires, and the near-identical CS13 (IPR036257 + IPR045187) is confined to Laurasiatheria. This is a recall-losing, training-set-shaped clade restriction rather than a biological one; the two branches should be merged and generalised.
Sound single-signature branch. IPR019133 is a whole-protein family (MICOS/mitofilin MIC60) that is definitionally mitochondrial inner-membrane, so a single InterPro family plus the prokaryote/virus exclusion is acceptable here. This is exactly the case the falcon report says is permissible for single-InterPro branches, and it contrasts sharply with the bare single-FunFam branches (CS608, CS812) below.
Sound but internally redundant. The small Tim chaperones are intermembrane space proteins, so GO:0005739 is correct. However IPR004217 (domain), IPR035427 (homologous superfamily of that same domain) and IPR050673 (family) all describe the same sequence region; the conjunction adds no discriminating power over IPR050673 alone. This shape (nested domain/superfamily/family triples) recurs throughout the rule and is the main driver of the SIGNIFICANT condition-overlap assessment.
The falcon deep-research report's flagship positive example: IPR004686 is the sideroflexin (SFXN) family, whose members are multi-pass mitochondrial inner-membrane transporters. GO:0005739 is well supported; the report argues mitochondrial inner membrane would be more informative for this branch. Retain, and consider propagating a submitochondrial child term.
Sound. TOM40 is the mitochondrial outer-membrane import channel. Here the nesting is defensible because IPR023614 is a promiscuous beta-barrel superfamily and IPR037930 supplies the specificity; the conjunction usefully excludes VDACs from the generic porin superfamily hit. Retain.
Included for contrast with the issue #6412 complaint. This is the OTHER SCP2-domain-containing branch in the rule - it targets HSDL2 (SDR + SCP2 domain), not the SCPx/thiolase architecture. Q9VJ43 does NOT match it (no SDR signature). It should therefore not be confused with the branch that actually fires on the Drosophila protein; it is CS779, not this set, that produces the reported false positive.
A thiolase branch pinned to a specific PANTHER subfamily (PTHR18919:SF153). Q9VJ43 is assigned to PTHR42870:SF1 (NON-SPECIFIC LIPID-TRANSFER PROTEIN-LIKE 2), so this set does not match it. Included as a positive illustration of the falcon report's point that a narrow PANTHER subfamily condition is a much safer localization proxy than a bare structural superfamily/FunFam, because paralogues within a thiolase-like fold differ in targeting (peroxisomal vs mitochondrial vs cytosolic).
Worst-case shape, included as a representative of the unlabeled single-FunFam class. CATH 2.130.10.10 is a beta-propeller superfamily - one of the most promiscuous folds in the proteome, occurring in nuclear, cytosolic, membrane-trafficking and mitochondrial proteins alike. A single unlabeled FunFam from it, conjoined only with NOT(Bacteria/Archaea/Viruses), provides no localization signal whatsoever. Branches of this shape should be dropped unless individually benchmarked against reviewed entries.
THE DEFECTIVE BRANCH underlying geneontology/go-annotation#6412. This is the condition set whose signature pair matches the architecture of Drosophila ScpX (Q9VJ43, 544 aa): an N-terminal thiolase domain (CATH 3.40.47.10, IPR020616/IPR055140/IPR016039) plus a C-terminal SCP2 sterol-binding domain (CATH 3.30.1050.10, IPR003033/IPR036527). Exhaustive scanning of all 1,490 condition sets shows only CS779 and CS812 could match Q9VJ43's signature complement; the InterPro/PANTHER SCP2 sets (CS249, CS303) cannot. (I could not query CATH FunFam assignments for Q9VJ43 directly, so this is an architecture-level match, not a verified FunFam hit.) The defect: the mitochondrial evidence for this family comes exclusively from an ISOFORM-SCOPED UniProt annotation. In mouse SCP2_MOUSE (P32020), ALTERNATIVE PRODUCTS records alternative initiation with two isoforms; the SUBCELLULAR LOCATION comment scoped to "Isoform SCPx" (P32020-1, the full-length thiolase+SCP2 protein that this FunFam pair detects) lists Peroxisome ONLY (ECO:0000269, PMID:26901662), whereas the comment scoped to "Isoform SCP2" (P32020-2, the short alternative-initiation product that LACKS the thiolase domain) lists Cytoplasm, Peroxisome, Endoplasmic reticulum and Mitochondrion (ECO:0000269, PMID:11003606 and PMID:26901662). ARBA has learned the SUBCELLULAR LOCATION comment while discarding its `molecule:` (isoform) qualifier, so it requires the thiolase FunFam - i.e. selects precisely the isoform that is NOT annotated mitochondrial. The same collapse is visible across sibling rules: the identical FunFam pair is CS2894 of ARBA00004496 (Cytoplasm), and 3.40.47.10:FF:000016 alone is CS80 of ARBA00004275 (Peroxisome), so this one architecture triggers three location rules and reproduces the union of the two isoforms' locations. Only the peroxisome call is consistent with what UniProt records for isoform SCPx. RETIRE or repair this branch (and CS2894 of ARBA00004496).
The second (and only other) set that could match Q9VJ43. A single, entirely UNLABELED FunFam from the thiolase CATH superfamily 3.40.47.10 plus the prokaryote/virus exclusion. Thiolase-fold proteins are distributed across mitochondria, peroxisomes and cytosol, so a bare FunFam from this superfamily cannot discriminate compartment. Representative of the 693 single-FunFam branches (46.5% of the rule), 240 of which carry no resolved label at all.
Representative clade-overfitting artefact. The FunFam label identifies ACAT1, the mitochondrial matrix acetoacetyl-CoA thiolase - a genuinely pan-metazoan (indeed pan-eukaryotic) mitochondrial enzyme - yet the branch is restricted to Anura (frogs). 187 of 1,490 sets carry a positive taxon condition and they use 140 distinct clades, each appearing only once or twice (Anura, Pongo, Bos, Homo, Mus, Kluyveromyces, Oryza, Camelineae, "Aspergillus subgen. Circumdati", ...). These read as training-set clade artefacts rather than biology: they neither add precision nor reflect the taxonomic distribution of the family, and they silently sacrifice recall.
1,490 OR-ed condition sets, i.e. ~124x the 12-condition-set threshold above which the project's own tooling refuses to analyse a rule. The complexity is not merely large but poorly structured: 693 sets (46.5%) are a single FunFam plus taxon, 240 of those FunFams have no resolved label at all; 180 sets are two FunFams, 131 are InterPro+InterPro+PANTHER, 102 are three FunFams, 81 a single InterPro, 19 a single PANTHER. Condition-type usage is taxon 1,490, FunFam 1,359, InterPro 885, PANTHER 287. All 1,490 signature sets are distinct (no exact duplicates), so the complexity is not literal duplication - it is the absence of any shared mechanistic basis: the sets have nothing in common except emitting the same location string. Nested InterPro triples (domain + homologous superfamily + family for the same region, e.g. CS23) add conditions without adding discrimination. A rule of this shape cannot be reviewed, benchmarked or maintained as a unit, which is why the deeper recommendation is to split it into per-family rules.
Literature support is bimodal, and a single enum cannot express that; MODERATE is chosen as the rule-level summary. For a substantial minority of branches the support is effectively STRONG: MIC60, TOM40, the small Tim chaperones, mitochondrially encoded cytochrome b and cytochrome c oxidase subunits, and sideroflexins are textbook mitochondrial proteins with abundant experimental localization evidence, and the falcon report singles out the sideroflexin branch (CS38/IPR004686) as well supported. For the branch the GO curator complained about, support is CONTRADICTED: Li, Fan & Papadopoulos (PMID:26901662) tested the putative N-terminal mitochondrial presequence of SCPX/SCP2 directly by live-cell confocal imaging of fluorescent fusions and concluded it is not sufficient to localize either protein to mitochondria, while C-terminal PTS1-mediated peroxisomal targeting is. The only primary evidence for mitochondrial SCP2 is Starodub et al. (PMID:11003606), an immunofluorescence study of the SHORT SCP-2 protein in L-cell fibroblasts that ranks mitochondria third behind peroxisomes and ER - and UniProt correctly scopes that evidence to isoform P32020-2, not to the SCPx architecture that CS779 detects. For the very large tail of unlabeled single-FunFam branches there is no identifiable literature at all, because the branches cannot even be resolved to a named family. The falcon report additionally warns that rules trained on noisy source annotations reinforce systematic errors, which is precisely what the isoform-collapse defect demonstrates.
Quantitative pairwise overlap could not be computed because `just analyze-rule` refuses to run on rules with >12 condition sets, so `pairwise_overlap` and `entries` are empty. Qualitative and cross-rule evidence nonetheless makes SIGNIFICANT the right call, on three distinct axes. (1) Within-set redundancy: the recurrent InterPro triple shape (domain + its homologous superfamily + the corresponding family, 99 sets of shape InterPro x3, e.g. CS23 = IPR004217 + IPR035427 + IPR050673) conjoins nested annotations of the same sequence region, which cannot increase specificity. (2) Between-set overlap within the rule: 693 single-FunFam sets drawn from broad CATH superfamilies will match overlapping protein sets, and multi-FunFam sets built from the same superfamily (3.40.47.10 appears in CS779, CS812, CS1124 among others) partially subsume one another. (3) Cross-rule overlap, which is the most consequential: 139/1,490 (9.3%) of this rule's condition sets have a signature set that appears identically in the Cytoplasm rule ARBA00004496, 19/1,490 (1.3%) in the Peroxisome rule ARBA00004275, and 3 in both. These compartments are not mutually exclusive - mitochondrion/cytoplasm and mitochondrion/peroxisome co-annotation is routine and frequently correct (fumarase, aconitase, several aminoacyl-tRNA synthetases, beta-oxidation enzymes), and the falcon report makes the same point: "For dual-localized families, GO:0005739 should coexist with the other supported component rather than suppress it." The 139 + 19 counts are therefore an upper bound on the sets that warrant per-set triage, not a count of collapsed antecedents; separating true dual localization from isoform collapse requires inspecting each set, which this review did not do. What is demonstrated is the single worked example CS779, where the shared signature requires the thiolase FunFam that isoform P32020-2 lacks: the same FunFam pair is CS2894 of ARBA00004496, and its thiolase half alone is CS80 of ARBA00004275. Separately, of the 885 distinct InterPro entries used by this rule, 493 already carry some InterPro2GO mapping but only 35 are mapped to GO:0005739 by InterPro curators. This is an argument from silence and should not be read as InterPro curators declining a mitochondrial claim: InterPro2GO maps a term only where it holds for all matches, CC coverage there is sparse by design, and this rule's condition sets are conjunctive, so in the 131 InterPro+InterPro+PANTHER, 99 InterPro x3, 99 InterPro+PANTHER and 67 InterPro x2 sets no single entry need imply mitochondrion for the set to. The comparison is like-for-like only in the 81 single-InterPro sets, and that restricted count was not computed.
GO:0005739 (mitochondrion) is the right granularity for a rule whose source assertion is the UniProt subcellular-location keyword Mitochondrion (SL-0173): for every true positive it is a correct, conservative cellular-component term, and it is the term GO_REF:0000044 legitimately produces from that keyword. The aspect and branch are right (cellular component, not molecular function or biological process), so it is not MISMATCHED, and it is certainly not TOO_NARROW. The honest qualifier is that it is frequently UNDERSPECIFIED rather than wrong: many branches identify families whose submitochondrial compartment is well established (inner membrane for sideroflexins and OXPHOS subunits, outer membrane for TOM40, intermembrane space for the Tim chaperones) and could support a child term in addition to the parent. I have deliberately not scored this TOO_BROAD, because the false positives this rule generates - Q9VJ43 being the reported case - are not failures of term granularity at all: no mitochondrial child or parent term would be correct there. Fixing them requires fixing the antecedent (isoform scoping, branch pruning), not the consequent. Scoring TOO_BROAD would misdirect the fix.
The dominant taxonomic condition is NOT(Bacteria/Archaea/Viruses), present as the ONLY taxon constraint in 1,303/1,490 sets (87%). This is a coarse "eukaryote-ish" filter and carries almost no organelle information: it does not distinguish mitochondria from cytosol, nucleus, ER, Golgi, peroxisome or - in plants and algae - plastid, and it is largely redundant with signatures that are already eukaryote-restricted. Combined with the 693 bare single-FunFam branches, this is the principal false-positive generator, and it is exactly how the Drosophila ScpX case arises: CS779's taxonomic condition does nothing to prevent a peroxisomal/cytosolic lipid-transfer protein from being called mitochondrial. A separate, opposite artefact coexists with this over-breadth and is worth recording even though the enum can only carry one value: the 187 sets that do have a positive taxon condition use 140 distinct clades, each occurring only once or twice (Anura, Pongo, Bos, Homo, Mus, Kluyveromyces, Oryza, Camelineae, "Aspergillus subgen. Circumdati", ...). These are TOO_NARROW in effect and read as training-set residue rather than biology - CS1124 confines the FunFam labelled "acetyl-CoA acetyltransferase, mitochondrial" (ACAT1), a pan-metazoan mitochondrial matrix thiolase, to frogs; CS9 and CS13 split cytochrome c oxidase subunit II between Euarchontoglires and Laurasiatheria. They sacrifice recall without buying precision. The rule therefore manages to be simultaneously too broad where it matters (the 87% with no positive constraint) and arbitrarily too narrow where it does constrain.
The rule is an aggregated umbrella of 1,490 independent branch-level classifiers and should be audited branch-by-branch rather than accepted or rejected wholesale.
The report's final verdict is that the rule should survive only as a container for branch-level classifiers, with generic-domain and organelle-confounded branches removed.
Isoform choice is explicitly listed as a mechanism by which a structural-domain signature can fail to predict localization - the exact failure mode reported in go-annotation issue
Localization is a property of the complete protein, not of one structural domain, so a CATH FunFam match is a weak localization proxy.
Single-signature branches are acceptable only when the signature is a mitochondria-specific whole-protein family, and unsafe when it is a generic domain - the basis for pruning the 693 bare single-FunFam sets.
The sideroflexin branch (CS38 / IPR004686) is a well-supported positive example for GO:0005739.
GO:0005739 is an appropriate cellular-component term when mitochondrial residence holds, but is often underspecified relative to submitochondrial child terms.
The NOT(Bacteria/Archaea/Viruses) filter provides essentially no organelle specificity within eukaryotes.
Positive lineage restrictions can be overfitted to sparse reviewed training examples - consistent with the 140 singleton clades observed here.
Rules trained on noisy source annotations reinforce systematic errors - the general form of the isoform-collapse defect documented here.
Branches without reviewed positive exemplars should be flagged as speculative rather than merged invisibly into a high-volume rule.
Isoform-specific localization should be documented rather than collapsed, where the annotation model permits it.
Live-cell confocal imaging of fluorescent SCPX and SCP2 fusions showed that the C-terminal PTS1 signal drives peroxisomal targeting, while the putative N-terminal mitochondrial presequence is not sufficient to localize either protein to mitochondria. This is direct evidence against the mitochondrial assertion that ARBA00004173 CS779 makes for the SCPx thiolase+SCP2 architecture.
The Scp2 gene uses two transcription initiation sites to produce the 58 kDa SCPX (thiolase + SCP2 domain) and the 15 kDa pro-SCP2 (SCP2 domain only); the two products differ in domain content, which is why an isoform-scoped location cannot be transferred by a thiolase-requiring signature.
Indirect immunofluorescence and confocal microscopy of L-cell fibroblasts overexpressing the short SCP-2 protein ranked its distribution peroxisomes > endoplasmic reticulum > mitochondria > lysosomes. This is the primary source of the mitochondrial claim, and it concerns the short SCP2 product (UniProt isoform P32020-2), not the full-length SCPx architecture that ARBA00004173 CS779 requires.
A GO curator reported that ARBA00004173 assigns a mitochondrial location to Drosophila melanogaster ScpX (Q9VJ43), and correctly diagnosed that in the mouse orthologue P32020 only the short isoform is potentially mitochondrial, with no evidence that D. melanogaster has an equivalent short isoform.
The rule has 1,490 OR-ed condition sets and exceeds the project's analysis threshold of 12, so `just analyze-rule ARBA00004173` refuses to run and no pairwise overlap statistics, heatmap or entries view are available.
All structural counts quoted in this review (condition-set shapes, taxon-condition counts, InterPro2GO redundancy, and the signature-set overlap with the sibling location rules ARBA00004496 and ARBA00004275) are regenerated by `uv run python rules/arba/ARBA00004173/ARBA00004173-stats.py`.
The rule's single consequent is the UniProt SUBCELLULAR LOCATION comment with value "Mitochondrion" (SL-0173), which GO_REF:0000044 maps to GO:0005739 with evidence IEA / ECO:0007322. Statistics are 0 reviewed and 536,854 unreviewed proteins; created 2020-05-12, modified 2025-12-14.
Condition-type usage across the 1,490 sets is taxon 1,490, FunFam 1,359, InterPro 885, PANTHER 287. Set shapes are 693 single FunFam (46.5%), 180 two FunFams, 131 InterPro+InterPro+PANTHER, 102 three FunFams, 99 InterPro+PANTHER, 99 three InterPro, 81 single InterPro, 67 two InterPro, 19 single PANTHER. All 1,490 signature sets are distinct.
1,303/1,490 sets (87%) have no positive taxon restriction, only NOT(Bacteria/Archaea/Viruses). The remaining 187 use 140 distinct positive clades, each appearing once or twice. Only 422/1,490 (28%) contain at least one signature whose resolved label mentions "mitochondri*".
Of the 885 distinct InterPro entries used by the rule, 493 have some InterPro2GO mapping but only 35 are mapped to GO:0005739 by InterPro2GO, so ~96% of the rule's InterPro conditions assert a mitochondrial location that InterPro curators did not assert.
Only 35 of the 885 InterPro entries used as conditions in ARBA00004173 are mapped to GO:0005739 by InterPro2GO, despite 493 of them having at least one InterPro2GO mapping.
id: ARBA00004173
description: >-
Aggregated ARBA localization rule that asserts the UniProt SUBCELLULAR LOCATION
"Mitochondrion" (SL-0173) for eukaryotic proteins matching any of 1,490 OR-ed
condition sets built from CATH FunFam, InterPro and PANTHER signatures. Via the
UniProtKB-SubCell -> GO mapping (GO_REF:0000044) the assertion is propagated to
GO:0005739 (mitochondrion) with evidence IEA / ECO:0007322. The rule currently
annotates 536,854 unreviewed (TrEMBL) proteins and 0 reviewed proteins. It is not
a single-family rule but an umbrella aggregating hundreds of independent
branch-level classifiers of very uneven quality, ranging from canonical
mitochondrial families (MIC60, TOM40, TIM/Tim10-like, cytochrome c oxidase
subunits, sideroflexins) to bare single unlabeled FunFams and clade-overfitted
singletons.
status: COMPLETE
rule_type: ARBA
rule:
rule_id: ARBA00004173
# 1490 condition sets total; 12 illustrative sets enumerated below with their
# true 1-based `number` from rules/arba/ARBA00004173/ARBA00004173.enriched.json.
# The full set cannot be enumerated here and `just analyze-rule` refuses to run
# on rules with >12 condition sets, so pairwise_overlap and entries stay empty.
condition_sets:
- number: 1
conditions:
- condition_type: INTERPRO
value: IPR005798
curie: InterPro:IPR005798
label: Cytochrome b/b6, C-terminal
interpro_type: DOMAIN
- condition_type: INTERPRO
value: IPR027387
curie: InterPro:IPR027387
label: Cytochrome b/b6-like domain superfamily
interpro_type: HOMOLOGOUS_SUPERFAMILY
- condition_type: TAXON
value: Eukaryota
curie: NCBITaxon:2759
label: Eukaryota
notes: >-
Sound. Mitochondrially encoded cytochrome b (MT-CYB and orthologues) is a
bona fide mitochondrial inner-membrane protein, so GO:0005739 is correct
(arguably underspecified relative to mitochondrial respiratory chain complex
III / inner membrane). I specifically checked the plant chloroplast
cytochrome b6f false-positive risk and it does not materialise: Arabidopsis
cytochrome b6 (P56773) carries IPR005797 (N-terminal), not IPR005798, and
plant petD (e.g. P56774, P05643, Q332U6) carries IPR005798 but not
IPR027387, so the two-InterPro conjunction excludes the plastid subunits.
This is an example of the rule's good branches.
- number: 9
conditions:
- condition_type: INTERPRO
value: IPR001505
curie: InterPro:IPR001505
label: Copper centre Cu(A)
interpro_type: BINDING_SITE
- condition_type: INTERPRO
value: IPR002429
curie: InterPro:IPR002429
label: Cytochrome c oxidase subunit II-like C-terminal
interpro_type: DOMAIN
- condition_type: TAXON
value: Euarchontoglires
curie: NCBITaxon:314146
label: Euarchontoglires
notes: >-
Biologically correct target (COX2 is mitochondrially encoded and resides in
the mitochondrial inner membrane) but the positive taxon condition is an
artefact: COX2 is pan-eukaryotic, yet this branch is confined to
Euarchontoglires, and the near-identical CS13 (IPR036257 + IPR045187) is
confined to Laurasiatheria. This is a recall-losing, training-set-shaped
clade restriction rather than a biological one; the two branches should be
merged and generalised.
- number: 15
conditions:
- condition_type: INTERPRO
value: IPR019133
curie: InterPro:IPR019133
label: MICOS complex subunit MIC60
interpro_type: FAMILY
- condition_type: TAXON
value: Bacteria
curie: NCBITaxon:2
label: Bacteria
negated: true
- condition_type: TAXON
value: Archaea
curie: NCBITaxon:2157
label: Archaea
negated: true
- condition_type: TAXON
value: Viruses
curie: NCBITaxon:10239
label: Viruses
negated: true
notes: >-
Sound single-signature branch. IPR019133 is a whole-protein family
(MICOS/mitofilin MIC60) that is definitionally mitochondrial inner-membrane,
so a single InterPro family plus the prokaryote/virus exclusion is
acceptable here. This is exactly the case the falcon report says is
permissible for single-InterPro branches, and it contrasts sharply with the
bare single-FunFam branches (CS608, CS812) below.
- number: 23
conditions:
- condition_type: INTERPRO
value: IPR004217
curie: InterPro:IPR004217
label: Tim10-like
interpro_type: DOMAIN
- condition_type: INTERPRO
value: IPR035427
curie: InterPro:IPR035427
label: Tim10-like domain superfamily
interpro_type: HOMOLOGOUS_SUPERFAMILY
- condition_type: INTERPRO
value: IPR050673
curie: InterPro:IPR050673
label: Mitochondrial import inner membrane translocase subunit
interpro_type: FAMILY
- condition_type: TAXON
value: Bacteria
curie: NCBITaxon:2
label: Bacteria
negated: true
- condition_type: TAXON
value: Archaea
curie: NCBITaxon:2157
label: Archaea
negated: true
- condition_type: TAXON
value: Viruses
curie: NCBITaxon:10239
label: Viruses
negated: true
notes: >-
Sound but internally redundant. The small Tim chaperones are intermembrane
space proteins, so GO:0005739 is correct. However IPR004217 (domain),
IPR035427 (homologous superfamily of that same domain) and IPR050673
(family) all describe the same sequence region; the conjunction adds no
discriminating power over IPR050673 alone. This shape (nested
domain/superfamily/family triples) recurs throughout the rule and is the
main driver of the SIGNIFICANT condition-overlap assessment.
- number: 38
conditions:
- condition_type: INTERPRO
value: IPR004686
curie: InterPro:IPR004686
label: Tricarboxylate/iron carrier
interpro_type: FAMILY
- condition_type: TAXON
value: Bacteria
curie: NCBITaxon:2
label: Bacteria
negated: true
- condition_type: TAXON
value: Archaea
curie: NCBITaxon:2157
label: Archaea
negated: true
- condition_type: TAXON
value: Viruses
curie: NCBITaxon:10239
label: Viruses
negated: true
notes: >-
The falcon deep-research report's flagship positive example: IPR004686 is
the sideroflexin (SFXN) family, whose members are multi-pass mitochondrial
inner-membrane transporters. GO:0005739 is well supported; the report argues
mitochondrial inner membrane would be more informative for this branch.
Retain, and consider propagating a submitochondrial child term.
- number: 74
conditions:
- condition_type: INTERPRO
value: IPR023614
curie: InterPro:IPR023614
label: Porin domain superfamily
interpro_type: HOMOLOGOUS_SUPERFAMILY
- condition_type: INTERPRO
value: IPR027246
curie: InterPro:IPR027246
label: Eukaryotic porin/Tom40
interpro_type: FAMILY
- condition_type: INTERPRO
value: IPR037930
curie: InterPro:IPR037930
label: Tom40
interpro_type: FAMILY
- condition_type: TAXON
value: Bacteria
curie: NCBITaxon:2
label: Bacteria
negated: true
- condition_type: TAXON
value: Archaea
curie: NCBITaxon:2157
label: Archaea
negated: true
- condition_type: TAXON
value: Viruses
curie: NCBITaxon:10239
label: Viruses
negated: true
notes: >-
Sound. TOM40 is the mitochondrial outer-membrane import channel. Here the
nesting is defensible because IPR023614 is a promiscuous beta-barrel
superfamily and IPR037930 supplies the specificity; the conjunction usefully
excludes VDACs from the generic porin superfamily hit. Retain.
- number: 249
conditions:
- condition_type: INTERPRO
value: IPR002347
curie: InterPro:IPR002347
label: Short-chain dehydrogenase/reductase SDR
interpro_type: FAMILY
- condition_type: INTERPRO
value: IPR003033
curie: InterPro:IPR003033
label: SCP2 sterol-binding domain
interpro_type: DOMAIN
- condition_type: INTERPRO
value: IPR051935
curie: InterPro:IPR051935
label: Hydroxysteroid dehydrogenase-like protein 2
interpro_type: FAMILY
- condition_type: TAXON
value: Bacteria
curie: NCBITaxon:2
label: Bacteria
negated: true
- condition_type: TAXON
value: Archaea
curie: NCBITaxon:2157
label: Archaea
negated: true
- condition_type: TAXON
value: Viruses
curie: NCBITaxon:10239
label: Viruses
negated: true
notes: >-
Included for contrast with the issue #6412 complaint. This is the OTHER
SCP2-domain-containing branch in the rule - it targets HSDL2
(SDR + SCP2 domain), not the SCPx/thiolase architecture. Q9VJ43 does NOT
match it (no SDR signature). It should therefore not be confused with the
branch that actually fires on the Drosophila protein; it is CS779, not this
set, that produces the reported false positive.
- number: 303
conditions:
- condition_type: INTERPRO
value: IPR016039
curie: InterPro:IPR016039
label: Thiolase-like
interpro_type: HOMOLOGOUS_SUPERFAMILY
- condition_type: INTERPRO
value: IPR020613
curie: InterPro:IPR020613
label: Thiolase, conserved site
interpro_type: CONSERVED_SITE
- condition_type: PANTHER
value: PTHR18919:SF153
curie: PANTHER:PTHR18919:SF153
- condition_type: TAXON
value: Bacteria
curie: NCBITaxon:2
label: Bacteria
negated: true
- condition_type: TAXON
value: Archaea
curie: NCBITaxon:2157
label: Archaea
negated: true
- condition_type: TAXON
value: Viruses
curie: NCBITaxon:10239
label: Viruses
negated: true
notes: >-
A thiolase branch pinned to a specific PANTHER subfamily (PTHR18919:SF153).
Q9VJ43 is assigned to PTHR42870:SF1 (NON-SPECIFIC LIPID-TRANSFER
PROTEIN-LIKE 2), so this set does not match it. Included as a positive
illustration of the falcon report's point that a narrow PANTHER subfamily
condition is a much safer localization proxy than a bare structural
superfamily/FunFam, because paralogues within a thiolase-like fold differ in
targeting (peroxisomal vs mitochondrial vs cytosolic).
- number: 608
conditions:
- condition_type: FUNFAM
value: 2.130.10.10:FF:000404
curie: CATH.FunFam:2.130.10.10:FF:000404
- condition_type: TAXON
value: Archaea
curie: NCBITaxon:2157
label: Archaea
negated: true
- condition_type: TAXON
value: Bacteria
curie: NCBITaxon:2
label: Bacteria
negated: true
- condition_type: TAXON
value: Viruses
curie: NCBITaxon:10239
label: Viruses
negated: true
notes: >-
Worst-case shape, included as a representative of the unlabeled
single-FunFam class. CATH 2.130.10.10 is a beta-propeller superfamily -
one of the most promiscuous folds in the proteome, occurring in nuclear,
cytosolic, membrane-trafficking and mitochondrial proteins alike. A single
unlabeled FunFam from it, conjoined only with NOT(Bacteria/Archaea/Viruses),
provides no localization signal whatsoever. Branches of this shape should be
dropped unless individually benchmarked against reviewed entries.
- number: 779
conditions:
- condition_type: FUNFAM
value: 3.30.1050.10:FF:000001
curie: CATH.FunFam:3.30.1050.10:FF:000001
label: Putative Non-specific lipid-transfer protein
- condition_type: FUNFAM
value: 3.40.47.10:FF:000016
curie: CATH.FunFam:3.40.47.10:FF:000016
label: Non-specific lipid-transfer protein
- condition_type: TAXON
value: Archaea
curie: NCBITaxon:2157
label: Archaea
negated: true
- condition_type: TAXON
value: Bacteria
curie: NCBITaxon:2
label: Bacteria
negated: true
- condition_type: TAXON
value: Viruses
curie: NCBITaxon:10239
label: Viruses
negated: true
notes: >-
THE DEFECTIVE BRANCH underlying geneontology/go-annotation#6412. This is the
condition set whose signature pair matches the architecture of Drosophila
ScpX (Q9VJ43, 544 aa): an N-terminal thiolase domain (CATH 3.40.47.10,
IPR020616/IPR055140/IPR016039) plus a C-terminal SCP2 sterol-binding domain
(CATH 3.30.1050.10, IPR003033/IPR036527). Exhaustive scanning of all 1,490
condition sets shows only CS779 and CS812 could match Q9VJ43's signature
complement; the InterPro/PANTHER SCP2 sets (CS249, CS303) cannot. (I could
not query CATH FunFam assignments for Q9VJ43 directly, so this is an
architecture-level match, not a verified FunFam hit.) The defect: the
mitochondrial evidence for this family comes exclusively from an
ISOFORM-SCOPED UniProt annotation. In mouse SCP2_MOUSE (P32020), ALTERNATIVE
PRODUCTS records alternative initiation with two isoforms; the SUBCELLULAR
LOCATION comment scoped to "Isoform SCPx" (P32020-1, the full-length
thiolase+SCP2 protein that this FunFam pair detects) lists Peroxisome ONLY
(ECO:0000269, PMID:26901662), whereas the comment scoped to "Isoform SCP2"
(P32020-2, the short alternative-initiation product that LACKS the thiolase
domain) lists Cytoplasm, Peroxisome, Endoplasmic reticulum and Mitochondrion
(ECO:0000269, PMID:11003606 and PMID:26901662). ARBA has learned the
SUBCELLULAR LOCATION comment while discarding its `molecule:` (isoform)
qualifier, so it requires the thiolase FunFam - i.e. selects precisely the
isoform that is NOT annotated mitochondrial. The same collapse is visible
across sibling rules: the identical FunFam pair is CS2894 of ARBA00004496
(Cytoplasm), and 3.40.47.10:FF:000016 alone is CS80 of ARBA00004275
(Peroxisome), so this one architecture triggers three location rules and
reproduces the union of the two isoforms' locations. Only the peroxisome
call is consistent with what UniProt records for isoform SCPx. RETIRE or
repair this branch (and CS2894 of ARBA00004496).
- number: 812
conditions:
- condition_type: FUNFAM
value: 3.40.47.10:FF:000020
curie: CATH.FunFam:3.40.47.10:FF:000020
- condition_type: TAXON
value: Archaea
curie: NCBITaxon:2157
label: Archaea
negated: true
- condition_type: TAXON
value: Bacteria
curie: NCBITaxon:2
label: Bacteria
negated: true
- condition_type: TAXON
value: Viruses
curie: NCBITaxon:10239
label: Viruses
negated: true
notes: >-
The second (and only other) set that could match Q9VJ43. A single, entirely
UNLABELED FunFam from the thiolase CATH superfamily 3.40.47.10 plus the
prokaryote/virus exclusion. Thiolase-fold proteins are distributed across
mitochondria, peroxisomes and cytosol, so a bare FunFam from this
superfamily cannot discriminate compartment. Representative of the 693
single-FunFam branches (46.5% of the rule), 240 of which carry no resolved
label at all.
- number: 1124
conditions:
- condition_type: FUNFAM
value: 3.40.47.10:FF:000007
curie: CATH.FunFam:3.40.47.10:FF:000007
label: acetyl-CoA acetyltransferase, mitochondrial
- condition_type: TAXON
value: Anura
curie: NCBITaxon:8342
label: Anura
notes: >-
Representative clade-overfitting artefact. The FunFam label identifies
ACAT1, the mitochondrial matrix acetoacetyl-CoA thiolase - a genuinely
pan-metazoan (indeed pan-eukaryotic) mitochondrial enzyme - yet the branch
is restricted to Anura (frogs). 187 of 1,490 sets carry a positive taxon
condition and they use 140 distinct clades, each appearing only once or
twice (Anura, Pongo, Bos, Homo, Mus, Kluyveromyces, Oryza, Camelineae,
"Aspergillus subgen. Circumdati", ...). These read as training-set clade
artefacts rather than biology: they neither add precision nor reflect the
taxonomic distribution of the family, and they silently sacrifice recall.
go_annotations:
- go_id: GO:0005739
go_label: mitochondrion
aspect: C
entries: []
reviewed_protein_count: 0
unreviewed_protein_count: 536854
created_date: '2020-05-12'
modified_date: '2025-12-14'
review_summary: >-
ARBA00004173 is not one rule but an umbrella of 1,490 independent, OR-ed
branch-level classifiers that all emit the same UniProt SUBCELLULAR LOCATION
value (Mitochondrion, SL-0173), which GO_REF:0000044 converts to GO:0005739
(IEA/ECO:0007322) on 536,854 unreviewed proteins with zero reviewed proteins
acting as controls. The rule is genuinely heterogeneous rather than uniformly
bad. Many branches are unimpeachable - MIC60 (CS15), TOM40 (CS74), Tim10-like
translocase subunits (CS23), mitochondrially encoded cytochrome b (CS1),
cytochrome c oxidase subunits, sideroflexins (CS38) - and for these GO:0005739
is correct, if often underspecified relative to available submitochondrial
child terms.
The GO curator complaint (geneontology/go-annotation#6412, @hattrill, about
Drosophila ScpX / Q9VJ43) exposes a specific and structural defect rather than a
one-off mistake. The branch whose signature pair matches Q9VJ43's architecture
is CS779 (FunFam 3.30.1050.10:FF:000001 AND FunFam 3.40.47.10:FF:000016 AND
NOT Bacteria/Archaea/Viruses), i.e. it requires the N-terminal thiolase domain
in addition to the C-terminal SCP2 domain. But in the mouse orthologue P32020
the mitochondrion assertion is scoped by UniProt to "Isoform SCP2" (P32020-2),
the short alternative-initiation product that LACKS the thiolase domain, while
the comment scoped to "Isoform SCPx" (P32020-1, the full-length architecture
CS779 actually detects) lists Peroxisome only. ARBA has evidently learned the
SUBCELLULAR LOCATION comment while discarding its `molecule:` (isoform)
qualifier, so the branch selects exactly the isoform that is not annotated
mitochondrial. The curator's diagnosis ("only the short isoform P32020_2 is
potentially mitochondrial") is correct and, on the UniProt record, even
understated.
The same SCPx architecture simultaneously fires ARBA00004496 (Cytoplasm; CS2894
is the identical FunFam pair) and ARBA00004275 (Peroxisome; CS80 is
3.40.47.10:FF:000016 alone), so the three sibling location rules jointly
reproduce the union of the two isoforms' recorded locations, of which only
Peroxisome is right for SCPx. How far this generalizes is not established here:
139/1,490 (9.3%) of this rule's condition sets have a signature set that also
appears verbatim in the Cytoplasm rule and 19/1,490 (1.3%) in the Peroxisome
rule (3 in both), but co-annotation to mitochondrion plus cytoplasm or
peroxisome is routine and often correct (fumarase, aconitase, several
aminoacyl-tRNA synthetases, beta-oxidation enzymes), so these counts are an
UPPER BOUND on candidate sets for per-set triage, not by themselves evidence of
collapse. Distinguishing genuine dual localization from isoform collapse
requires inspecting each set - or a baseline measuring how often reviewed
proteins matching those signatures legitimately carry both SL values - and
neither was done. The isoform-collapse mechanism itself is verified for exactly
one orthologue, mouse P32020; human P22307 and rat P11915 were not checked, and
ARBA's actual training provenance for CS779 was not established.
Independently of scale, the literature actively argues against mitochondrial residence for this
family: Li, Fan & Papadopoulos (PMID:26901662) showed by live-cell confocal
imaging that the N-terminal presequence of SCPX/SCP2 is not sufficient to direct
the proteins to mitochondria, and that PTS1-mediated peroxisomal targeting
dominates.
Structurally the rule is far outside any parsimony envelope: 693 sets (46.5%)
are a single FunFam plus taxon (240 with no resolved label at all), 1,303
(87%) have no positive taxon condition beyond NOT(Bacteria/Archaea/Viruses),
only 422 (28%) contain any signature whose label mentions "mitochondri*" (a
weak proxy), and of the 885 distinct InterPro entries used, 493 have some
InterPro2GO mapping but only 35 are mapped to GO:0005739 by InterPro curators.
That last figure is a weak proxy too and is NOT evidence that InterPro curators
rejected a mitochondrial location: InterPro2GO maps a term only where it holds
for every match, its CC coverage is deliberately sparse, and - decisively - this
rule's condition sets are conjunctive, so for the 131 InterPro+InterPro+PANTHER,
99 InterPro x3, 99 InterPro+PANTHER and 67 InterPro x2 sets no individual entry
need imply mitochondrion for the set to. Only the 81 single-InterPro sets permit
a like-for-like comparison, and that restricted statistic was not computed.
Recommended action is MODIFY rather than DEPRECATE: the biologically sound
branches are numerous and valuable, and wholesale retirement would lose a large
amount of correct annotation. The deeper fix is SPLIT into per-family rules,
mirroring the falcon report's framing that the rule should survive only "as a
container for branch-level classifiers".
Caveats on this review: `just analyze-rule ARBA00004173` refuses to run on rules
with more than 12 condition sets, so no pairwise overlap statistics, heatmap or
`entries` view could be generated, and `sync-rule-review-single` / `render-rule`
are not runnable. Only one deep-research provider succeeded (falcon); the
perplexity run failed with HTTP 401 (quota exhausted). Twelve illustrative
condition sets are enumerated above with their true 1-based numbers; the other
1,478 have not been individually adjudicated.
action: MODIFY
action_rationale: >-
MODIFY, not DEPRECATE. Unlike a rule that is wrong throughout, ARBA00004173
contains a large core of correct branches keyed on whole-protein mitochondrial
families (MIC60, TOM40, Tim chaperones, COX subunits, sideroflexins, MT-encoded
OXPHOS subunits) for which GO:0005739 is exactly the right assertion; deleting
the rule would discard correct annotation on a large fraction of 536,854
proteins. The defect the GO curators reported is specific, mechanistically
identifiable, and fixable: ARBA is learning UniProt SUBCELLULAR LOCATION
comments without honouring their `molecule:` (isoform) scoping, so an
architecture-specific signature (thiolase + SCP2 FunFam pair, CS779) inherits a
location that UniProt records only for a different, domain-deficient isoform
(P32020-2). Because the failure is a property of the training procedure rather
than of one hand-written branch, it warrants a targeted engineering fix plus
branch pruning rather than either blanket acceptance or blanket removal. Its
prevalence is unquantified: 139 of this rule's condition sets share a signature
set with the Cytoplasm rule ARBA00004496 and 19 with the Peroxisome rule
ARBA00004275, but genuine dual localization produces the same signal, so those
counts bound the triage list from above rather than counting defects, and the
mechanism is confirmed only for mouse P32020. A
secondary, independent problem is the very large tail of low-information
branches (693 single-FunFam sets, 240 unlabeled) and 140 singleton positive
taxon clades that look like training-set residue. If UniProt is unwilling to
make ARBA isoform-aware, the fallback should be SPLIT into per-family rules so
that each branch can be accepted, audited or retired on its own evidence.
suggested_modifications:
- >-
Retire or repair CS779 (FunFam 3.30.1050.10:FF:000001 AND FunFam
3.40.47.10:FF:000016 AND NOT Bacteria/Archaea/Viruses) and its sibling CS2894 in
the Cytoplasm rule ARBA00004496 (the identical FunFam pair). The mitochondrion
and cytoplasm calls for the SCPx thiolase+SCP2 architecture derive from a
UniProt SUBCELLULAR LOCATION comment scoped to isoform P32020-2, which lacks the
thiolase domain that these branches require. For this architecture only the
peroxisome call (ARBA00004275 CS80) should be retained. This directly resolves
the false GO:0005739 IEA on Drosophila ScpX (Q9VJ43) reported in
geneontology/go-annotation#6412.
- >-
Make ARBA isoform-aware at the training stage: exclude, or explicitly scope,
SUBCELLULAR LOCATION comments that carry a `molecule:` (isoform) qualifier
whenever the learned signature is architecture-specific and the named isoform
differs in domain content from the displayed sequence. At minimum, do not let a
location asserted for an alternative-initiation or alternative-splice product be
transferred by a signature that requires a domain absent from that product.
- >-
Audit the 139 condition sets whose signature set also appears in ARBA00004496
(Cytoplasm) and the 19 that also appear in ARBA00004275 (Peroxisome) - 155
distinct sets, since 3 appear in both. They are an upper bound on candidates for
collapsed isoform- or
condition-specific localization, not a defect count: many families genuinely
occupy more than one of these compartments, so each set needs individual
inspection - ideally against a baseline of how often reviewed proteins matching
the same signature legitimately carry both SUBCELLULAR LOCATION values. Sets
where the shared signature requires a domain absent from the isoform bearing the
location comment (the CS779 pattern) are the ones to triage first.
- >-
Drop, or gate behind benchmarking, condition sets consisting of a single FunFam
plus only NOT(Bacteria/Archaea/Viruses) where the FunFam has no
mitochondria-specific label (693 single-FunFam sets, of which 240 have no
resolved label at all; e.g. CS608 = 2.130.10.10:FF:000404, CS812 =
3.40.47.10:FF:000020). Require each retained branch to have at least one
reviewed Swiss-Prot positive exemplar with experimental mitochondrial evidence.
- >-
Replace the 140 singleton positive taxon clades (187 sets; e.g. CS1124 =
mitochondrial acetyl-CoA acetyltransferase FunFam restricted to Anura, CS9 =
COX2 restricted to Euarchontoglires, CS13 = COX2 restricted to Laurasiatheria)
with evidence-based taxonomic scope derived from the phylogenetic distribution
of experimentally localized orthologues. Merge branches that differ only in
clade.
- >-
Collapse redundant nested InterPro conjunctions where a domain, its homologous
superfamily and the corresponding family all describe the same region and the
family alone is diagnostic (e.g. CS23: IPR004217 + IPR035427 + IPR050673).
Retain nesting only where the broad signature is promiscuous and the narrow one
supplies genuine discrimination (e.g. CS74 Tom40 within the porin superfamily).
- >-
Where branch-level evidence supports it, propagate a submitochondrial child term
in addition to GO:0005739 (mitochondrial inner membrane for sideroflexins/CS38
and the OXPHOS branches, mitochondrial outer membrane for TOM40/CS74,
mitochondrial intermembrane space for the Tim chaperones/CS23) rather than
leaving every prediction at the organelle level.
- >-
Strategic option (deeper fix): SPLIT ARBA00004173 into per-family rules so that
each branch carries its own provenance, taxonomic scope, GO granularity and
benchmark, instead of 1,490 classifiers of wildly differing quality sharing one
rule identifier and one blanket ECO:0007322 evidence code. This also makes
individual branches citable and retractable in response to GO curator reports.
parsimony:
assessment: OVERLY_COMPLEX
notes: >-
1,490 OR-ed condition sets, i.e. ~124x the 12-condition-set threshold above
which the project's own tooling refuses to analyse a rule. The complexity is
not merely large but poorly structured: 693 sets (46.5%) are a single FunFam
plus taxon, 240 of those FunFams have no resolved label at all; 180 sets are
two FunFams, 131 are InterPro+InterPro+PANTHER, 102 are three FunFams, 81 a
single InterPro, 19 a single PANTHER. Condition-type usage is taxon 1,490,
FunFam 1,359, InterPro 885, PANTHER 287. All 1,490 signature sets are distinct
(no exact duplicates), so the complexity is not literal duplication - it is
the absence of any shared mechanistic basis: the sets have nothing in common
except emitting the same location string. Nested InterPro triples
(domain + homologous superfamily + family for the same region, e.g. CS23) add
conditions without adding discrimination. A rule of this shape cannot be
reviewed, benchmarked or maintained as a unit, which is why the deeper
recommendation is to split it into per-family rules.
supported_by:
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-analysis-notes.md
supporting_text: Rule ARBA00004173 has 1490 condition sets, which exceeds the
maximum of 12. Analysis is skipped for rules with too many condition sets as
they would require excessive UniProt API queries and take too long.
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-deep-research-falcon.md
supporting_text: Treat each of the 1,490 condition sets as an independently
testable classifier.
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-deep-research-falcon.md
supporting_text: The rule should be retained only as a container for
branch-level classifiers, with systematic removal or refinement of
generic-domain, fragment-prone, paralogue-ambiguous, and organelle-confounded
branches.
literature_support:
assessment: MODERATE
notes: >-
Literature support is bimodal, and a single enum cannot express that; MODERATE
is chosen as the rule-level summary. For a substantial minority of branches the
support is effectively STRONG: MIC60, TOM40, the small Tim chaperones,
mitochondrially encoded cytochrome b and cytochrome c oxidase subunits, and
sideroflexins are textbook mitochondrial proteins with abundant experimental
localization evidence, and the falcon report singles out the sideroflexin
branch (CS38/IPR004686) as well supported. For the branch the GO curator
complained about, support is CONTRADICTED: Li, Fan & Papadopoulos
(PMID:26901662) tested the putative N-terminal mitochondrial presequence of
SCPX/SCP2 directly by live-cell confocal imaging of fluorescent fusions and
concluded it is not sufficient to localize either protein to mitochondria,
while C-terminal PTS1-mediated peroxisomal targeting is. The only primary
evidence for mitochondrial SCP2 is Starodub et al. (PMID:11003606), an
immunofluorescence study of the SHORT SCP-2 protein in L-cell fibroblasts that
ranks mitochondria third behind peroxisomes and ER - and UniProt correctly
scopes that evidence to isoform P32020-2, not to the SCPx architecture that
CS779 detects. For the very large tail of unlabeled single-FunFam branches
there is no identifiable literature at all, because the branches cannot even be
resolved to a named family. The falcon report additionally warns that rules
trained on noisy source annotations reinforce systematic errors, which is
precisely what the isoform-collapse defect demonstrates.
supported_by:
- reference_id: PMID:26901662
supporting_text: the N-terminal mitochondrial targeting sequence is not powerful
enough to localize the SCPX and SCP2 proteins to the mitochondria.
- reference_id: PMID:26901662
supporting_text: The Scp2 gene contains two transcription initiation sites,
giving rise to the 58 kDa sterol carrier protein-x (SCPX) and 15 kDa pro-SCP2
proteins
- reference_id: PMID:11003606
supporting_text: detected SCP-2 in peroxisomes > endoplasmic reticulum >
mitochondria >
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-deep-research-falcon.md
supporting_text: Sideroflexins are mitochondrial inner-membrane proteins,
although their transported substrates and physiological roles differ among
paralogues. That branch is well supported for GO:0005739.
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-deep-research-falcon.md
supporting_text: Thus, family rules trained on noisy source annotations can
reinforce systematic errors.
- reference_id: https://github.com/geneontology/go-annotation/issues/6412
supporting_text: From orthology to P32020, only the sort isoform P32020_2 is
potentially mitochondrial.
condition_overlap:
assessment: SIGNIFICANT
notes: >-
Quantitative pairwise overlap could not be computed because `just analyze-rule`
refuses to run on rules with >12 condition sets, so `pairwise_overlap` and
`entries` are empty. Qualitative and cross-rule evidence nonetheless makes
SIGNIFICANT the right call, on three distinct axes. (1) Within-set redundancy:
the recurrent InterPro triple shape (domain + its homologous superfamily + the
corresponding family, 99 sets of shape InterPro x3, e.g. CS23 = IPR004217 +
IPR035427 + IPR050673) conjoins nested annotations of the same sequence region,
which cannot increase specificity. (2) Between-set overlap within the rule:
693 single-FunFam sets drawn from broad CATH superfamilies will match
overlapping protein sets, and multi-FunFam sets built from the same superfamily
(3.40.47.10 appears in CS779, CS812, CS1124 among others) partially subsume one
another. (3) Cross-rule overlap, which is the most consequential: 139/1,490
(9.3%) of this rule's condition sets have a signature set that appears
identically in the Cytoplasm rule ARBA00004496, 19/1,490 (1.3%) in the
Peroxisome rule ARBA00004275, and 3 in both. These compartments are not
mutually exclusive - mitochondrion/cytoplasm and mitochondrion/peroxisome
co-annotation is routine and frequently correct (fumarase, aconitase, several
aminoacyl-tRNA synthetases, beta-oxidation enzymes), and the falcon report
makes the same point: "For dual-localized families, GO:0005739 should coexist
with the other supported component rather than suppress it." The 139 + 19
counts are therefore an upper bound on the sets that warrant per-set triage,
not a count of collapsed antecedents; separating true dual localization from
isoform collapse requires inspecting each set, which this review did not do.
What is demonstrated is the single worked example CS779, where the shared
signature requires the thiolase FunFam that isoform P32020-2 lacks: the same
FunFam pair is CS2894 of ARBA00004496, and its thiolase half alone is CS80 of
ARBA00004275. Separately, of the 885 distinct InterPro entries used by this
rule, 493 already carry some InterPro2GO mapping but only 35 are mapped to
GO:0005739 by InterPro curators. This is an argument from silence and should
not be read as InterPro curators declining a mitochondrial claim: InterPro2GO
maps a term only where it holds for all matches, CC coverage there is sparse by
design, and this rule's condition sets are conjunctive, so in the 131
InterPro+InterPro+PANTHER, 99 InterPro x3, 99 InterPro+PANTHER and 67
InterPro x2 sets no single entry need imply mitochondrion for the set to. The
comparison is like-for-like only in the 81 single-InterPro sets, and that
restricted count was not computed.
supported_by:
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-analysis-notes.md
supporting_text: Rule ARBA00004173 has 1490 condition sets, which exceeds the
maximum of 12. Analysis is skipped for rules with too many condition sets as
they would require excessive UniProt API queries and take too long.
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-deep-research-falcon.md
supporting_text: Multiple signatures may either add specificity or simply be
nested/redundant annotations of the same sequence region.
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-deep-research-falcon.md
supporting_text: Where a PANTHER subfamily is sufficient and more specific, a
parent-family condition may be redundant.
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-deep-research-falcon.md
supporting_text: For dual-localized families, GO:0005739 should coexist with the
other supported component rather than suppress it.
go_specificity:
assessment: APPROPRIATE
notes: >-
GO:0005739 (mitochondrion) is the right granularity for a rule whose source
assertion is the UniProt subcellular-location keyword Mitochondrion (SL-0173):
for every true positive it is a correct, conservative cellular-component term,
and it is the term GO_REF:0000044 legitimately produces from that keyword. The
aspect and branch are right (cellular component, not molecular function or
biological process), so it is not MISMATCHED, and it is certainly not
TOO_NARROW. The honest qualifier is that it is frequently UNDERSPECIFIED rather
than wrong: many branches identify families whose submitochondrial compartment
is well established (inner membrane for sideroflexins and OXPHOS subunits,
outer membrane for TOM40, intermembrane space for the Tim chaperones) and could
support a child term in addition to the parent. I have deliberately not scored
this TOO_BROAD, because the false positives this rule generates - Q9VJ43 being
the reported case - are not failures of term granularity at all: no
mitochondrial child or parent term would be correct there. Fixing them requires
fixing the antecedent (isoform scoping, branch pruning), not the consequent.
Scoring TOO_BROAD would misdirect the fix.
supported_by:
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-deep-research-falcon.md
supporting_text: GO:0005739 denotes the mitochondrion as a cellular component.
It is appropriate if the protein resides in any mitochondrial compartment
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-deep-research-falcon.md
supporting_text: For branches supported by submitochondrial evidence, more
precise cellular-component terms should be propagated in addition to the
parent
taxonomic_scope:
assessment: TOO_BROAD
notes: >-
The dominant taxonomic condition is NOT(Bacteria/Archaea/Viruses), present as
the ONLY taxon constraint in 1,303/1,490 sets (87%). This is a coarse
"eukaryote-ish" filter and carries almost no organelle information: it does not
distinguish mitochondria from cytosol, nucleus, ER, Golgi, peroxisome or - in
plants and algae - plastid, and it is largely redundant with signatures that
are already eukaryote-restricted. Combined with the 693 bare single-FunFam
branches, this is the principal false-positive generator, and it is exactly how
the Drosophila ScpX case arises: CS779's taxonomic condition does nothing to
prevent a peroxisomal/cytosolic lipid-transfer protein from being called
mitochondrial.
A separate, opposite artefact coexists with this over-breadth and is worth
recording even though the enum can only carry one value: the 187 sets that do
have a positive taxon condition use 140 distinct clades, each occurring only
once or twice (Anura, Pongo, Bos, Homo, Mus, Kluyveromyces, Oryza, Camelineae,
"Aspergillus subgen. Circumdati", ...). These are TOO_NARROW in effect and
read as training-set residue rather than biology - CS1124 confines the
FunFam labelled "acetyl-CoA acetyltransferase, mitochondrial" (ACAT1), a
pan-metazoan mitochondrial matrix thiolase, to frogs; CS9 and CS13 split
cytochrome c oxidase subunit II between Euarchontoglires and Laurasiatheria.
They sacrifice recall without buying precision. The rule therefore manages to
be simultaneously too broad where it matters (the 87% with no positive
constraint) and arbitrarily too narrow where it does constrain.
supported_by:
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-deep-research-falcon.md
supporting_text: It cannot distinguish mitochondrial from plastid targeting in
plants and algae, or mitochondrial from peroxisomal, ER, and Golgi
localization in other eukaryotes.
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-deep-research-falcon.md
supporting_text: They can also be overfitted if derived from sparse reviewed
examples. Taxonomic exclusions should therefore be supported by phylogenetic
inspection of experimentally localized orthologues, not merely by absence of
training examples.
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-deep-research-falcon.md
supporting_text: a domain shared by proteins in several compartments is not
intrinsically a localization signal
confidence: 0.35
references:
- id: file:rules/arba/ARBA00004173/ARBA00004173-deep-research-falcon.md
title: Deep research analysis via Falcon - UniProt rule ARBA00004173
findings:
- statement: The rule is an aggregated umbrella of 1,490 independent branch-level
classifiers and should be audited branch-by-branch rather than accepted or
rejected wholesale.
supporting_text: Treat each of the 1,490 condition sets as an independently
testable classifier.
- statement: The report's final verdict is that the rule should survive only as a
container for branch-level classifiers, with generic-domain and
organelle-confounded branches removed.
supporting_text: The rule should be retained only as a container for
branch-level classifiers, with systematic removal or refinement of
generic-domain, fragment-prone, paralogue-ambiguous, and organelle-confounded
branches.
- statement: Isoform choice is explicitly listed as a mechanism by which a
structural-domain signature can fail to predict localization - the exact
failure mode reported in go-annotation issue #6412 for CS779.
supporting_text: alternative initiation, splicing, and competing targeting
sequences can alter localization.
- statement: Localization is a property of the complete protein, not of one
structural domain, so a CATH FunFam match is a weak localization proxy.
supporting_text: localization is a property of the complete protein—including
terminal targeting information, transmembrane segments, isoform choice, and
cellular context—not necessarily of one structural domain
- statement: Single-signature branches are acceptable only when the signature is a
mitochondria-specific whole-protein family, and unsafe when it is a generic
domain - the basis for pruning the 693 bare single-FunFam sets.
supporting_text: Conditions such as CS7, CS15, CS31, CS34, CS38, and CS39 rely
on one InterPro entry plus a broad taxonomic exclusion. These are acceptable
only when the InterPro entry is a mitochondria-specific whole-protein family;
they are unsafe if it is a generic domain.
- statement: The sideroflexin branch (CS38 / IPR004686) is a well-supported
positive example for GO:0005739.
supporting_text: Sideroflexins are mitochondrial inner-membrane proteins,
although their transported substrates and physiological roles differ among
paralogues. That branch is well supported for GO:0005739.
- statement: GO:0005739 is an appropriate cellular-component term when
mitochondrial residence holds, but is often underspecified relative to
submitochondrial child terms.
supporting_text: For branches supported by submitochondrial evidence, more
precise cellular-component terms should be propagated in addition to the
parent
- statement: The NOT(Bacteria/Archaea/Viruses) filter provides essentially no
organelle specificity within eukaryotes.
supporting_text: It cannot distinguish mitochondrial from plastid targeting in
plants and algae, or mitochondrial from peroxisomal, ER, and Golgi
localization in other eukaryotes.
- statement: Positive lineage restrictions can be overfitted to sparse reviewed
training examples - consistent with the 140 singleton clades observed here.
supporting_text: They can also be overfitted if derived from sparse reviewed
examples. Taxonomic exclusions should therefore be supported by phylogenetic
inspection of experimentally localized orthologues, not merely by absence of
training examples.
- statement: Rules trained on noisy source annotations reinforce systematic
errors - the general form of the isoform-collapse defect documented here.
supporting_text: Thus, family rules trained on noisy source annotations can
reinforce systematic errors.
- statement: Branches without reviewed positive exemplars should be flagged as
speculative rather than merged invisibly into a high-volume rule.
supporting_text: Branches with no reviewed positive exemplars should be flagged
as speculative rather than merged invisibly into the same high-volume rule.
- statement: Isoform-specific localization should be documented rather than
collapsed, where the annotation model permits it.
supporting_text: Conditional or isoform-specific localization should be
documented where the annotation model permits it.
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Falcon deep-research report generated for this rule. Its rule-level
statistics (1,490 condition sets; 536,854 unreviewed proteins; condition-type
usage taxon 1,490 / FunFam 1,359 / InterPro 885 / PANTHER 287) were
independently re-derived from ARBA00004173.enriched.json and match exactly.
Its identification of IPR004686 as the sideroflexin family and its CS38
numbering were verified against the rule JSON. The report is an
LLM-generated synthesis, so its literature citations were treated as leads
rather than as verified facts, and no claim in this review rests on a
citation appearing only in that report. The companion perplexity run failed
(HTTP 401, quota exhausted), so this is the only deep-research provider
available.
- id: PMID:26901662
title: Sterol Carrier Protein-2, a Nonspecific Lipid-Transfer Protein, in
Intracellular Cholesterol Trafficking in Testicular Leydig Cells.
findings:
- statement: Live-cell confocal imaging of fluorescent SCPX and SCP2 fusions
showed that the C-terminal PTS1 signal drives peroxisomal targeting, while
the putative N-terminal mitochondrial presequence is not sufficient to
localize either protein to mitochondria. This is direct evidence against the
mitochondrial assertion that ARBA00004173 CS779 makes for the SCPx
thiolase+SCP2 architecture.
supporting_text: the N-terminal mitochondrial targeting sequence is not powerful
enough to localize the SCPX and SCP2 proteins to the mitochondria.
- statement: The Scp2 gene uses two transcription initiation sites to produce the
58 kDa SCPX (thiolase + SCP2 domain) and the 15 kDa pro-SCP2 (SCP2 domain
only); the two products differ in domain content, which is why an
isoform-scoped location cannot be transferred by a thiolase-requiring
signature.
supporting_text: The Scp2 gene contains two transcription initiation sites,
giving rise to the 58 kDa sterol carrier protein-x (SCPX) and 15 kDa pro-SCP2
proteins
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PMID verified against the cached publication record (Li NC, Fan J,
Papadopoulos V, PLoS One 2016; full text available). This is the ECO:0000269
source that UniProt cites for BOTH the "Isoform SCPx" peroxisome-only
location and part of the "Isoform SCP2" multi-compartment location on P32020,
confirmed by fetching the P32020 record from the UniProt REST API. Its
experimental conclusion directly contradicts mitochondrial targeting of the
full-length SCPx architecture.
- id: PMID:11003606
title: Sterol carrier protein-2 localization in endoplasmic reticulum and role in
phospholipid formation.
findings:
- statement: Indirect immunofluorescence and confocal microscopy of L-cell
fibroblasts overexpressing the short SCP-2 protein ranked its distribution
peroxisomes > endoplasmic reticulum > mitochondria > lysosomes. This is the
primary source of the mitochondrial claim, and it concerns the short
SCP2 product (UniProt isoform P32020-2), not the full-length SCPx
architecture that ARBA00004173 CS779 requires.
supporting_text: detected SCP-2 in peroxisomes > endoplasmic reticulum >
mitochondria >
full_text_unavailable: true
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PMID verified against the cached publication record (Starodub et al., Am J
Physiol Cell Physiol 2000); the cache is abstract-only
(full_text_available: false), so only the abstract was assessed. Confirmed
via the UniProt REST API that P32020 cites this PMID exclusively under the
SUBCELLULAR LOCATION comment scoped to "Isoform SCP2" (P32020-2) - it is not
cited for the "Isoform SCPx" comment, which lists Peroxisome only. Cited here
to establish the isoform scoping of the mitochondrial evidence, not to
dispute the curator's original annotation.
- id: https://github.com/geneontology/go-annotation/issues/6412
title: 'go-annotation issue #6412: ARBA00004173 mitochondrion annotation on
UniProt:Q9VJ43 (Drosophila melanogaster ScpX)'
findings:
- statement: A GO curator reported that ARBA00004173 assigns a mitochondrial
location to Drosophila melanogaster ScpX (Q9VJ43), and correctly diagnosed
that in the mouse orthologue P32020 only the short isoform is potentially
mitochondrial, with no evidence that D. melanogaster has an equivalent short
isoform.
supporting_text: From orthology to P32020, only the sort isoform P32020_2 is
potentially mitochondrial.
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
The complaint was independently verified. QuickGO confirms Q9VJ43 carries
GO:0005739 IEA via GO_REF:0000044 with with/from UniProtKB-SubCell:SL-0173,
assigned by UniProt; the UniProt REST record for Q9VJ43 shows three ARBA
location calls (Cytoplasm/ARBA00004496, Mitochondrion/ARBA00004173,
Peroxisome/ARBA00004275). The curator's reading of P32020 is correct and, if
anything, understated - UniProt scopes the mitochondrion location strictly to
Isoform SCP2 (P32020-2) while Isoform SCPx (P32020-1) is annotated Peroxisome
only.
- id: file:rules/arba/ARBA00004173/ARBA00004173-analysis-notes.md
title: ARBA00004173 reproducible rule statistics and `analyze-rule` refusal output
findings:
- statement: The rule has 1,490 OR-ed condition sets and exceeds the project's
analysis threshold of 12, so `just analyze-rule ARBA00004173` refuses to run
and no pairwise overlap statistics, heatmap or entries view are available.
supporting_text: Rule ARBA00004173 has 1490 condition sets, which exceeds the
maximum of 12. Analysis is skipped for rules with too many condition sets as
they would require excessive UniProt API queries and take too long.
- statement: All structural counts quoted in this review (condition-set shapes,
taxon-condition counts, InterPro2GO redundancy, and the signature-set overlap
with the sibling location rules ARBA00004496 and ARBA00004275) are regenerated
by `uv run python rules/arba/ARBA00004173/ARBA00004173-stats.py`.
- id: file:rules/arba/ARBA00004173/ARBA00004173.json
title: ARBA rule ARBA00004173 raw rule definition (1,490 condition sets)
findings:
- statement: The rule's single consequent is the UniProt SUBCELLULAR LOCATION
comment with value "Mitochondrion" (SL-0173), which GO_REF:0000044 maps to
GO:0005739 with evidence IEA / ECO:0007322. Statistics are 0 reviewed and
536,854 unreviewed proteins; created 2020-05-12, modified 2025-12-14.
- statement: Condition-type usage across the 1,490 sets is taxon 1,490, FunFam
1,359, InterPro 885, PANTHER 287. Set shapes are 693 single FunFam (46.5%),
180 two FunFams, 131 InterPro+InterPro+PANTHER, 102 three FunFams, 99
InterPro+PANTHER, 99 three InterPro, 81 single InterPro, 67 two InterPro, 19
single PANTHER. All 1,490 signature sets are distinct.
- statement: 1,303/1,490 sets (87%) have no positive taxon restriction, only
NOT(Bacteria/Archaea/Viruses). The remaining 187 use 140 distinct positive
clades, each appearing once or twice. Only 422/1,490 (28%) contain at least
one signature whose resolved label mentions "mitochondri*".
- statement: Of the 885 distinct InterPro entries used by the rule, 493 have some
InterPro2GO mapping but only 35 are mapped to GO:0005739 by InterPro2GO, so
~96% of the rule's InterPro conditions assert a mitochondrial location that
InterPro curators did not assert.
- id: file:rules/arba/_interpro2go.txt
title: InterPro2GO mapping file (GO Consortium)
findings:
- statement: Only 35 of the 885 InterPro entries used as conditions in
ARBA00004173 are mapped to GO:0005739 by InterPro2GO, despite 493 of them
having at least one InterPro2GO mapping.
supported_by:
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-analysis-notes.md
supporting_text: Rule ARBA00004173 has 1490 condition sets, which exceeds the
maximum of 12. Analysis is skipped for rules with too many condition sets as
they would require excessive UniProt API queries and take too long.
- reference_id: https://github.com/geneontology/go-annotation/issues/6412
supporting_text: From orthology to P32020, only the sort isoform P32020_2 is
potentially mitochondrial.
- reference_id: PMID:26901662
supporting_text: the N-terminal mitochondrial targeting sequence is not powerful
enough to localize the SCPX and SCP2 proteins to the mitochondria.
- reference_id: PMID:11003606
supporting_text: detected SCP-2 in peroxisomes > endoplasmic reticulum >
mitochondria >
- reference_id: file:rules/arba/ARBA00004173/ARBA00004173-deep-research-falcon.md
supporting_text: The rule should be retained only as a container for branch-level
classifiers, with systematic removal or refinement of generic-domain,
fragment-prone, paralogue-ambiguous, and organelle-confounded branches.