FGA

Summary: Fibrinogen contributes to receptor-dependent endothelial adhesion and survival.

Reason: PMID:10903502 tests human fibrinogen as an assembled ligand, with ICAM-1-blocking and recognition-peptide controls. The γ117–133 peptide reproduces important responses, so this is not evidence for an autonomous α-chain ICAM-1-binding site. Retain the imported contributes_to assertion as a non-core contribution of the fibrinogen subunit to the receptor-binding complex, without assigning receptor activity to FGA.

Summary: Receptor interaction is supported at the fibrinogen-complex level.

Reason: The actual InterPro IPR012290 mapping supplies this receptor-binding term from the fibrinogen coiled-coil family. Human fibrinogen supports receptor-dependent adhesion and survival in PMID:10903502, but its ICAM1 contact was mapped using a gamma-chain peptide. Retain the broader complex-level interaction without claiming that the FGA coiled coil independently contacts ICAM1 or that all alpha-chain products share that activity.

Summary: The α chain is a structural participant in fibrinogen assembly.

Reason: PMID:8910396 follows human fibrinogen chains expressed in BHK cells and corroborates assembly intermediates in human hepatoma cells. Immunoprecipitation and two-dimensional gels detect αγ intermediates and assembled αβγ-containing fibrinogen after addition of the missing chain. The α chain supplies structure in the complex; this is more than a loss-of-function requirement. The broad structural term also covers soluble-complex assembly, beyond extracellular-matrix incorporation. GO:0005198 remains informative for the soluble fibrinogen heteromer as well as extracellular fibrin structure; its broader complex-structural scope is not exhausted by the ECM-specific descendant GO:0005201.

Summary: FGA encodes a structural chain required to assemble functional fibrinogen.

Reason: PMID:10891444 identifies human FGA variants in congenital afibrinogenemia. Those patient data establish necessity, while the actual chain-assembly experiments in PMID:8910396 establish the structural work supporting this molecular function. The clinical study sequenced the short-chain coding exons and did not establish equal behavior of the alternative αE product. Retain the general structural activity without turning the disease phenotype into a distinct enzymatic function. GO:0005198 remains informative for the soluble fibrinogen heteromer as well as extracellular fibrin structure; its broader complex-structural scope is not exhausted by the ECM-specific descendant GO:0005201.

Summary: The exact FGA proteomic target record remains unresolved in this study.

Reason: The recovered original Figure 5B names FGA in a gene-expression heatmap. That is not the missing protein-identification row supporting this HDA annotation. The operative proteomic supplement and its sample-specific FGA join were not recovered. Independent fibrin biology does not verify this particular high-throughput target record, so retain uncertainty rather than alleging a wrong-gene assignment. The general ECM structural activity claim has positive independent support elsewhere in this review. This UNDECIDED action is restricted to the unresolved original HDA protein/sample assertion, under the standing instruction to retain uncertainty when relevant target evidence cannot be accessed; it is not a negative gene-level claim or a requirement to rediscover all established biology. The original evidence code, qualifier and source remain unchanged.

Summary: The fibrinogen α chain contributes to an extracellular structural matrix.

Reason: PMID:25037231 identifies FGA in the actual human tissue-proteomics target data. Its matrisome category is a classification, not a mechanical assay. The functional interpretation is independently supported by human α-chain-containing fibrin and αC-truncation experiments: altered αC regions change protofibril formation and fiber architecture. Retain the structural role at gene level without claiming that every detected peptide represents intact fibrin, αE, or the same processed product.

Summary: The fibrinogen α chain contributes to an extracellular structural matrix.

Reason: PMID:28675934 identifies FGA in the actual human tissue-proteomics target data. Its matrisome category is a classification, not a mechanical assay. The functional interpretation is independently supported by human α-chain-containing fibrin and αC-truncation experiments: altered αC regions change protofibril formation and fiber architecture. Retain the structural role at gene level without claiming that every detected peptide represents intact fibrin, αE, or the same processed product.

Summary: FGA was recovered as a keratin-18 interaction partner in a yeast two-hybrid screen.

Reason: PMID:10954706 reports 25 independent fibrinogen α-chain clones among positive clones from a human liver library screened with full-length K18 bait. The subsequent filament-regulation experiments concern Mrj, not FGA. Binding to a K18 construct does not establish binding to assembled keratin or intermediate filaments, so neither GO:1990254 nor GO:0019215 is justified. Preserve the supported interaction as non-core under the project binding policy. The campaign-specific curation instructions in projects/CLINGEN_MENDELIAN.md explicitly retain supported generic interactions as KEEP_AS_NON_CORE when no evidence-backed specific binding term is established; this is a documented departure from the generic validator policy, not a claim that its warning is absent.

Summary: The source-specific fibrinogen–thrombin interaction could not be fully adjudicated.

Reason: The original Magdeburg dysfibrinogenemia paper and the exact thrombin interaction record were identified, but the relevant full experimental report was not recovered. A thrombin cleavage reaction alone would not establish a separate protease-binding function of the α chain. Do not replace the annotation with GO:0002020 on that assumption or negate the curator’s positive interaction; leave this source-specific decision unresolved.

Summary: The original supplemental FGA kinase-substrate record remains incompletely verified.

Reason: The main PMID:22582013 article is available, and IntAct maps FAM20C and FGA to a Table S1 kinase assay. The curated record includes a peptide-label discrepancy, but the actual original supplemental table was not recovered. A sequence match or a phosphate-transfer assay does not by itself establish a distinct protein-kinase-binding function. Preserve the source-specific uncertainty without rewriting the source or asserting that the curator chose the wrong gene.

Summary: FAM20C phosphorylates the fibrinogen α chain in the reported substrate assay.

Reason: The actual PMID:26091039 Figure 4A shows fibrinogen-chain staining and α-chain phosphorylation with wild-type FAM20C versus its D478A control. The corresponding IntAct event is a kinase assay/phosphorylation record, not an independently measured co-immunoprecipitation or binding-affinity experiment. Retain the curated generic interaction as non-core in its enzyme–substrate context; GO:0019901 would overstate the separate binding evidence. This is not kinase activity of FGA, and the experiment does not compare natural FGA splice products. The campaign-specific curation instructions in projects/CLINGEN_MENDELIAN.md explicitly retain supported generic interactions as KEEP_AS_NON_CORE when no evidence-backed specific binding term is established; this is a documented departure from the generic validator policy, not a claim that its warning is absent.

Summary: The curated FGA–YWHAQ association supports a partner-class binding refinement with unresolved physiological context.

Reason: The exact human YWHAQ bait/FGA prey record is an anti-tag affinity-purification/mass-spectrometry association. GO:0071889 specifies the identified 14-3-3 partner class; refining the existing curator-assigned IPI protein-binding claim does not promote the experiment to purified direct binding. The original Methods use tagged ORFs and detergent lysates. FGA secretion and YWHAQ intracellular localization raise a real compartment-compatibility concern that this assay does not resolve: association could be indirect, construct-dependent or enabled after lysis. No endogenous colocalization, direct affinity, phosphorylation-dependent interface, regulatory activity or physiological core function is inferred. Background-aware filtering supports retaining the reported association but does not eliminate these alternatives. BioPlex 3.0 reanalyzes earlier datasets, so the two papers are not independent replication. Gene-level grouping and the reported accession do not resolve an intact natural splice or cleavage product.

Proposed replacements: 14-3-3 protein binding

Summary: The curated FGA–YWHAQ association supports a partner-class binding refinement with unresolved physiological context.

Reason: The exact human FGA bait/YWHAQ prey record is an anti-tag affinity-purification/mass-spectrometry association. GO:0071889 specifies the identified 14-3-3 partner class; refining the existing curator-assigned IPI protein-binding claim does not promote the experiment to purified direct binding. The original Methods use tagged ORFs and detergent lysates. FGA secretion and YWHAQ intracellular localization raise a real compartment-compatibility concern that this assay does not resolve: association could be indirect, construct-dependent or enabled after lysis. No endogenous colocalization, direct affinity, phosphorylation-dependent interface, regulatory activity or physiological core function is inferred. Background-aware filtering supports retaining the reported association but does not eliminate these alternatives. BioPlex 3.0 reanalyzes earlier datasets, so the two papers are not independent replication. Gene-level grouping and the reported accession do not resolve an intact natural splice or cleavage product.

Proposed replacements: 14-3-3 protein binding

Summary: Human fibrinogen is present extracellularly as a plasma protein.

Reason: PMID:19296670 studies purified human plasma fibrinogen directly. This supports extracellular-region localization of the gene product even though the crystallized preparation contains proteolytic heterogeneity. It does not resolve every circulating splice or cleavage product separately.

Summary: The human fibrinogen α-chain product has a well-supported extracellular location.

Reason: The original PMID:9628725 full experimental article was not recovered; its verified abstract identifies human fibrin double-D structural material. The generic extracellular claim is independently established by directly examined human plasma fibrinogen in PMID:19296670 and secreted assembled fibrinogen in PMID:8910396. Accept that same broad location while retaining the source-access limit and making no new claim about the exact fragment composition.

Summary: Fibrinogen-derived α-chain material is extracellular after platelet release and fibrin formation.

Reason: PMID:6777381 directly analyzes secretion products of activated human platelets. Its Results identify conversion of fibrinogen to fibrin and calcium-dependent retention of fibrin chains at the platelet surface. The positive extracellular observation is retained without treating the measured fibrin as an unprocessed precursor or assigning the study’s thrombospondin mechanism to FGA.

Summary: FGA-containing fibrinogen and its released products are extracellular.

Reason: UniProt SL-0243 is the Secreted vocabulary mapping. The reviewed target record and actual Reactome entities support extracellular fibrinogen, fibrin and fibrinopeptide A. This source is a localization-vocabulary mapping, not an HPA image experiment; the broad compartment covers products outside the fibrinogen complex as well.

Summary: Extracellular plasma fibrinogen is a supported broad location.

Reason: PMID:14718574 is a verified compilation of plasma-proteome sources; its full underlying protein list was not recovered here. The identical broad extracellular claim is directly supported by independently read human plasma fibrinogen experiments. Retain the location while distinguishing compilation evidence from a new target-specific localization assay.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-114560 reaches FGA [extracellular region] (36–866; route 114560 → 139933 → 140586 → 140583); FGA [plasma membrane] (36–866; route 114560 → 114559 → 139934 → 140919 → 140916). Fibrin is associated with the extracellular face of an integrin-containing plasma-membrane complex. This is peripheral receptor association, not an integral membrane topology. Factor XIII or the receptor supplies its own catalytic/signaling activity.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-140840 reaches FGA(20-35) [extracellular region] (20–35; route 140840 → 140867); FGA(20-866) [extracellular region] (20–866; route 140840 → 114618 → 140841); FGA [extracellular region] (36–866; route 140840 → 140586 → 140583). The source separately represents secreted fibrinogen, released fibrinopeptide A and the resulting fibrin chain. Thrombin performs the cleavage; FGA is not a protease.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-140842 reaches FGA [extracellular region] (36–866; route 140842 → 140586 → 140583). FGA is a structural subunit of assembling fibrin. The depicted multimer size is a modeling choice, not a fixed natural oligomer stoichiometry.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-140851 reaches FGA [extracellular region] (36–866; route 140851 → 139933 → 140586 → 140583). The target is in the fibrin input. Factor XIIIa performs covalent cross-linking; the output is an OtherEntity without an explicit subunit route, so no missing composition is fabricated.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-166072 reaches FGA(20-35) [extracellular region] (20–35; route 166072 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-166082 reaches FGA(20-35) [extracellular region] (20–35; route 166082 → 937033 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-166091 reaches FGA(20-35) [extracellular region] (20–35; route 166091 → 937048 → 937033 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-166119 reaches FGA(20-35) [extracellular region] (20–35; route 166119 → 937018 → 937048 → 937033 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-166284 reaches FGA(20-35) [extracellular region] (20–35; route 166284 → 166118 → 937048 → 937033 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-166286 reaches FGA(20-35) [extracellular region] (20–35; route 166286 → 166281 → 166080 → 937033 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-166362 reaches FGA(20-35) [extracellular region] (20–35; route 166362 → 937048 → 937033 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-166363 reaches FGA(20-35) [extracellular region] (20–35; route 166363 → 166360 → 937048 → 937033 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-216069 reaches FGA [extracellular region] (36–866; route 216069 → 139933 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-216082 reaches FGA [extracellular region] (36–866; route 216082 → 139933 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-2201316 reaches FGA(20-35) [extracellular region] (20–35; route 2201316 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-2201322 reaches FGA(20-35) [extracellular region] (20–35; route 2201322 → 2201331 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-2262775 reaches FGA(20-35) [extracellular region] (20–35; route 2262775 → 937048 → 937033 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-2262777 reaches FGA(20-35) [extracellular region] (20–35; route 2262777 → 937055 → 937048 → 937033 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-2559414 reaches FGA(20-35) [extracellular region] (20–35; route 2559414 → 2559411 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-354066 reaches FGA [extracellular region] (36–866; route 354066 → 377622 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-354073 reaches FGA [extracellular region] (36–866; route 354073 → 354103 → 377622 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-354087 reaches FGA [extracellular region] (36–866; route 354087 → 354080 → 377622 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-354124 reaches FGA [extracellular region] (36–866; route 354124 → 354135 → 377622 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-354149 reaches FGA [extracellular region] (36–866; route 354149 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-354165 reaches FGA [extracellular region] (36–866; route 354165 → 354113 → 354080 → 377622 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-372693 reaches FGA [extracellular region] (36–866; route 372693 → 372688 → 354080 → 377622 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-372697 reaches FGA [extracellular region] (36–866; route 372697 → 372646 → 354080 → 377622 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-372705 reaches FGA [extracellular region] (36–866; route 372705 → 354080 → 377622 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-377640 reaches FGA [extracellular region] (36–866; route 377640 → 377620 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-377641 reaches FGA [extracellular region] (36–866; route 377641 → 354137 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-377643 reaches FGA [extracellular region] (36–866; route 377643 → 377616 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-377644 reaches FGA [extracellular region] (36–866; route 377644 → 377619 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-429415 reaches FGA [extracellular region] (36–866; route 429415 → 377622 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-429441 reaches FGA [extracellular region] (36–866; route 429441 → 429424 → 377622 → 377603 → 140586 → 140583). The target persists as an extracellular fibrin/fibrinogen ligand within an integrin-associated complex or set. The event title names a receptor or intracellular signaling step; it does not transfer that step to FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-481007 reaches FGA(20-866) [platelet alpha granule lumen] (20–866; route 481007 → 481003 → 114617 → 140920); FGA(20-866) [extracellular region] (20–866; route 481007 → 481033 → 114618 → 140841). FGA is a fibrinogen subunit in the lumenal cargo set and the extracellular released set. Cargo localization does not establish that FGA executes the exocytosis machinery.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-5602353 reaches FGA(20-35) [extracellular region] (20–35; route 5602353 → 937033 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-5602383 reaches FGA(20-35) [extracellular region] (20–35; route 5602383 → 9037685 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-5602606 reaches FGA(20-35) [extracellular region] (20–35; route 5602606 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-8870678 reaches FGA(20-35) [extracellular region] (20–35; route 8870678 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-937022 reaches FGA(20-35) [extracellular region] (20–35; route 937022 → 166080 → 937033 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-937059 reaches FGA(20-35) [extracellular region] (20–35; route 937059 → 937028 → 937048 → 937033 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-937079 reaches FGA(20-35) [extracellular region] (20–35; route 937079 → 166062 → 2201325 → 181230 → 9708724 → 8870679 → 8870680 → 140867). The curated ligand set contains FGA residues 20–35 (fibrinopeptide A). This supports the extracellular compartment represented by the source; it does not independently establish that the isolated peptide is the experimentally identified TLR4 agonist, or that FGA performs the intracellular kinase/adaptor step.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-976734 reaches Variant fibrinogen alpha chain [extracellular region] (20–866; route 976734 → 977144 → 976760 → 976911 → 976905). The target is explicitly a variant FGA entity in an amyloid model. Its extracellular location is compatible with FGA secretion, but the pathological fibril model is not a core physiological activity of normal FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-977136 reaches Variant fibrinogen alpha chain [extracellular region] (20–866; route 977136 → 977175 → 977105 → 976905). The target is explicitly a variant FGA entity in an amyloid model. Its extracellular location is compatible with FGA secretion, but the pathological fibril model is not a core physiological activity of normal FGA.

Summary: FGA-derived extracellular material is explicitly present in the curated reaction entities.

Reason: R-HSA-9936699 reaches FGA(20-866) [extracellular region] (20–866; route 9936699 → 114618 → 140841). The source places intact fibrinogen in an extracellular amyloid-associated complex. Complex membership supplies the location claim; it does not make FGA a catalyst of amyloid formation.

Summary: FGA is a structural subunit of the fibrinogen complex.

Reason: The positive IBD at PTN008715159 agrees with the actual fibrinogen heterohexamer architecture. The chicken donor structure in PMID:11601975 contains two alpha chains together with two beta and two gamma chains. Human target complex records independently support the same composition. The newly recovered official tree places human P02671 leaf PTN002499061 beneath PTN008715159, and its ungapped 866-residue MSA sequence exactly matches the preserved canonical UniProt sequence.

Summary: The α chain is an established subunit of the fibrinogen complex.

Reason: The full PMID:16846481 source was not recovered, so its particular variant or review details are not treated as independently verified assays. The same generic complex-membership claim is established directly by human-chain assembly experiments and the human fibrinogen structure. Retain that positive claim with curator deference; unlike the separately collapsed processed-product row, this source row has no raw free-fibrinopeptide-A identity.

Summary: The α chain is an established subunit of the fibrinogen complex.

Reason: The full PMID:18676163 source was not recovered, so its particular variant or review details are not treated as independently verified assays. The same generic complex-membership claim is established directly by human-chain assembly experiments and the human fibrinogen structure. Retain that positive claim with curator deference; unlike the separately collapsed processed-product row, this source row has no raw free-fibrinopeptide-A identity.

Summary: The α chain is incorporated into assembled fibrinogen.

Reason: Human-chain cell-fusion experiments in PMID:8910396 detect α, β and γ chains in the assembled intracellular and secreted complex. The paper also examines assembly intermediates in human hepatoma cells. This directly supports complex membership, without equating experimental chain constructs with both natural splice products.

Summary: The combined electronic inference correctly places FGA in fibrinogen.

Reason: ARBA00086903 contains a human-compatible FunFam branch, and IPR012290 matches the target coiled-coil region. The actual Reactome fibrinogen entity has two FGA subunits with FGB and FGG. This is complex membership, not a claim that an isolated alpha chain reproduces the complete fibrinogen complex.

Summary: The merged source row combines mature-chain and free-fibrinopeptide-A identities.

Reason: The accepted raw source contains distinct PRO_0000009021 (fibrinopeptide A, canonical residues 20–35) and PRO_0000009022 (mature α chain, 36–866) contexts that project to this one seed row. PMID:19296670 establishes an α-chain-containing fibrinogen complex, but its heterogeneous purified preparation and partial fibrinopeptide cleavage do not establish free fibrinopeptide A as a stable complex subunit. Preserve both raw joins and the positive mature-chain evidence; one unqualified decision for the collapsed product assertion remains unresolved. Declaring both cleavage products in functional_isoforms documents their identities but does not add a product discriminator to this collapsed imported annotation. A mature-chain-only positive decision would silently discard the free-peptide assertion; the mixed mapping therefore remains unresolved without editing the source.

Summary: The α chain is an established subunit of the fibrinogen complex.

Reason: The full PMID:10467729 source was not recovered, so its particular variant or review details are not treated as independently verified assays. The same generic complex-membership claim is established directly by human-chain assembly experiments and the human fibrinogen structure. Retain that positive claim with curator deference; unlike the separately collapsed processed-product row, this source row has no raw free-fibrinopeptide-A identity.

Summary: FGA has a supported ER localization during its biosynthetic passage.

Reason: The actual HPA target record contains enhanced Hep-G2 immunofluorescence localization to the ER with HPA051370 and HPA064755. Both inspected images show the reported reticular/perinuclear pattern. Retain the experimentally observed ER compartment as a biosynthetic location; these images do not resolve the ER lumen or distinguish the two natural splice products.

Summary: FGA is modeled in the ER lumen as a secretory-pathway kinase substrate.

Reason: The actual FAM20C substrate routes identify FGA [endoplasmic reticulum lumen] (36–866; route 8952289 → 8952321 → 8956956 → 8956714); p-FGA [endoplasmic reticulum lumen] (36–866; route 8952289 → 8952335 → 8956996 → 8957043). FGA is a member of the FAM20C substrate set, not the kinase. The model uses residues 36–866 in the ER lumen; these literal modeled coordinates are retained as provenance, not treated as an independent demonstration of thrombin-like fibrinopeptide release in the ER. ER-lumen residence is a biosynthetic/processing location, distinct from the principal extracellular structural activity.

Summary: The modeled membrane association is covered more precisely by the existing external-side annotation.

Reason: The actual route identifies FGA in the platelet-surface fibrin–integrin complex: FGA [extracellular region] (36–866; route 114560 → 139933 → 140586 → 140583); FGA [plasma membrane] (36–866; route 114560 → 114559 → 139934 → 140919 → 140916). Fibrin is associated with the extracellular face of an integrin-containing plasma-membrane complex. This is peripheral receptor association, not an integral membrane topology. Factor XIII or the receptor supplies its own catalytic/signaling activity. GO:0009897 external side of plasma membrane is a verified part_of descendant of GO:0005886 and explicitly includes peripheral association. The retained specific row 77 covers this extracellular association; no broader membrane topology is demonstrated by this event.

Summary: The modeled membrane association is covered more precisely by the existing external-side annotation.

Reason: The actual route identifies FGA in the platelet-surface fibrin–integrin complex: FGA [plasma membrane] (36–866; route 9921091 → 114559 → 139934 → 140919 → 140916). Fibrin is associated with the extracellular face of an integrin-containing plasma-membrane complex. This is peripheral receptor association, not an integral membrane topology. Factor XIII or the receptor supplies its own catalytic/signaling activity. GO:0009897 external side of plasma membrane is a verified part_of descendant of GO:0005886 and explicitly includes peripheral association. The retained specific row 77 covers this extracellular association; no broader membrane topology is demonstrated by this event.

Summary: Immobilized fibrinogen supports endothelial cell–matrix adhesion.

Reason: PMID:10903502 measures endothelial attachment to human fibrinogen and recognition fragments/peptides. The positive substrate-adhesion context is retained as non-core; receptor recognition by the assembled ligand, including a γ-chain peptide, is not evidence that isolated α chain independently performs every binding step.

Summary: The coagulation mapping is covered by retained specific coagulation and platelet roles.

Reason: IPR037579 is the actual target-matching family mapping. FGA contributes structure to fibrin formation rather than acting as a coagulation protease. The retained common-pathway annotation GO:0072377 and platelet-aggregation annotations provide the specific roles; the saved strict is_a/part_of ontology relationships place these within blood coagulation. No additional target role is demonstrated by this broad family mapping.

Summary: Fibrin derived from platelet fibrinogen associates with the external platelet surface.

Reason: PMID:6777381 detects surface-iodinated fibrin chains after human platelet activation, and divalent-cation conditions alter their retention. This is extracellular surface association, not a transmembrane topology or exclusive residence. Retain the conditional location as non-core and preserve the fibrin-versus-fibrinogen distinction.

Summary: FGA-derived material associates with the extracellular face of activated platelets.

Reason: The actual ARBA00043397 rule matches a target FunFam branch. Independent evidence includes the Reactome surface fibrin–integrin complexes and the original PMID:6777381 observation of secreted fibrin on stimulated platelet surfaces. GO:0009897 explicitly includes peripheral association. This is an extracellular ligand association, not an integral-membrane topology or a universal localization of every product.

Summary: Cell surface is a supported parent of the more precise external plasma-membrane location.

Reason: The same PMID:6777381 surface-labeling experiment supports the external side of the platelet plasma membrane, retained separately. Official typed ancestry places GO:0009897 under GO:0009986. The broader location adds no distinct compartment in this source context; this is a precision judgment, not a rejection of the positive surface association.

Summary: The broad platelet-activation mapping is covered by platelet aggregation.

Reason: IPR012290 maps the actual target coiled-coil family to platelet activation. The specific retained GO:0070527 platelet aggregation is a verified part_of child of this term and captures fibrinogen's adhesive contribution. This mapping alone does not establish that FGA executes platelet secretion, calcium sensing or the intracellular activation machinery.

Summary: Human alpha-C assemblies support the more specific enzyme-substrate adaptor interpretation.

Reason: The preserved IBD at PTN008715159 asserts broad GO:0030674 and uses the chicken FGA structure PMID:11601975. Complex architecture alone is not an adaptor assay. Independent human evidence in PMID:21806028 shows that the same Aα221–610 oligomer preparation binds the enzyme tPA and its substrate plasminogen in both assay orientations and enhances coupled plasmin generation, unlike weak monomer controls. This supports the verified enzyme-substrate adaptor child term. The refinement does not alter the literal broad IBD or infer ancestral placement of the child term. Simultaneous ternary occupancy, stoichiometry and comparative substrate preference were not directly measured. The newly recovered official tree places human P02671 leaf PTN002499061 beneath PTN008715159, and its ungapped 866-residue MSA sequence exactly matches the preserved canonical UniProt sequence.

Proposed replacements: enzyme-substrate adaptor activity

Summary: FGA is detected in human tissue extracellular-matrix preparations.

Reason: The actual PMID:25037231 target data contain FGA/P02671 in fractionated human tissue material. Retain this positive matrix-associated location as non-core. Bulk proteomic fractions and protein groups do not resolve intact precursor, αE, free fibrinopeptide A, or every insoluble fibrin assembly; they also do not exclude plasma-derived material.

Summary: The exact FGA proteomic target record remains unresolved in this study.

Reason: The recovered original Figure 5B names FGA in a gene-expression heatmap. That is not the missing protein-identification row supporting this HDA annotation. The operative proteomic supplement and its sample-specific FGA join were not recovered. Independent fibrin biology does not verify this particular high-throughput target record, so retain uncertainty rather than alleging a wrong-gene assignment. The general extracellular-matrix localization claim has positive independent support elsewhere in this review. This UNDECIDED action is restricted to the unresolved original HDA protein/sample assertion, under the standing instruction to retain uncertainty when relevant target evidence cannot be accessed; it is not a negative gene-level claim or a requirement to rediscover all established biology. The original evidence code, qualifier and source remain unchanged.

Summary: FGA is detected in human tissue extracellular-matrix preparations.

Reason: The actual PMID:28675934 target data contain FGA/P02671 in fractionated human tissue material. Retain this positive matrix-associated location as non-core. Bulk proteomic fractions and protein groups do not resolve intact precursor, αE, free fibrinopeptide A, or every insoluble fibrin assembly; they also do not exclude plasma-derived material.

Summary: The platelet α-granule annotation is retained as a contextual storage location.

Reason: PMID:6777381 examines proteins released from activated human platelets and discusses fibrinogen among previously established α-granule constituents. Its surface experiments directly measure extracellular fibrin after release, rather than newly resolving α-granule lumen by microscopy. Retain the curator-supported storage context as non-core, with that source boundary explicit and without transferring thrombospondin-specific evidence to FGA.

Summary: FGA-containing fibrinogen is stored in the platelet alpha-granule lumen.

Reason: ARBA00084788 contains the actual target-matching FunFam branch. The independent Reactome R-HSA-481007 input route reaches lumenal FGA entity 140920 through the fibrinogen cargo complex. Retain the storage location without assigning the exocytosis machinery or a particular granule-entry mechanism to FGA.

Summary: Fibrinogen containing FGA is explicit platelet alpha-granule lumen cargo.

Reason: The input path 481007 → 481003 → 114617 → 140920 reaches FGA(20–866) in the platelet alpha-granule lumen. FGA is a fibrinogen subunit in the lumenal cargo set and the extracellular released set. Cargo localization does not establish that FGA executes the exocytosis machinery. Retain this storage compartment as non-core; the model does not identify a granule-entry mechanism or distinguish the two natural splice products experimentally.

Summary: Assembled αC regions contribute cofactor activity to plasminogen activation.

Reason: The original PMID:16846481 R16C report remains abstract-only in the available evidence. The same gene-level participation is independently established by human recombinant αC oligomers that bind tPA and plasminogen and enhance plasmin generation, and by reduced but persistent activation on αC-truncated human fibrin. Thus FGA-derived structure supplies template/cofactor work; tPA performs the proteolytic activation. Activity depends on assembly state and is not assigned to free fibrinopeptide A or equally to all splice products.

Summary: FGA alpha-C assemblies contribute cofactor activity to plasminogen activation.

Reason: The ARBA00087422 inference is supported by actual human alpha-C assembly evidence. In PMID:21806028, oligomeric Aα221–610 assemblies bind tPA and plasminogen and strongly enhance plasmin generation, whereas soluble monomers have weak activity and internally cross-linked monomers are intermediate. PMID:37082262 shows reduced, not abolished, activation with alpha-C-truncated fibrin. FGA supplies a binding/template contribution; tPA performs the proteolysis. These construct-dependent results do not establish equal activity of every splice or processed product.

Summary: FGA contributes within the fibrinogen complex to contextual heterotypic adhesion.

Reason: The verified PMID:8100742 abstract reports increased adhesion of myeloid and lymphoid cells to endothelium with fibrinogen or normal human plasma and describes complementary-receptor bridging. FGA supplies structure to the intact fibrinogen complex; involvement in this contextual adhesion process does not require an autonomous alpha-chain receptor-binding interface. Retain the existing claim as non-core by explicit deference to the reliable curator attribution, not by claiming new chain-resolved experiments. The operative full Methods/Results remain inaccessible, so direct alpha-chain contacts, a chain-specific perturbation and equivalent activity of all products are unresolved. The positive IBD and exact target descent support this curator deferral; target P02671 in WITH/FROM is legitimate descendant evidence, not circularity. Verified ancestry is not additional biological experimentation.

Summary: FGA contributes within the fibrinogen complex to contextual heterotypic adhesion.

Reason: The verified PMID:8100742 abstract reports increased adhesion of myeloid and lymphoid cells to endothelium with fibrinogen or normal human plasma and describes complementary-receptor bridging. FGA supplies structure to the intact fibrinogen complex; involvement in this contextual adhesion process does not require an autonomous alpha-chain receptor-binding interface. Retain the existing claim as non-core by explicit deference to the reliable curator attribution, not by claiming new chain-resolved experiments. The operative full Methods/Results remain inaccessible, so direct alpha-chain contacts, a chain-specific perturbation and equivalent activity of all products are unresolved.

Summary: FGA contributes within the fibrinogen complex to contextual heterotypic adhesion.

Reason: The verified PMID:8100742 abstract reports increased adhesion of myeloid and lymphoid cells to endothelium with fibrinogen or normal human plasma and describes complementary-receptor bridging. FGA supplies structure to the intact fibrinogen complex; involvement in this contextual adhesion process does not require an autonomous alpha-chain receptor-binding interface. Retain the existing claim as non-core by explicit deference to the reliable curator attribution, not by claiming new chain-resolved experiments. The operative full Methods/Results remain inaccessible, so direct alpha-chain contacts, a chain-specific perturbation and equivalent activity of all products are unresolved. The verified human-compatible ARBA FunFam branch supports the existing inference but supplies no new chain-resolved experiment.

Summary: The inherited fibrinolysis role is supported by an alpha-C cofactor contribution.

Reason: The literal positive IBD at PTN008715159 agrees with independent human alpha-C evidence. PMID:21806028 demonstrates tPA/plasminogen binding and enhanced plasmin formation by oligomeric alpha-C assemblies, and PMID:37082262 finds reduced activation after alpha-C truncation in fibrin. This is positive participation as a template/cofactor, beyond simply being the substrate of lysis. The disagreement with earlier monomer-binding results remains explicit. The newly recovered official tree places human P02671 leaf PTN002499061 beneath PTN008715159, and its ungapped 866-residue MSA sequence exactly matches the preserved canonical UniProt sequence.

Summary: Fibrin α-chain assemblies actively support fibrinolysis as a cofactor template.

Reason: FGA-derived fibrin is not merely a substrate that disappears during lysis. Actual human αC-oligomer experiments enhance tPA-mediated plasmin formation, and αC truncation reduces that support in human fibrin. These provide participation evidence for the existing fibrinolysis annotation while the original PMID:16846481 full assay remains inaccessible. The α chain is not itself a plasminogen-activating protease, and free fibrinopeptide A is not assigned this cofactor role.

Summary: The electronic fibrinolysis annotation has direct cofactor support.

Reason: ARBA00088389 matches the target FunFam branch. Human alpha-C assemblies support tPA-mediated plasminogen activation, and alpha-C truncation reduces activation on fibrin in the inspected primary studies. This supports a contribution to fibrinolysis rather than the inference that every protein being degraded participates in its own degradation. Soluble monomer, oligomer and intact fibrin preparations are not interchangeable.

Summary: Human fibrinogen supports bacterial agglutination in the reported assay.

Reason: PMID:24367264 directly compares purified human fibrinogen with other protein conditions and demonstrates fibrinogen-containing bacterial clumps. Retain this host-ligand context as non-core. The assay concerns the intact fibrinogen complex and does not isolate an α-chain binding site or establish an intrinsic antimicrobial catalytic function.

Summary: Human fibrinogen promotes vasoconstriction in the reported rat vascular preparations.

Reason: The actual PMID:15739255 Methods identify purified human plasma fibrinogen and plasmin-derived fragment D; the responding vessels are rat. Results and Figures 6–8 support an endothelium-dependent response with ICAM-1 and endothelin-receptor pharmacology. Retain the contextual positive process without making it a human in-vivo demonstration, an autonomous α-chain activity, or an exclusive receptor mechanism.

Summary: Human fibrinogen can promote vasoconstriction in a bounded rat vascular model.

Reason: ARBA00086111 matches the actual target FunFam branch. The recovered original PMID:15739255 identifies human plasma fibrinogen and its fragment D applied to rat vessels; binding and vasoconstriction were reduced by anti-fibrinogen/ICAM1 controls, with endothelial and endothelin-receptor dependence. This is a conditional whole-complex effect, not autonomous alpha-chain receptor contact or direct smooth-muscle contractile machinery. PMID:19193866 provides complementary human-fibrinogen/rat-endothelial secretion context.

Summary: Fibrinogen stimulates endothelial release of stored mediators in the tested context.

Reason: PMID:19193866 measures increased endothelin-1 and von Willebrand factor release after human fibrinogen exposure in rat endothelial preparations, with ERK-pathway support. Retain positive regulation of exocytosis as a non-core ligand effect. Fibrinogen is not the vesicle-fusion machinery, and the result does not demonstrate secretion regulation by every isolated FGA product.

Summary: Fibrinogen promotes endothelial protein secretion in the reported preparation.

Reason: The actual PMID:19193866 release measurements include both peptide hormone endothelin-1 and nonhormonal von Willebrand factor. Protein secretion therefore retains useful output scope beyond the separate peptide-hormone annotation. Keep the positive response as non-core and bounded to intact human fibrinogen acting on rat endothelial cells, rather than a secretory-machinery function of the α chain.

Summary: The α chain contributes as a subunit of fibrinogen that binds ICAM-1.

Reason: PMID:9182580 directly demonstrates specific, saturable fibrinogen binding to human Raji cells, competition and ICAM-1 antibody blockade. Human plasma fibrinogen and its fragments were tested; γ-chain recognition peptides account for important activity, whereas the α-chain peptide comparisons concern proliferation rather than a definitive negative binding assay. Preserve the weaker imported contributes_to claim for the assembled ligand, not an autonomous α-chain ICAM-1-binding site.

Summary: FGA αC regions contribute directly to fibrin polymer assembly.

Reason: The original PMID:12706644 full Magdeburg assay was not recovered. Independent human plasma-fibrinogen truncation experiments directly show that removing αC portions changes the lag phase, protofibril association and resulting fiber architecture. This supports the same generic polymerization claim by structural participation, not merely because thrombin consumes a substrate. The artificial truncations are not natural splice products.

Summary: FGA contributes directly to fibrin polymer assembly.

Reason: Both ARBA00028914 and the target-matching IPR012290 coiled-coil family map protein polymerization. Actual Reactome fibrin assembly includes FGA-containing monomers; thrombin cleavage exposes the chain's polymerization interface, while alpha-C interactions contribute lateral assembly. FGA supplies structure to the growing polymer, so the role is more than being cleaved. Factor XIII supplies the cross-linking enzyme activity, and the literal modeled chain coordinates are not generalized across both splice products.

Summary: Fibrin surface association changes with extracellular calcium conditions.

Reason: PMID:6777381 directly varies divalent-cation conditions and measures fibrin retention on activated human platelets. That supports a contextual calcium response by the extracellular fibrinogen-derived material. It does not identify FGA as a calcium sensor or show that FGA performs platelet secretion; those stronger interpretations are not retained.

Summary: Calcium-dependent platelet-surface association is a contextual response.

Reason: ARBA00088699 matches the actual target FunFam branch. The recovered original PMID:6777381 identifies secreted fibrinogen converted to fibrin and its calcium-dependent binding to activated human platelets, including fibrin-chain surface labeling in Figure 3. Retain this bounded extracellular-association response; the evidence does not assign calcium sensing, an intracellular calcium-signaling activity or the secretion machinery to FGA.

Summary: The α chain performs structural work during fibrinogen-complex assembly.

Reason: PMID:8910396 follows pre-existing chain complexes into assembled fibrinogen after cell fusion, including experiments that inhibit new protein synthesis. The α chain joins other subunits and supplies part of the resulting macromolecular structure. This establishes assembly participation rather than relying solely on the failure of assembly when a chain is absent. This intracellular assembly of the soluble heteromer through alpha–gamma and beta–gamma intermediates is distinct from subsequent extracellular fibrin polymerization. Although GO:0051258 is an is_a child of GO:0065003, that narrower polymerization claim does not exhaust the independently observed complex-assembly scope, so TOO_GENERAL is not appropriate here.

Summary: FGA participates structurally in fibrinogen-complex assembly.

Reason: PMID:18676163 reports a human FGA variant affecting assembly, but its full original experiment remains inaccessible here. The identical general assembly role is directly established by independently read human-chain experiments in PMID:8910396. Accept that role while retaining the access limit for the variant-specific mechanism and making no equal-product claim. This intracellular assembly of the soluble heteromer through alpha–gamma and beta–gamma intermediates is distinct from subsequent extracellular fibrin polymerization. Although GO:0051258 is an is_a child of GO:0065003, that narrower polymerization claim does not exhaust the independently observed complex-assembly scope, so TOO_GENERAL is not appropriate here.

Summary: FGA is detected in a human urinary low-density membrane preparation enriched in exosomes.

Reason: The actual PMID:19056867 Table 1 identifies fibrinogen α-E preproprotein separately from the neighboring FGG entry, with five unique peptides and 17 spectra. Retain the positive exosome-associated proteomic context as non-core. The protein label and group-level peptides do not prove an intact αE precursor, isoform-specific sequence coverage, or intraluminal residence.

Summary: The original FGA target join in this urinary exosome dataset is unavailable.

Reason: PMID:23533145 study identity and exosome-proteomics Methods were recovered, but the exact FGA supplemental protein record was not. A positive urinary FGA result in another paper does not establish this source-specific sample/target assertion. Keep the curator’s annotation unresolved rather than infer a wrong protein, absent localization or contamination. The general urinary-exosome association claim has positive independent support elsewhere in this review. This UNDECIDED action is restricted to the unresolved original HDA protein/sample assertion, under the standing instruction to retain uncertainty when relevant target evidence cannot be accessed; it is not a negative gene-level claim or a requirement to rediscover all established biology. The original evidence code, qualifier and source remain unchanged.

Summary: Fibrinogen ligation promotes endothelial ERK1/2 activation.

Reason: PMID:10903502 directly measures ERK1/2 phosphorylation and uses receptor-recognition and MEK-pathway controls in the endothelial adhesion/survival setting. The response is elicited by intact human fibrinogen or a γ-chain recognition peptide. Retain the downstream signaling context as non-core; it is not kinase activity of FGA or a direct α-chain-specific signaling mechanism.

Summary: Fibrinogen exposure activates ERK signaling in the tested endothelial system.

Reason: The actual PMID:19193866 Results connect human fibrinogen exposure, ERK phosphorylation and mediator release in rat endothelial preparations. Keep the positive signaling context as non-core, with species and intact-complex limits. The experiment does not confer kinase activity on the α chain.

Summary: Fibrinogen supports platelet aggregation, while the cited disease proteomics alone is not causal proof.

Reason: PMID:23382103 identifies reduced fibrinogen α-chain abundance in platelets from patients with myelodysplastic syndromes and measures accompanying functional defects. That association does not isolate FGA as the cause. Independent human platelet experiments demonstrate aggregation support by isolated α-chain preparations and by α-chain-containing fibrinogen, establishing structural participation in the same process. The isolated-chain preparations are artificial, not a comparison of natural splice products.

Summary: The inherited platelet-aggregation role is supported by fibrinogen's adhesive contribution.

Reason: The positive IBD at PTN008715159 has human and zebrafish descendant evidence. The actual human-chain study PMID:6281794 reports platelet aggregation with alpha-chain preparations, weaker than with gamma-chain preparations and dependent on the preparation's assembly state. Together with intact fibrinogen's adhesive role, this supports positive participation rather than mere necessity. The newly recovered official tree places human P02671 leaf PTN002499061 beneath PTN008715159, and its ungapped 866-residue MSA sequence exactly matches the preserved canonical UniProt sequence. Equal activity of all natural products is not established.

Summary: The fibrinogen α chain contributes to platelet aggregation.

Reason: PMID:6281794 directly tests purified human fibrinogen chains with human platelets. The α-chain preparation supports weaker aggregation than γ chain or intact fibrinogen under the reported activation conditions; the β-chain control does not. These experiments demonstrate functional structural participation, while the authors’ chain self-association caveat limits extrapolation from reduced/carboxymethylated preparations to intact circulating products.

Summary: The electronic platelet-aggregation inference is supported.

Reason: ARBA00085186 contains a target-matching primate FunFam branch. Intact fibrinogen and the alpha-chain preparations in PMID:6281794 support platelet aggregation, with weaker alpha-chain reactivity and a self-association caveat. FGA contributes to the adhesive assembly; this does not make every chain or released fibrinopeptide independently sufficient for aggregation.

Summary: FGA contributes the fibrin structure formed in the common coagulation pathway.

Reason: The positive IBD at PTN008715159 agrees with the actual formation of FGA-containing fibrin monomers and polymers in the common pathway. The official term includes stable fibrin assembly after thrombin cleavage. FGA supplies the polymer's structural subunit; thrombin and Factor XIII perform their respective catalytic steps. A released fibrinopeptide is not assigned the same structural role merely because the seed lost product qualifiers elsewhere.

Summary: The mature α-chain product contributes structure to the common coagulation pathway.

Reason: The raw source explicitly identifies PRO_0000009022, the mature α chain, rather than free fibrinopeptide A. Human FGA deficiency in PMID:10891444 establishes clinical necessity; independent chain assembly and αC-dependent fibrin-polymerization experiments establish the structural work supporting coagulation. Retain the existing process with that product scope, without assigning thrombin’s proteolytic activity or blanket canonical-coordinate processing to both natural splice forms.

Summary: FGA contributes fibrin structure to the common coagulation pathway.

Reason: Although the full PMID:12706644 variant experiments were inaccessible, the general process claim is independently supported by directly observed human α-chain assembly and αC-dependent fibrin polymerization. Retain the structural contribution without claiming that FGA catalyzes coagulation proteolysis or that the specific Magdeburg biochemical defect was fully rechecked.

Summary: One seed row collapses mature-chain clot formation and free-fibrinopeptide-A source contexts.

Reason: Raw contexts 130 and 134 separately identify fibrinopeptide A (PRO_0000009021) and mature α chain (PRO_0000009022), then collapse into this seed assertion. Mature α chain contributes to fibrin structure, but cleavage/release of fibrinopeptide A does not by itself show that the free peptide performs clot formation. The original PMID:16846481 full R16C experiments were not recovered. Preserve the mixed source mapping and positive mature-chain biology while leaving the joint row unresolved; do not silently turn it into a precursor-only claim. Declaring both cleavage products in functional_isoforms documents their identities but does not add a product discriminator to this collapsed imported annotation. A mature-chain-only positive decision would silently discard the free-peptide assertion; the mixed mapping therefore remains unresolved without editing the source.

Summary: Fibrin clot formation is covered by the retained common-pathway assertion.

Reason: ARBA00090798 matches the actual target FunFam branch. GO:0072377 blood coagulation, common pathway is a verified part_of child of GO:0072378 and explicitly includes assembly of cleaved fibrin into a stable cross-linked complex. The retained row 115 captures FGA's structural role; the broader rule adds no separate upstream enzymatic activity.

Summary: The FGA blood-microparticle target record remains inaccessible.

Reason: The original PMID:22516433 identity and abstract were verified, but the relevant original protein table could not be accessed. Other vesicle or plasma studies cannot establish this specific microparticle identification. Retain uncertainty without asserting a wrong-gene annotation or excluding extracellular association.

Summary: Fibrinogen stimulates endothelin-1 release in the reported endothelial context.

Reason: PMID:19193866 measures increased release of the peptide hormone endothelin-1 after human fibrinogen exposure in rat endothelial preparations, with ERK-pathway involvement. Retain this ligand-induced output as non-core. It is neither hormone activity of fibrinogen nor direct operation of the endothelial secretion machinery.

Summary: Intact fibrinogen can promote peptide-hormone release in a bounded endothelial model.

Reason: ARBA00087042 is supported contextually by PMID:19193866: human plasma fibrinogen increased endothelin-1 release from rat heart microvascular endothelial cells, with ICAM1 and MEK/ERK controls. The assay used the intact fibrinogen complex, not isolated alpha chain or human endothelial cells. Retain the conditional regulatory output without assigning secretory machinery or hormone activity to FGA.

Summary: FGA-derived fibrin can contribute to the noncollagenous interstitial matrix.

Reason: PMID:36399478 describes MatrisomeDB reprocessing and classification; this lane read those Methods but did not recover a separate current FGA query result. Independent exact FGA target records in human tissue ECM preparations support a noncollagenous matrix-associated pool. Retain the broad contextual location with curator deference, without claiming a new MatrisomeDB target measurement, excluding plasma-derived material, or making all circulating fibrinogen an interstitial matrix constituent.

Summary: The particular trophoblast spreading assay remains incompletely accessible.

Reason: The verified PMID:24041635 abstract reports enhanced spreading of early-term human trophoblasts on fibrin compared with other substrate conditions. The operative Methods, figures and relevant α-chain context were not recovered. Retain the positive reported observation but leave this source-specific process unresolved; neither general fibrin structure nor a separate endothelial assay substitutes for this target-cell comparison.

Summary: Fibrinogen ligation protects TNFα-treated endothelial cells from apoptosis.

Reason: PMID:10903502 Table 1 and associated experiments measure reduced annexin-V positivity during adhesion of TNFα-treated endothelial cells to fibrinogen or its γ-chain recognition peptide, with ICAM-1/ERK controls. Retain the contextual negative regulation of the death-receptor-associated apoptotic response as non-core. The evidence does not make FGA a death receptor, caspase inhibitor or autonomous α-chain anti-apoptotic factor.

Summary: A conditional anti-apoptotic effect is supported for the fibrinogen complex.

Reason: ARBA00088654 is consistent with the inspected PMID:10903502 adhesion/survival experiments in TNFalpha-conditioned endothelial cells. Intact human fibrinogen, fragment D and a gamma-chain ICAM1-binding peptide supported survival, with ICAM1/ERK controls. Retain the complex-associated regulatory context without claiming that FGA is a death-receptor inhibitor or that its isolated chain supplies the mapped gamma-chain contact.

Summary: FGA is present in the deposited human cerebrospinal-fluid vesicle-enriched dataset.

Reason: The original PXD000608 proteinGroups table contains FGA with majority accessions P02671/P02671-2 and positive measurements in exosome-enriched and soluble fractions. Retain extracellular-vesicle association as non-core, without inferring exclusive localization, vesicle-lumen residence, a natural-splice-specific protein or free fibrinopeptide A from database labels. The full protein group and blank identification flags are preserved in the source table; the publisher main-text access remained limited.

Summary: The negative-coagulation annotation is specifically attached to fibrinopeptide A in the raw source.

Reason: Raw context 131 identifies PRO_0000009021, fibrinopeptide A, rather than the fibrinogen precursor or mature α chain. The full PMID:11529842 review and the relevant supporting mechanism were not recovered. General fibrin–thrombin interactions or the requirement to cleave FPA cannot establish an inhibitory activity of the released peptide. Preserve the source and explicit product mapping while leaving the claim unresolved.

Summary: Fibrinogen supports endothelial survival in the tested adhesion conditions.

Reason: PMID:10903502 measures endothelial apoptosis directly and tests ICAM-1 recognition, MEK inhibition and dominant-negative ERK controls. Retain the positive survival effect as a non-core property of the assembled ligand in this cellular context. The γ-chain peptide results prevent an unsupported claim that the isolated α chain independently supplies the entire anti-apoptotic mechanism.

Summary: Fibrinogen-associated endothelial survival is a non-core regulatory context.

Reason: ARBA00087055 matches the target FunFam branch, and PMID:10903502 reports reduced endothelial apoptosis during adhesion to intact human fibrinogen with receptor/ERK-dependent effects. The active gamma-chain peptide and fragment D limit any autonomous alpha-chain interpretation. Retain the conditional complex-level effect rather than a universal anti-apoptotic function of FGA products.