{"gene":"RAB3C","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1994,"finding":"RAB3C is localized on synaptic vesicles and, like RAB3A, undergoes membrane dissociation-association cycles in parallel with exocytotic neurotransmitter release. Stimulation of neurotransmitter release in isolated nerve terminals caused dissociation of RAB3C from synaptic vesicle and/or recycling membranes. Immunoisolation with anti-RAB3A antibodies co-enriched RAB3C, demonstrating co-localization on the same organelle.","method":"Synaptic vesicle purification, immunoisolation with monoclonal antibodies (Co-IP), subcellular fractionation with stimulation of exocytosis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal immunoisolation and fractionation with stimulation paradigm; replicated across multiple experimental conditions in the same study","pmids":["8157621"],"is_preprint":false},{"year":1997,"finding":"RAB3C has distinct biochemical properties from RAB3A and RAB3B: its Kd for GTPγS is 204 nM (intermediate between RAB3A at 15 nM and RAB3B at 2700 nM). Truncation of the C-terminal 31 amino acids decreased GTPγS binding affinity; replacing RAB3C's C-terminus with that of RAB3A decreased binding affinity further. RAB3C is localized to vesicle-like structures in chromaffin cells (distinct from RAB3B which localizes to plasma membrane). Cell lysate increased intrinsic GTPase activity ~3-fold.","method":"In vitro GTPγS binding assays, C-terminal truncation and domain-swap mutagenesis, immunostaining/subcellular localization","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro biochemical assays with mutagenesis, single lab, multiple orthogonal methods","pmids":["9164844"],"is_preprint":false},{"year":2008,"finding":"Zwint-1 was identified as a RAB3C-specific binding protein. The interaction depends on a unique residue in RAB3C that determines binding efficiency to Zwint-1 but is not required for rabphilin3a interaction. RAB3C and Zwint-1 co-localize extensively in primary hippocampal neurons. SNAP25 binds to the same region in Zwint-1 as RAB3C, suggesting Zwint-1 may link RAB3C to SNARE-mediated presynaptic events.","method":"Binding partner screen, pulldown/co-immunoprecipitation, site-directed mutagenesis of critical RAB3C residue, co-localization in primary hippocampal neurons, SNAP25-Zwint-1 binding assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal binding assays with mutagenesis and co-localization, single lab, multiple orthogonal methods","pmids":["18625232"],"is_preprint":false},{"year":1995,"finding":"In cardiac muscle of lean rats, insulin stimulation causes translocation of RAB3C from microsomal membranes to plasma membranes (by subcellular fractionation and Western blotting). This insulin-dependent translocation is absent in insulin-resistant obese Zucker rats. RAB3C was not detectable in GLUT4-enriched membrane vesicles from either group.","method":"Subcellular fractionation, Western blotting, in vivo insulin stimulation in lean vs. insulin-resistant rats","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — subcellular fractionation with in vivo stimulus, single lab, single method","pmids":["8543030"],"is_preprint":false},{"year":2022,"finding":"RAB3C protein is localized to the manchette structure (which assists sperm head shaping) and the sperm tail in murine elongated spermatids. In mature human spermatozoa, RAB3C is concentrated in the postacrosomal region, neck, and midpiece. In human sperm harboring a SEPT14 mutation (which causes teratozoospermia), RAB3C signals are delocalized and decreased, associated with defective head and tail morphology, suggesting RAB3C localization depends on SEPT14.","method":"Immunofluorescence in murine testicular tissue and human spermatozoa, comparison of SEPT14 mutant vs. control sperm","journal":"Medicina (Kaunas, Lithuania)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, immunofluorescence localization only without functional rescue or direct mechanistic experiment","pmids":["36295569"],"is_preprint":false}],"current_model":"RAB3C is a synaptic vesicle-associated small GTPase that cycles on and off vesicle membranes during exocytosis; its C-terminus regulates GTP binding affinity, it interacts with the kinetochore protein Zwint-1 via a unique residue distinct from the rabphilin3a binding determinant, undergoes insulin-dependent translocation to the plasma membrane in cardiac muscle, and localizes to the manchette and tail structures during spermatogenesis in a SEPT14-dependent manner."},"narrative":{"mechanistic_narrative":"RAB3C is a small GTPase of the RAB3 family that associates with synaptic vesicles and undergoes regulated membrane dissociation-association cycles coupled to exocytotic neurotransmitter release [PMID:8157621]. It is distinguished from its paralogs RAB3A and RAB3B by an intermediate affinity for GTP, with its C-terminal 31 residues governing nucleotide binding affinity, and by a vesicle-like (rather than plasma membrane) localization in secretory cells [PMID:9164844]. RAB3C engages the kinetochore protein Zwint-1 through a unique residue that is distinct from the determinant required for rabphilin3a binding; because SNAP25 occupies the same region of Zwint-1, this interaction places RAB3C near the SNARE machinery of presynaptic terminals [PMID:18625232]. Beyond the synaptic and secretory context, RAB3C undergoes insulin-dependent translocation from microsomal to plasma membranes in cardiac muscle, a movement lost in insulin-resistant animals [PMID:8543030]. No catalytic effector or upstream regulator beyond these interactions has been characterized in the available corpus.","teleology":[{"year":1994,"claim":"Established that RAB3C is a genuine synaptic vesicle component whose membrane cycling is coupled to exocytosis, placing it in the regulated secretion machinery alongside RAB3A.","evidence":"Synaptic vesicle purification, immunoisolation, and subcellular fractionation under exocytosis stimulation in nerve terminals","pmids":["8157621"],"confidence":"High","gaps":["Functional consequence of RAB3C cycling for release kinetics not tested","No effector identified that reads the GTP-bound state","Relationship to RAB3A function (redundant vs. distinct) unresolved"]},{"year":1995,"claim":"Extended RAB3C beyond neurons by showing insulin triggers its membrane translocation in cardiac muscle, linking it to hormone-regulated trafficking.","evidence":"Subcellular fractionation and Western blotting after in vivo insulin stimulation in lean vs. insulin-resistant rats","pmids":["8543030"],"confidence":"Medium","gaps":["Single method without functional readout of the trafficking event","Cargo vesicle identity unclear (not in GLUT4 vesicles)","Molecular basis of insulin-dependent translocation unknown"]},{"year":1997,"claim":"Defined the biochemical individuality of RAB3C, showing its intermediate GTP affinity and that the C-terminus tunes nucleotide binding, distinguishing it from paralogs.","evidence":"In vitro GTPgammaS binding assays with C-terminal truncation and domain-swap mutagenesis plus subcellular localization in chromaffin cells","pmids":["9164844"],"confidence":"Medium","gaps":["Structural basis for C-terminal modulation of GTP affinity not determined","Physiological significance of intermediate affinity untested in cells","GAP/GEF responsible for the ~3-fold GTPase stimulation not identified"]},{"year":2008,"claim":"Identified Zwint-1 as a RAB3C-specific partner engaged via a unique residue distinct from the rabphilin3a determinant, and connected RAB3C to SNARE components through shared Zwint-1 binding with SNAP25.","evidence":"Binding partner screen, pulldown/co-IP, site-directed mutagenesis, and co-localization in hippocampal neurons","pmids":["18625232"],"confidence":"Medium","gaps":["Functional outcome of the RAB3C-Zwint-1-SNAP25 link not demonstrated in release assays","Whether interaction is GTP-state dependent unaddressed","Single lab, no in vivo loss-of-function validation"]},{"year":2022,"claim":"Placed RAB3C in spermatogenesis by localizing it to the manchette and sperm tail and showing its distribution depends on SEPT14, tying it to sperm morphogenesis.","evidence":"Immunofluorescence in murine testicular tissue and human spermatozoa comparing SEPT14 mutant vs. control","pmids":["36295569"],"confidence":"Low","gaps":["Localization-only study without functional rescue or direct mechanistic experiment","Direct physical interaction with SEPT14 not demonstrated","Role of RAB3C GTPase activity in sperm morphogenesis unknown"]},{"year":null,"claim":"The effector pathway downstream of GTP-bound RAB3C and the unifying function across synaptic, cardiac, and spermatid contexts remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No characterized GEF/GAP cycle for RAB3C","No loss-of-function phenotype linking RAB3C to a defined secretory or developmental output","Mechanistic connection between its membrane cycling and downstream fusion machinery unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["ZWINT","SNAP25","RPH3A","SEPT14"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96E17","full_name":"Ras-related protein Rab-3C","aliases":[],"length_aa":227,"mass_kda":26.0,"function":"The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96E17/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB3C","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RAB3C","total_profiled":1310},"omim":[{"mim_id":"612829","title":"RAS-ASSOCIATED PROTEIN RAB3C; RAB3C","url":"https://www.omim.org/entry/612829"},{"mim_id":"606630","title":"PROTEIN REGULATING SYNAPTIC MEMBRANE EXOCYTOSIS 2; RIMS2","url":"https://www.omim.org/entry/606630"},{"mim_id":"604350","title":"RAS-ASSOCIATED PROTEIN RAB3D; RAB3D","url":"https://www.omim.org/entry/604350"},{"mim_id":"601554","title":"DYNEIN, LIGHT CHAIN, TCTEX TYPE, 1; DYNLT1","url":"https://www.omim.org/entry/601554"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"adrenal gland","ntpm":8.5},{"tissue":"brain","ntpm":31.9}],"url":"https://www.proteinatlas.org/search/RAB3C"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q96E17","domains":[{"cath_id":"3.40.50.300","chopping":"26-198","consensus_level":"high","plddt":94.0352,"start":26,"end":198}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96E17","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96E17-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96E17-F1-predicted_aligned_error_v6.png","plddt_mean":82.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB3C","jax_strain_url":"https://www.jax.org/strain/search?query=RAB3C"},"sequence":{"accession":"Q96E17","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96E17.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96E17/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96E17"}},"corpus_meta":[{"pmid":"8157621","id":"PMC_8157621","title":"Rab3C is a synaptic vesicle protein that dissociates from synaptic vesicles after stimulation of exocytosis.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8157621","citation_count":133,"is_preprint":false},{"pmid":"18625232","id":"PMC_18625232","title":"A unique residue in rab3c determines the interaction with novel binding protein Zwint-1.","date":"2008","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/18625232","citation_count":26,"is_preprint":false},{"pmid":"8185573","id":"PMC_8185573","title":"Distribution and regulation of rab3C, a small molecular weight GTP-binding protein.","date":"1994","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8185573","citation_count":15,"is_preprint":false},{"pmid":"9164844","id":"PMC_9164844","title":"Characterization of Rab3A, Rab3B and Rab3C: different biochemical properties and intracellular localization in bovine chromaffin cells.","date":"1997","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/9164844","citation_count":12,"is_preprint":false},{"pmid":"8543030","id":"PMC_8543030","title":"Insulin-dependent translocation of the small GTP-binding protein rab3C in cardiac muscle: studies on insulin-resistant Zucker rats.","date":"1995","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8543030","citation_count":12,"is_preprint":false},{"pmid":"38770826","id":"PMC_38770826","title":"Citrulline facilitates the glycolysis, proliferation, and metastasis of lung cancer cells by regulating RAB3C.","date":"2024","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38770826","citation_count":5,"is_preprint":false},{"pmid":"12296628","id":"PMC_12296628","title":"Cloning, mapping, and characterization of the human Rab3C gene.","date":"2002","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12296628","citation_count":4,"is_preprint":false},{"pmid":"11573517","id":"PMC_11573517","title":"Molecular cloning of the mouse homologue of Rab3c.","date":"2001","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11573517","citation_count":4,"is_preprint":false},{"pmid":"36295569","id":"PMC_36295569","title":"Localization Patterns of RAB3C Are Associated with Murine and Human Sperm Formation.","date":"2022","source":"Medicina (Kaunas, Lithuania)","url":"https://pubmed.ncbi.nlm.nih.gov/36295569","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.18.670791","title":"Aberrant epithelialization: A plausible factor for the development of endometrial polyps","date":"2025-08-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.18.670791","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6267,"output_tokens":1501,"usd":0.020658,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8210,"output_tokens":2241,"usd":0.048537,"stage2_stop_reason":"end_turn"},"total_usd":0.069195,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"RAB3C is localized on synaptic vesicles and, like RAB3A, undergoes membrane dissociation-association cycles in parallel with exocytotic neurotransmitter release. Stimulation of neurotransmitter release in isolated nerve terminals caused dissociation of RAB3C from synaptic vesicle and/or recycling membranes. Immunoisolation with anti-RAB3A antibodies co-enriched RAB3C, demonstrating co-localization on the same organelle.\",\n      \"method\": \"Synaptic vesicle purification, immunoisolation with monoclonal antibodies (Co-IP), subcellular fractionation with stimulation of exocytosis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal immunoisolation and fractionation with stimulation paradigm; replicated across multiple experimental conditions in the same study\",\n      \"pmids\": [\"8157621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"RAB3C has distinct biochemical properties from RAB3A and RAB3B: its Kd for GTPγS is 204 nM (intermediate between RAB3A at 15 nM and RAB3B at 2700 nM). Truncation of the C-terminal 31 amino acids decreased GTPγS binding affinity; replacing RAB3C's C-terminus with that of RAB3A decreased binding affinity further. RAB3C is localized to vesicle-like structures in chromaffin cells (distinct from RAB3B which localizes to plasma membrane). Cell lysate increased intrinsic GTPase activity ~3-fold.\",\n      \"method\": \"In vitro GTPγS binding assays, C-terminal truncation and domain-swap mutagenesis, immunostaining/subcellular localization\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro biochemical assays with mutagenesis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"9164844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Zwint-1 was identified as a RAB3C-specific binding protein. The interaction depends on a unique residue in RAB3C that determines binding efficiency to Zwint-1 but is not required for rabphilin3a interaction. RAB3C and Zwint-1 co-localize extensively in primary hippocampal neurons. SNAP25 binds to the same region in Zwint-1 as RAB3C, suggesting Zwint-1 may link RAB3C to SNARE-mediated presynaptic events.\",\n      \"method\": \"Binding partner screen, pulldown/co-immunoprecipitation, site-directed mutagenesis of critical RAB3C residue, co-localization in primary hippocampal neurons, SNAP25-Zwint-1 binding assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal binding assays with mutagenesis and co-localization, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18625232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"In cardiac muscle of lean rats, insulin stimulation causes translocation of RAB3C from microsomal membranes to plasma membranes (by subcellular fractionation and Western blotting). This insulin-dependent translocation is absent in insulin-resistant obese Zucker rats. RAB3C was not detectable in GLUT4-enriched membrane vesicles from either group.\",\n      \"method\": \"Subcellular fractionation, Western blotting, in vivo insulin stimulation in lean vs. insulin-resistant rats\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — subcellular fractionation with in vivo stimulus, single lab, single method\",\n      \"pmids\": [\"8543030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RAB3C protein is localized to the manchette structure (which assists sperm head shaping) and the sperm tail in murine elongated spermatids. In mature human spermatozoa, RAB3C is concentrated in the postacrosomal region, neck, and midpiece. In human sperm harboring a SEPT14 mutation (which causes teratozoospermia), RAB3C signals are delocalized and decreased, associated with defective head and tail morphology, suggesting RAB3C localization depends on SEPT14.\",\n      \"method\": \"Immunofluorescence in murine testicular tissue and human spermatozoa, comparison of SEPT14 mutant vs. control sperm\",\n      \"journal\": \"Medicina (Kaunas, Lithuania)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, immunofluorescence localization only without functional rescue or direct mechanistic experiment\",\n      \"pmids\": [\"36295569\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB3C is a synaptic vesicle-associated small GTPase that cycles on and off vesicle membranes during exocytosis; its C-terminus regulates GTP binding affinity, it interacts with the kinetochore protein Zwint-1 via a unique residue distinct from the rabphilin3a binding determinant, undergoes insulin-dependent translocation to the plasma membrane in cardiac muscle, and localizes to the manchette and tail structures during spermatogenesis in a SEPT14-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAB3C is a small GTPase of the RAB3 family that associates with synaptic vesicles and undergoes regulated membrane dissociation-association cycles coupled to exocytotic neurotransmitter release [#0]. It is distinguished from its paralogs RAB3A and RAB3B by an intermediate affinity for GTP, with its C-terminal 31 residues governing nucleotide binding affinity, and by a vesicle-like (rather than plasma membrane) localization in secretory cells [#1]. RAB3C engages the kinetochore protein Zwint-1 through a unique residue that is distinct from the determinant required for rabphilin3a binding; because SNAP25 occupies the same region of Zwint-1, this interaction places RAB3C near the SNARE machinery of presynaptic terminals [#2]. Beyond the synaptic and secretory context, RAB3C undergoes insulin-dependent translocation from microsomal to plasma membranes in cardiac muscle, a movement lost in insulin-resistant animals [#3]. No catalytic effector or upstream regulator beyond these interactions has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that RAB3C is a genuine synaptic vesicle component whose membrane cycling is coupled to exocytosis, placing it in the regulated secretion machinery alongside RAB3A.\",\n      \"evidence\": \"Synaptic vesicle purification, immunoisolation, and subcellular fractionation under exocytosis stimulation in nerve terminals\",\n      \"pmids\": [\"8157621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of RAB3C cycling for release kinetics not tested\",\n        \"No effector identified that reads the GTP-bound state\",\n        \"Relationship to RAB3A function (redundant vs. distinct) unresolved\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Extended RAB3C beyond neurons by showing insulin triggers its membrane translocation in cardiac muscle, linking it to hormone-regulated trafficking.\",\n      \"evidence\": \"Subcellular fractionation and Western blotting after in vivo insulin stimulation in lean vs. insulin-resistant rats\",\n      \"pmids\": [\"8543030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single method without functional readout of the trafficking event\",\n        \"Cargo vesicle identity unclear (not in GLUT4 vesicles)\",\n        \"Molecular basis of insulin-dependent translocation unknown\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined the biochemical individuality of RAB3C, showing its intermediate GTP affinity and that the C-terminus tunes nucleotide binding, distinguishing it from paralogs.\",\n      \"evidence\": \"In vitro GTPgammaS binding assays with C-terminal truncation and domain-swap mutagenesis plus subcellular localization in chromaffin cells\",\n      \"pmids\": [\"9164844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis for C-terminal modulation of GTP affinity not determined\",\n        \"Physiological significance of intermediate affinity untested in cells\",\n        \"GAP/GEF responsible for the ~3-fold GTPase stimulation not identified\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified Zwint-1 as a RAB3C-specific partner engaged via a unique residue distinct from the rabphilin3a determinant, and connected RAB3C to SNARE components through shared Zwint-1 binding with SNAP25.\",\n      \"evidence\": \"Binding partner screen, pulldown/co-IP, site-directed mutagenesis, and co-localization in hippocampal neurons\",\n      \"pmids\": [\"18625232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional outcome of the RAB3C-Zwint-1-SNAP25 link not demonstrated in release assays\",\n        \"Whether interaction is GTP-state dependent unaddressed\",\n        \"Single lab, no in vivo loss-of-function validation\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed RAB3C in spermatogenesis by localizing it to the manchette and sperm tail and showing its distribution depends on SEPT14, tying it to sperm morphogenesis.\",\n      \"evidence\": \"Immunofluorescence in murine testicular tissue and human spermatozoa comparing SEPT14 mutant vs. control\",\n      \"pmids\": [\"36295569\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Localization-only study without functional rescue or direct mechanistic experiment\",\n        \"Direct physical interaction with SEPT14 not demonstrated\",\n        \"Role of RAB3C GTPase activity in sperm morphogenesis unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The effector pathway downstream of GTP-bound RAB3C and the unifying function across synaptic, cardiac, and spermatid contexts remain undefined.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No characterized GEF/GAP cycle for RAB3C\",\n        \"No loss-of-function phenotype linking RAB3C to a defined secretory or developmental output\",\n        \"Mechanistic connection between its membrane cycling and downstream fusion machinery unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ZWINT\",\n      \"SNAP25\",\n      \"RPH3A\",\n      \"SEPT14\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}