{"gene":"SYN2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2013,"finding":"Loss-of-function mutations in SYN2 (nonsense A94fs199X and missense Y236S, G464R) impair synaptic vesicle cycling and axon outgrowth. When expressed in SYN2 knockout neurons, wild-type human Synapsin II fully rescues the knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants fail to rescue, establishing that Synapsin II regulates neurotransmitter release and synaptogenesis through its intact protein.","method":"Expression of wild-type and mutant human SYN2 in SYN2 knockout neurons; functional rescue assays measuring synaptic vesicle cycling and axon outgrowth phenotypes","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic rescue in KO neurons with multiple mutants and two orthogonal phenotypic readouts (vesicle cycling and axon outgrowth), single lab","pmids":["23956174"],"is_preprint":false},{"year":1995,"finding":"The human SYN2 gene was mapped to chromosome 3p and the mouse Syn2 gene to chromosome 6 band F, establishing that SYN2 encodes a neuron-specific phosphoprotein of small synaptic vesicles and is located on autosomes (distinct from SYN1 on the X chromosome).","method":"PCR amplification from somatic hybrid cell lines, single-strand conformation analysis, FISH, and backcross panel genotyping","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal mapping with multiple orthogonal methods (somatic hybrid PCR, FISH, genetic backcross), single lab","pmids":["7587399"],"is_preprint":false}],"current_model":"Synapsin II (SYN2) is a neuron-specific phosphoprotein of small synaptic vesicles that regulates neurotransmitter release and synaptogenesis; loss-of-function mutations impair synaptic vesicle cycling and axon outgrowth, as demonstrated by failure of ASD-associated missense mutants to rescue SYN2 knockout neuronal phenotypes."},"narrative":{"mechanistic_narrative":"Synapsin II (SYN2) is a neuron-specific phosphoprotein of small synaptic vesicles that regulates neurotransmitter release and synaptogenesis [PMID:23956174, PMID:7587399]. Genetic rescue experiments in SYN2 knockout neurons establish that the intact protein is required for normal synaptic vesicle cycling and axon outgrowth: wild-type human Synapsin II fully restores these phenotypes, whereas an ASD-associated nonsense allele (A94fs199X) is not expressed and missense alleles (Y236S, G464R) fail to rescue [PMID:23956174]. The SYN2 gene maps to chromosome 3p, an autosomal location distinct from the X-linked SYN1 [PMID:7587399]. Beyond these genetic and functional rescue findings, no further molecular mechanism — binding partners, vesicle-association determinants, or phosphorylation-dependent regulation — has been characterized in the available corpus.","teleology":[{"year":1995,"claim":"Before its chromosomal assignment, it was unknown where SYN2 resided in the genome and whether it was distinct from the X-linked SYN1; mapping placed SYN2 on autosomal chromosome 3p, defining it as a separate neuron-specific synaptic vesicle phosphoprotein gene.","evidence":"PCR from somatic hybrid cell lines, single-strand conformation analysis, FISH, and backcross genotyping in human and mouse","pmids":["7587399"],"confidence":"Medium","gaps":["Mapping does not address the protein's biochemical activity or binding partners","No functional consequence of the locus established at this stage"]},{"year":2013,"claim":"It was unknown whether SYN2 missense variants found in disease were functionally damaging; rescue assays in SYN2 knockout neurons showed that wild-type but not mutant Synapsin II restores synaptic vesicle cycling and axon outgrowth, establishing that the intact protein drives neurotransmitter release and synaptogenesis.","evidence":"Expression of wild-type and mutant human SYN2 in SYN2 knockout neurons with vesicle cycling and axon outgrowth readouts","pmids":["23956174"],"confidence":"Medium","gaps":["Single-lab study; phenotypes not independently replicated","Molecular mechanism by which missense mutations disrupt function not resolved (no binding, localization, or phosphorylation analysis)","Direct physical partners and vesicle-association determinants not identified"]},{"year":null,"claim":"The molecular basis of Synapsin II function — its direct interaction partners, vesicle-tethering mechanism, and phosphoregulation — remains uncharacterized in the available corpus.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified binding partners or substrates","No structural model of the protein","Mechanism linking the protein to vesicle cycling and axon outgrowth not defined"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92777","full_name":"Synapsin-2","aliases":["Synapsin II"],"length_aa":582,"mass_kda":63.0,"function":"Neuronal phosphoprotein that coats synaptic vesicles, binds to the cytoskeleton, and is believed to function in the regulation of neurotransmitter release. May play a role in noradrenaline secretion by sympathetic neurons (By similarity)","subcellular_location":"Synapse","url":"https://www.uniprot.org/uniprotkb/Q92777/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SYN2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":74,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"PDCD6IP","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SYN2","total_profiled":1310},"omim":[{"mim_id":"612679","title":"CUGBP- AND ELAV-LIKE FAMILY, MEMBER 4; CELF4","url":"https://www.omim.org/entry/612679"},{"mim_id":"604998","title":"CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE I; CAMK1","url":"https://www.omim.org/entry/604998"},{"mim_id":"602705","title":"SYNAPSIN III; SYN3","url":"https://www.omim.org/entry/602705"},{"mim_id":"600755","title":"SYNAPSIN II; SYN2","url":"https://www.omim.org/entry/600755"},{"mim_id":"313440","title":"SYNAPSIN I; SYN1","url":"https://www.omim.org/entry/313440"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":119.7}],"url":"https://www.proteinatlas.org/search/SYN2"},"hgnc":{"alias_symbol":["SYNII","SYNIIa","SYNIIb"],"prev_symbol":[]},"alphafold":{"accession":"Q92777","domains":[{"cath_id":"3.40.50.20","chopping":"114-215","consensus_level":"high","plddt":96.9635,"start":114,"end":215},{"cath_id":"3.30.470.20","chopping":"216-248_309-390","consensus_level":"medium","plddt":97.1171,"start":216,"end":390},{"cath_id":"3.30.1490.20","chopping":"249-308","consensus_level":"medium","plddt":96.9195,"start":249,"end":308}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92777","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92777-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92777-F1-predicted_aligned_error_v6.png","plddt_mean":73.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SYN2","jax_strain_url":"https://www.jax.org/strain/search?query=SYN2"},"sequence":{"accession":"Q92777","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92777.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92777/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92777"}},"corpus_meta":[{"pmid":"28280153","id":"PMC_28280153","title":"Deep functional analysis of synII, a 770-kilobase synthetic yeast chromosome.","date":"2017","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28280153","citation_count":153,"is_preprint":false},{"pmid":"23956174","id":"PMC_23956174","title":"SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23956174","citation_count":70,"is_preprint":false},{"pmid":"16131404","id":"PMC_16131404","title":"Association study of polymorphisms in synaptic vesicle-associated genes, SYN2 and CPLX2, with schizophrenia.","date":"2005","source":"Behavioral and brain functions : BBF","url":"https://pubmed.ncbi.nlm.nih.gov/16131404","citation_count":67,"is_preprint":false},{"pmid":"22143050","id":"PMC_22143050","title":"The enantiomers of syn-2,3-difluoro-4-aminobutyric acid elicit opposite responses at the GABA(C) receptor.","date":"2011","source":"Chemical communications (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/22143050","citation_count":34,"is_preprint":false},{"pmid":"31135217","id":"PMC_31135217","title":"Syn-2, 3-diols and anti-inflammatory indole derivatives from Streptomyces sp. CB09001.","date":"2019","source":"Natural product research","url":"https://pubmed.ncbi.nlm.nih.gov/31135217","citation_count":12,"is_preprint":false},{"pmid":"30666415","id":"PMC_30666415","title":"A case of nasal low-grade non-intestinal-type adenocarcinoma with aberrant CDX2 expression and a novel SYN2-PPARG gene fusion in a 13-year-old girl.","date":"2019","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30666415","citation_count":11,"is_preprint":false},{"pmid":"21465568","id":"PMC_21465568","title":"Lack of association between synapsin II (SYN2) gene polymorphism and susceptibility epilepsy: a case-control study and meta-analysis.","date":"2011","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21465568","citation_count":9,"is_preprint":false},{"pmid":"7587399","id":"PMC_7587399","title":"Mapping of synapsin II (SYN2) genes to human chromosome 3p and mouse chromosome 6 band F.","date":"1995","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7587399","citation_count":8,"is_preprint":false},{"pmid":"38238071","id":"PMC_38238071","title":"Small cell lung cancer with SYN2::PPARG fusion.","date":"2023","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/38238071","citation_count":3,"is_preprint":false},{"pmid":"39417931","id":"PMC_39417931","title":"A Case of Acinic Cell Carcinoma with SYN2::PPARG Fusion.","date":"2024","source":"Head and neck pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39417931","citation_count":2,"is_preprint":false},{"pmid":"42008002","id":"PMC_42008002","title":"High-Grade Acinic Cell Carcinoma of the Parotid with SYN2::PPARG Fusion.","date":"2026","source":"Head and neck pathology","url":"https://pubmed.ncbi.nlm.nih.gov/42008002","citation_count":0,"is_preprint":false},{"pmid":"41877551","id":"PMC_41877551","title":"Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass C with SYN2::PPARG fusion in an older adult.","date":"2026","source":"CNS oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41877551","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.17.676758","title":"Proteomic and Kinetic Characterization of Prion Seeding in Distinct Human CJD Strains Unveils Early Diagnostic Biomarkers","date":"2025-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.17.676758","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8002,"output_tokens":630,"usd":0.016728,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6993,"output_tokens":1185,"usd":0.032295,"stage2_stop_reason":"end_turn"},"total_usd":0.049023,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss-of-function mutations in SYN2 (nonsense A94fs199X and missense Y236S, G464R) impair synaptic vesicle cycling and axon outgrowth. When expressed in SYN2 knockout neurons, wild-type human Synapsin II fully rescues the knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants fail to rescue, establishing that Synapsin II regulates neurotransmitter release and synaptogenesis through its intact protein.\",\n      \"method\": \"Expression of wild-type and mutant human SYN2 in SYN2 knockout neurons; functional rescue assays measuring synaptic vesicle cycling and axon outgrowth phenotypes\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic rescue in KO neurons with multiple mutants and two orthogonal phenotypic readouts (vesicle cycling and axon outgrowth), single lab\",\n      \"pmids\": [\"23956174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The human SYN2 gene was mapped to chromosome 3p and the mouse Syn2 gene to chromosome 6 band F, establishing that SYN2 encodes a neuron-specific phosphoprotein of small synaptic vesicles and is located on autosomes (distinct from SYN1 on the X chromosome).\",\n      \"method\": \"PCR amplification from somatic hybrid cell lines, single-strand conformation analysis, FISH, and backcross panel genotyping\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal mapping with multiple orthogonal methods (somatic hybrid PCR, FISH, genetic backcross), single lab\",\n      \"pmids\": [\"7587399\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Synapsin II (SYN2) is a neuron-specific phosphoprotein of small synaptic vesicles that regulates neurotransmitter release and synaptogenesis; loss-of-function mutations impair synaptic vesicle cycling and axon outgrowth, as demonstrated by failure of ASD-associated missense mutants to rescue SYN2 knockout neuronal phenotypes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Synapsin II (SYN2) is a neuron-specific phosphoprotein of small synaptic vesicles that regulates neurotransmitter release and synaptogenesis [#0, #1]. Genetic rescue experiments in SYN2 knockout neurons establish that the intact protein is required for normal synaptic vesicle cycling and axon outgrowth: wild-type human Synapsin II fully restores these phenotypes, whereas an ASD-associated nonsense allele (A94fs199X) is not expressed and missense alleles (Y236S, G464R) fail to rescue [#0]. The SYN2 gene maps to chromosome 3p, an autosomal location distinct from the X-linked SYN1 [#1]. Beyond these genetic and functional rescue findings, no further molecular mechanism — binding partners, vesicle-association determinants, or phosphorylation-dependent regulation — has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Before its chromosomal assignment, it was unknown where SYN2 resided in the genome and whether it was distinct from the X-linked SYN1; mapping placed SYN2 on autosomal chromosome 3p, defining it as a separate neuron-specific synaptic vesicle phosphoprotein gene.\",\n      \"evidence\": \"PCR from somatic hybrid cell lines, single-strand conformation analysis, FISH, and backcross genotyping in human and mouse\",\n      \"pmids\": [\"7587399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mapping does not address the protein's biochemical activity or binding partners\",\n        \"No functional consequence of the locus established at this stage\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"It was unknown whether SYN2 missense variants found in disease were functionally damaging; rescue assays in SYN2 knockout neurons showed that wild-type but not mutant Synapsin II restores synaptic vesicle cycling and axon outgrowth, establishing that the intact protein drives neurotransmitter release and synaptogenesis.\",\n      \"evidence\": \"Expression of wild-type and mutant human SYN2 in SYN2 knockout neurons with vesicle cycling and axon outgrowth readouts\",\n      \"pmids\": [\"23956174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; phenotypes not independently replicated\",\n        \"Molecular mechanism by which missense mutations disrupt function not resolved (no binding, localization, or phosphorylation analysis)\",\n        \"Direct physical partners and vesicle-association determinants not identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular basis of Synapsin II function — its direct interaction partners, vesicle-tethering mechanism, and phosphoregulation — remains uncharacterized in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No identified binding partners or substrates\",\n        \"No structural model of the protein\",\n        \"Mechanism linking the protein to vesicle cycling and axon outgrowth not defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}