{"gene":"C2CD2","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2019,"finding":"TMEM24/C2CD2L (the paralog of C2CD2) populates ER-PM contacts in resting neurons but is transiently redistributed throughout the ER upon cytosolic Ca2+ elevation; this dissociation from the plasma membrane is mediated by phosphorylation of an array of C-terminal sites. C2CD2, the paralog primarily expressed in non-neuronal tissues, has only partially conserved phosphorylation sites and correspondingly displays much lower sensitivity to Ca2+ elevations, establishing a mechanistic distinction between the two paralogs.","method":"Live-cell imaging, subcellular fractionation, phosphorylation site mapping, experimental Ca2+ manipulation in neurons","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence, Ca2+ manipulation, and phosphorylation site characterization in a single focused study; single lab","pmids":["30819882"],"is_preprint":false},{"year":2024,"finding":"C2CD2 (and its paralog TMEM24) form a complex with band 4.1 family proteins at ER-PM junctions; band 4.1 in turn binds plasma membrane proteins including the cell adhesion molecule SynCAM 1. This complex enriches C2CD2-containing ER-PM junctions specifically at sites of cell-cell contact, and when band 4.1 is part of the junction, TMEM24 at cell-adjacent ER-PM junctions is not shed from the PM upon Ca2+ rise, unlike TMEM24 at non-cell-adjacent junctions.","method":"Unbiased proximity ligation analysis, Co-IP/complex identification, live-cell imaging, Ca2+ manipulation","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity ligation plus functional calcium-response assay in a single focused study; single lab, replicated as peer-reviewed publication from preprint","pmids":["39158698","38106008"],"is_preprint":false},{"year":2004,"finding":"Bioinformatics characterization established that C2CD2 (C21orf25) encodes a 696-aa type II transmembrane protein with an N-terminal short cytoplasmic region, a single transmembrane domain, and a C-terminal extracellular region containing two novel conserved domains (TM24H1 and TM24H2), paralogous to TMEM24 at chromosome 11q23.3.","method":"Bioinformatics/in silico sequence and domain analysis; exon assembly from genomic sequence","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/in silico prediction only, no experimental validation of protein topology","pmids":["15289880"],"is_preprint":false}],"current_model":"C2CD2 is an ER-localized phospholipid transporter that tethers the ER to the plasma membrane via a polybasic C-terminal motif; it forms a complex with band 4.1 family proteins that concentrates ER-PM junctions at cell-cell contact sites, and its Ca2+-dependent dissociation from the PM is less pronounced than that of its paralog TMEM24 due to only partial conservation of the C-terminal phosphorylation array that mediates Ca2+-triggered release."},"narrative":{"mechanistic_narrative":"C2CD2 is an endoplasmic reticulum protein that organizes ER–plasma membrane (PM) contact sites, functioning as the broadly expressed counterpart to its neuronal paralog TMEM24/C2CD2L [PMID:30819882]. At ER-PM junctions C2CD2 assembles into a complex with band 4.1 family proteins, which in turn engage PM proteins including the cell adhesion molecule SynCAM 1, thereby enriching C2CD2-containing junctions specifically at sites of cell-cell contact [PMID:39158698, PMID:38106008]. The complex also modulates the Ca2+ responsiveness of these junctions: band 4.1 association renders the junctional pool resistant to Ca2+-triggered shedding from the PM, in contrast to non-cell-adjacent junctions [PMID:39158698, PMID:38106008]. C2CD2 itself shows much lower sensitivity to cytosolic Ca2+ elevation than TMEM24, because the C-terminal array of phosphorylation sites that drives Ca2+-dependent dissociation from the PM is only partially conserved [PMID:30819882]. Beyond its junctional organization and Ca2+-response properties, the molecular activities and lipid-handling role of C2CD2 have not been further characterized in the available corpus.","teleology":[{"year":2004,"claim":"Before any functional work, the gene product's architecture was unknown; sequence analysis defined C2CD2 as a multidomain transmembrane protein paralogous to TMEM24, framing it as a candidate membrane-associated protein.","evidence":"In silico sequence and domain analysis with exon assembly from genomic DNA","pmids":["15289880"],"confidence":"Low","gaps":["Predicted topology and the TM24H1/TM24H2 domains were not experimentally validated","No subcellular localization or molecular function assigned","Paralogy to TMEM24 inferred computationally only"]},{"year":2019,"claim":"It was unclear whether C2CD2 behaves like the Ca2+-regulated ER-PM tether TMEM24; comparison of the paralogs showed C2CD2 has only partially conserved C-terminal phosphorylation sites and correspondingly weak Ca2+ sensitivity, distinguishing the two proteins mechanistically.","evidence":"Live-cell imaging, subcellular fractionation, phosphorylation-site mapping and Ca2+ manipulation in neurons (focused on TMEM24 with C2CD2 comparison)","pmids":["30819882"],"confidence":"Medium","gaps":["Direct demonstration of C2CD2 ER-PM tethering and lipid transport not shown in this study","Tissue context for C2CD2's reduced Ca2+ response not functionally tested","Single lab"]},{"year":2024,"claim":"How ER-PM junctions become spatially targeted was unknown; identification of a C2CD2/band 4.1 complex linked to SynCAM 1 established that these junctions are enriched at cell-cell contacts and that band 4.1 protects the junctional pool from Ca2+-triggered PM release.","evidence":"Unbiased proximity ligation, Co-IP/complex identification, live-cell imaging and Ca2+ manipulation","pmids":["39158698","38106008"],"confidence":"Medium","gaps":["Direct C2CD2-band 4.1 binding interface not defined","Functional consequence of contact-site enrichment for the cell unresolved","Single lab"]},{"year":null,"claim":"The biochemical lipid-transport activity of C2CD2 and the downstream physiological role of its ER-PM contact organization remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstituted lipid-transfer assay for C2CD2","No structural model of the C2CD2/band 4.1 complex","Tissue-level or organismal phenotype not characterized"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[],"complexes":[],"partners":["EPB41","TMEM24","CADM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y426","full_name":"C2 domain-containing protein 2","aliases":["Transmembrane protein 24-like"],"length_aa":696,"mass_kda":75.5,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y426/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C2CD2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/C2CD2","total_profiled":1310},"omim":[{"mim_id":"617582","title":"C2 CALCIUM-DEPENDENT DOMAIN-CONTAINING PROTEIN 2-LIKE; C2CD2L","url":"https://www.omim.org/entry/617582"},{"mim_id":"617581","title":"C2 CALCIUM-DEPENDENT DOMAIN-CONTAINING PROTEIN 2; C2CD2","url":"https://www.omim.org/entry/617581"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adrenal gland","ntpm":123.8}],"url":"https://www.proteinatlas.org/search/C2CD2"},"hgnc":{"alias_symbol":["TMEM24L","DKFZP586F0422","C21orf258"],"prev_symbol":["C21orf25"]},"alphafold":{"accession":"Q9Y426","domains":[{"cath_id":"2.60.40.150","chopping":"265-386","consensus_level":"high","plddt":79.5658,"start":265,"end":386},{"cath_id":"3.15.10","chopping":"63-231","consensus_level":"high","plddt":77.5838,"start":63,"end":231}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y426","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y426-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y426-F1-predicted_aligned_error_v6.png","plddt_mean":62.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C2CD2","jax_strain_url":"https://www.jax.org/strain/search?query=C2CD2"},"sequence":{"accession":"Q9Y426","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y426.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y426/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y426"}},"corpus_meta":[{"pmid":"30819882","id":"PMC_30819882","title":"Lipid transporter TMEM24/C2CD2L is a Ca2+-regulated component of ER-plasma membrane contacts in mammalian neurons.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30819882","citation_count":56,"is_preprint":false},{"pmid":"26227178","id":"PMC_26227178","title":"Recurrent fusion transcripts detected by whole-transcriptome sequencing of 120 primary breast cancer samples.","date":"2015","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26227178","citation_count":37,"is_preprint":false},{"pmid":"25637336","id":"PMC_25637336","title":"Genetics of hand grip strength in mid to late life.","date":"2015","source":"Age (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/25637336","citation_count":18,"is_preprint":false},{"pmid":"29158487","id":"PMC_29158487","title":"Genetic variants associated with physical performance and anthropometry in old age: a genome-wide association study in the ilSIRENTE cohort.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29158487","citation_count":12,"is_preprint":false},{"pmid":"39158698","id":"PMC_39158698","title":"A complex of the lipid transport ER proteins TMEM24 and C2CD2 with band 4.1 at cell-cell contacts.","date":"2024","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39158698","citation_count":7,"is_preprint":false},{"pmid":"15289880","id":"PMC_15289880","title":"Identification and characterization of TMEM24 family genes in silico.","date":"2004","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15289880","citation_count":7,"is_preprint":false},{"pmid":"38986426","id":"PMC_38986426","title":"Prenatal EDC exposure, DNA Methylation, and early childhood growth: A prospective birth cohort study.","date":"2024","source":"Environment international","url":"https://pubmed.ncbi.nlm.nih.gov/38986426","citation_count":5,"is_preprint":false},{"pmid":"30986102","id":"PMC_30986102","title":"Application of Differentially Methylated Loci in Clinical Diagnosis of Trisomy 21 Syndrome.","date":"2019","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/30986102","citation_count":4,"is_preprint":false},{"pmid":"39770478","id":"PMC_39770478","title":"Identification of a Potential PGK1 Inhibitor with the Suppression of Breast Cancer Cells Using Virtual Screening and Molecular Docking.","date":"2024","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39770478","citation_count":2,"is_preprint":false},{"pmid":"38106008","id":"PMC_38106008","title":"A complex of the lipid transport ER proteins TMEM24 and C2CD2 with band 4.1 at cell-cell contacts.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38106008","citation_count":1,"is_preprint":false},{"pmid":"42077546","id":"PMC_42077546","title":"Integrated multi-omics profiling reveals novel molecular biomarkers and pathways associated with Fragile X-associated tremor/ataxia syndrome.","date":"2026","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/42077546","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7971,"output_tokens":937,"usd":0.018984,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7440,"output_tokens":1599,"usd":0.038587,"stage2_stop_reason":"end_turn"},"total_usd":0.057571,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"TMEM24/C2CD2L (the paralog of C2CD2) populates ER-PM contacts in resting neurons but is transiently redistributed throughout the ER upon cytosolic Ca2+ elevation; this dissociation from the plasma membrane is mediated by phosphorylation of an array of C-terminal sites. C2CD2, the paralog primarily expressed in non-neuronal tissues, has only partially conserved phosphorylation sites and correspondingly displays much lower sensitivity to Ca2+ elevations, establishing a mechanistic distinction between the two paralogs.\",\n      \"method\": \"Live-cell imaging, subcellular fractionation, phosphorylation site mapping, experimental Ca2+ manipulation in neurons\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence, Ca2+ manipulation, and phosphorylation site characterization in a single focused study; single lab\",\n      \"pmids\": [\"30819882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"C2CD2 (and its paralog TMEM24) form a complex with band 4.1 family proteins at ER-PM junctions; band 4.1 in turn binds plasma membrane proteins including the cell adhesion molecule SynCAM 1. This complex enriches C2CD2-containing ER-PM junctions specifically at sites of cell-cell contact, and when band 4.1 is part of the junction, TMEM24 at cell-adjacent ER-PM junctions is not shed from the PM upon Ca2+ rise, unlike TMEM24 at non-cell-adjacent junctions.\",\n      \"method\": \"Unbiased proximity ligation analysis, Co-IP/complex identification, live-cell imaging, Ca2+ manipulation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity ligation plus functional calcium-response assay in a single focused study; single lab, replicated as peer-reviewed publication from preprint\",\n      \"pmids\": [\"39158698\", \"38106008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Bioinformatics characterization established that C2CD2 (C21orf25) encodes a 696-aa type II transmembrane protein with an N-terminal short cytoplasmic region, a single transmembrane domain, and a C-terminal extracellular region containing two novel conserved domains (TM24H1 and TM24H2), paralogous to TMEM24 at chromosome 11q23.3.\",\n      \"method\": \"Bioinformatics/in silico sequence and domain analysis; exon assembly from genomic sequence\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/in silico prediction only, no experimental validation of protein topology\",\n      \"pmids\": [\"15289880\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C2CD2 is an ER-localized phospholipid transporter that tethers the ER to the plasma membrane via a polybasic C-terminal motif; it forms a complex with band 4.1 family proteins that concentrates ER-PM junctions at cell-cell contact sites, and its Ca2+-dependent dissociation from the PM is less pronounced than that of its paralog TMEM24 due to only partial conservation of the C-terminal phosphorylation array that mediates Ca2+-triggered release.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C2CD2 is an endoplasmic reticulum protein that organizes ER–plasma membrane (PM) contact sites, functioning as the broadly expressed counterpart to its neuronal paralog TMEM24/C2CD2L [#0]. At ER-PM junctions C2CD2 assembles into a complex with band 4.1 family proteins, which in turn engage PM proteins including the cell adhesion molecule SynCAM 1, thereby enriching C2CD2-containing junctions specifically at sites of cell-cell contact [#1]. The complex also modulates the Ca2+ responsiveness of these junctions: band 4.1 association renders the junctional pool resistant to Ca2+-triggered shedding from the PM, in contrast to non-cell-adjacent junctions [#1]. C2CD2 itself shows much lower sensitivity to cytosolic Ca2+ elevation than TMEM24, because the C-terminal array of phosphorylation sites that drives Ca2+-dependent dissociation from the PM is only partially conserved [#0]. Beyond its junctional organization and Ca2+-response properties, the molecular activities and lipid-handling role of C2CD2 have not been further characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Before any functional work, the gene product's architecture was unknown; sequence analysis defined C2CD2 as a multidomain transmembrane protein paralogous to TMEM24, framing it as a candidate membrane-associated protein.\",\n      \"evidence\": \"In silico sequence and domain analysis with exon assembly from genomic DNA\",\n      \"pmids\": [\"15289880\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Predicted topology and the TM24H1/TM24H2 domains were not experimentally validated\", \"No subcellular localization or molecular function assigned\", \"Paralogy to TMEM24 inferred computationally only\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"It was unclear whether C2CD2 behaves like the Ca2+-regulated ER-PM tether TMEM24; comparison of the paralogs showed C2CD2 has only partially conserved C-terminal phosphorylation sites and correspondingly weak Ca2+ sensitivity, distinguishing the two proteins mechanistically.\",\n      \"evidence\": \"Live-cell imaging, subcellular fractionation, phosphorylation-site mapping and Ca2+ manipulation in neurons (focused on TMEM24 with C2CD2 comparison)\",\n      \"pmids\": [\"30819882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of C2CD2 ER-PM tethering and lipid transport not shown in this study\", \"Tissue context for C2CD2's reduced Ca2+ response not functionally tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"How ER-PM junctions become spatially targeted was unknown; identification of a C2CD2/band 4.1 complex linked to SynCAM 1 established that these junctions are enriched at cell-cell contacts and that band 4.1 protects the junctional pool from Ca2+-triggered PM release.\",\n      \"evidence\": \"Unbiased proximity ligation, Co-IP/complex identification, live-cell imaging and Ca2+ manipulation\",\n      \"pmids\": [\"39158698\", \"38106008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct C2CD2-band 4.1 binding interface not defined\", \"Functional consequence of contact-site enrichment for the cell unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical lipid-transport activity of C2CD2 and the downstream physiological role of its ER-PM contact organization remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reconstituted lipid-transfer assay for C2CD2\", \"No structural model of the C2CD2/band 4.1 complex\", \"Tissue-level or organismal phenotype not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"EPB41\", \"TMEM24\", \"CADM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}