{"gene":"CACNG6","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2026,"finding":"CACNG6 downregulation inhibits calcium ion influx, which indirectly modulates the MAPK signaling pathway, as demonstrated in a mouse pneumonia model using M2 macrophage-mediated nanoparticle drug delivery.","method":"In vivo mouse pneumonia model with PT@M2 nanoparticle treatment; CACNG6 expression modulation with downstream MAPK pathway readout","journal":"Journal of controlled release : official journal of the Controlled Release Society","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single study, single lab, mechanistic link between CACNG6, calcium influx, and MAPK pathway inferred from expression modulation in a complex in vivo system without direct reconstitution or mutagenesis","pmids":["41819427"],"is_preprint":false}],"current_model":"CACNG6 encodes a voltage-dependent calcium channel gamma subunit that stabilizes the calcium channel; experimental evidence suggests that its downregulation inhibits calcium ion influx and indirectly modulates the MAPK pathway, but rigorous mechanistic characterization (structure, in vitro reconstitution, or direct interaction studies) of the human protein remains lacking in the available literature."},"narrative":{"mechanistic_narrative":"CACNG6 is implicated in calcium ion influx, where its downregulation reduces calcium entry and indirectly modulates the MAPK signaling pathway in a mouse pneumonia model [PMID:41819427]. Beyond this single in vivo association, no direct mechanistic characterization of the human protein — including structure, in vitro reconstitution, or interaction studies — has been established in the available corpus.","teleology":[{"year":2026,"claim":"To address whether CACNG6 influences calcium signaling and downstream pathways in an inflammatory context, expression modulation in a pneumonia model linked CACNG6 downregulation to reduced calcium influx and altered MAPK activity.","evidence":"In vivo mouse pneumonia model with PT@M2 nanoparticle drug delivery, modulating CACNG6 expression with MAPK pathway readout","pmids":["41819427"],"confidence":"Low","gaps":["Mechanistic link inferred from expression modulation in a complex in vivo system without reconstitution or mutagenesis","No direct evidence that CACNG6 itself conducts or gates the calcium flux observed","No demonstration of a direct molecular connection between CACNG6 and MAPK components"]},{"year":null,"claim":"Whether CACNG6 functions as a bona fide calcium channel subunit and how it physically engages channel or signaling partners remains uncharacterized.","evidence":"No direct interaction, structural, or reconstitution data in the available corpus","pmids":[],"confidence":"Low","gaps":["No structural model or in vitro reconstitution of the human protein","No direct physical interaction partners identified","Causal role in calcium influx not established by mutagenesis"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WXS5","full_name":"Voltage-dependent calcium channel gamma-8 subunit","aliases":["Neuronal voltage-gated calcium channel gamma-8 subunit","Transmembrane AMPAR regulatory protein gamma-8","TARP gamma-8"],"length_aa":425,"mass_kda":43.3,"function":"Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit (By similarity). Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization and by mediating their resensitization. Does not show subunit-specific AMPA receptor regulation and regulates all AMPAR subunits","subcellular_location":"Cell membrane; Postsynaptic density membrane","url":"https://www.uniprot.org/uniprotkb/Q8WXS5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CACNG6","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/CACNG6","total_profiled":1310},"omim":[{"mim_id":"606900","title":"CALCIUM CHANNEL, VOLTAGE-DEPENDENT, GAMMA-8 SUBUNIT; CACNG8","url":"https://www.omim.org/entry/606900"},{"mim_id":"606899","title":"CALCIUM CHANNEL, VOLTAGE-DEPENDENT, GAMMA-7 SUBUNIT; CACNG7","url":"https://www.omim.org/entry/606899"},{"mim_id":"606898","title":"CALCIUM CHANNEL, VOLTAGE-DEPENDENT, GAMMA-6 SUBUNIT; CACNG6","url":"https://www.omim.org/entry/606898"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli fibrillar center","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skeletal muscle","ntpm":84.9},{"tissue":"tongue","ntpm":28.0}],"url":"https://www.proteinatlas.org/search/CACNG6"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q8WXS5","domains":[{"cath_id":"1.20.140.150","chopping":"25-43_118-187_201-239","consensus_level":"medium","plddt":84.195,"start":25,"end":239}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXS5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXS5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXS5-F1-predicted_aligned_error_v6.png","plddt_mean":58.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CACNG6","jax_strain_url":"https://www.jax.org/strain/search?query=CACNG6"},"sequence":{"accession":"Q8WXS5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WXS5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WXS5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXS5"}},"corpus_meta":[{"pmid":"27760167","id":"PMC_27760167","title":"Genomic Regions Associated with Feed Efficiency Indicator Traits in an Experimental Nellore Cattle Population.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27760167","citation_count":59,"is_preprint":false},{"pmid":"27102562","id":"PMC_27102562","title":"Evaluation of voltage-dependent calcium channel γ gene families identified several novel potential susceptible genes to schizophrenia.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27102562","citation_count":54,"is_preprint":false},{"pmid":"20860846","id":"PMC_20860846","title":"Association of CACNG6 polymorphisms with aspirin-intolerance asthmatics in a Korean population.","date":"2010","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20860846","citation_count":21,"is_preprint":false},{"pmid":"31213979","id":"PMC_31213979","title":"Proestrus Differentially Regulates Expression of Ion Channel and Calcium Homeostasis Genes in GnRH Neurons of Mice.","date":"2019","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31213979","citation_count":21,"is_preprint":false},{"pmid":"27746059","id":"PMC_27746059","title":"Identification of Transcription Factor-Gene Regulatory Network in Acute Myocardial Infarction.","date":"2016","source":"Heart, lung & circulation","url":"https://pubmed.ncbi.nlm.nih.gov/27746059","citation_count":16,"is_preprint":false},{"pmid":"38526604","id":"PMC_38526604","title":"Bioinformatics-based screening and analysis of the key genes involved in the influence of antiangiogenesis on myeloid-derived suppressor cells and their effects on the immune microenvironment.","date":"2024","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38526604","citation_count":8,"is_preprint":false},{"pmid":"40301928","id":"PMC_40301928","title":"Identifying therapeutic target genes for diabetic retinopathy using systematic druggable genome-wide Mendelian randomization.","date":"2025","source":"Diabetology & metabolic syndrome","url":"https://pubmed.ncbi.nlm.nih.gov/40301928","citation_count":4,"is_preprint":false},{"pmid":"37792466","id":"PMC_37792466","title":"Detection of genomic variations and selection signatures in Wagyu using whole-genome sequencing data.","date":"2023","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37792466","citation_count":4,"is_preprint":false},{"pmid":"34758154","id":"PMC_34758154","title":"Web-based transcriptome analysis determines a sixteen-gene signature and associated drugs on hearing loss patients: A bioinformatics approach.","date":"2021","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/34758154","citation_count":4,"is_preprint":false},{"pmid":"41398767","id":"PMC_41398767","title":"Systematic druggable genome-wide mendelian randomization identifies therapeutic targets for childhood asthma.","date":"2025","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41398767","citation_count":1,"is_preprint":false},{"pmid":"42238898","id":"PMC_42238898","title":"Identification of highly expressed genes and efficient core promoters specific to buffalo skeletal muscles.","date":"2025","source":"Archives animal breeding","url":"https://pubmed.ncbi.nlm.nih.gov/42238898","citation_count":0,"is_preprint":false},{"pmid":"41819427","id":"PMC_41819427","title":"M2 macrophage-mediated tigecycline nanoparticles for combating CRKP pneumonia via antibacterial and immunomodulatory therapy.","date":"2026","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/41819427","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9170,"output_tokens":343,"usd":0.016328,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6597,"output_tokens":733,"usd":0.025655,"stage2_stop_reason":"end_turn"},"total_usd":0.041983,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2026,\n      \"finding\": \"CACNG6 downregulation inhibits calcium ion influx, which indirectly modulates the MAPK signaling pathway, as demonstrated in a mouse pneumonia model using M2 macrophage-mediated nanoparticle drug delivery.\",\n      \"method\": \"In vivo mouse pneumonia model with PT@M2 nanoparticle treatment; CACNG6 expression modulation with downstream MAPK pathway readout\",\n      \"journal\": \"Journal of controlled release : official journal of the Controlled Release Society\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single study, single lab, mechanistic link between CACNG6, calcium influx, and MAPK pathway inferred from expression modulation in a complex in vivo system without direct reconstitution or mutagenesis\",\n      \"pmids\": [\"41819427\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CACNG6 encodes a voltage-dependent calcium channel gamma subunit that stabilizes the calcium channel; experimental evidence suggests that its downregulation inhibits calcium ion influx and indirectly modulates the MAPK pathway, but rigorous mechanistic characterization (structure, in vitro reconstitution, or direct interaction studies) of the human protein remains lacking in the available literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CACNG6 is implicated in calcium ion influx, where its downregulation reduces calcium entry and indirectly modulates the MAPK signaling pathway in a mouse pneumonia model [#0]. Beyond this single in vivo association, no direct mechanistic characterization of the human protein — including structure, in vitro reconstitution, or interaction studies — has been established in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2026,\n      \"claim\": \"To address whether CACNG6 influences calcium signaling and downstream pathways in an inflammatory context, expression modulation in a pneumonia model linked CACNG6 downregulation to reduced calcium influx and altered MAPK activity.\",\n      \"evidence\": \"In vivo mouse pneumonia model with PT@M2 nanoparticle drug delivery, modulating CACNG6 expression with MAPK pathway readout\",\n      \"pmids\": [\"41819427\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Mechanistic link inferred from expression modulation in a complex in vivo system without reconstitution or mutagenesis\",\n        \"No direct evidence that CACNG6 itself conducts or gates the calcium flux observed\",\n        \"No demonstration of a direct molecular connection between CACNG6 and MAPK components\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether CACNG6 functions as a bona fide calcium channel subunit and how it physically engages channel or signaling partners remains uncharacterized.\",\n      \"evidence\": \"No direct interaction, structural, or reconstitution data in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model or in vitro reconstitution of the human protein\",\n        \"No direct physical interaction partners identified\",\n        \"Causal role in calcium influx not established by mutagenesis\"\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":"loss","faith_supported":1,"faith_total":1,"faith_pct":100.0}}