{"gene":"CACNG8","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2016,"finding":"CACNG8 (TARP-γ8) acts as an accessory protein required for the activity of novel AMPA receptor modulators; these compounds partially disrupt the interaction between TARP-γ8 and the pore-forming subunit of the AMPA receptor channel, as demonstrated using wild-type and mutant forms of TARP-γ8 in calcium flux, radioligand binding, and electrophysiological assays.","method":"Calcium flux assay, radioligand binding, electrophysiology using wild-type and mutant TARP-γ8 constructs; pharmacological occupancy studies in vivo","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 1/2 / Moderate — multiple orthogonal biochemical and electrophysiological assays with mutant forms directly testing the TARP–pore-subunit interaction, single lab but rigorous multimethod study","pmids":["26989142"],"is_preprint":false},{"year":2022,"finding":"Knockout of TARP γ-8 (CACNG8) in mice leads to dysfunction of the synaptic AMPA receptor complex in hippocampal synaptosomes and dysregulation of dopaminergic and glutamatergic transmission in the prefrontal cortex, establishing TARP γ-8 as a regulator of AMPAR complex function at synapses.","method":"TARP γ-8 knockout mice; synaptosomal proteomic analysis; behavioral phenotyping; methylphenidate rescue experiments","journal":"Zoological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined synaptosomal proteomic readout and pharmacological rescue, single lab with two orthogonal methods","pmids":["36031768"],"is_preprint":false},{"year":2021,"finding":"A SNP (rs10420324G) in the CACNG8 gene suppresses transcription, likely through modulation of a local G-quadruplex DNA structure; reduced TARP γ-8 expression in heterozygous knockout mice impairs synaptic AMPAR function in layer 2–3 pyramidal neurons of the prefrontal cortex.","method":"Reporter gene expression assay in vitro; behavioral characterization of TARP γ-8 knockout and heterozygous mice; electrophysiological recording of prefrontal cortex neurons","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay for transcriptional mechanism plus electrophysiology in knockout mice, single lab with two orthogonal methods","pmids":["34099816"],"is_preprint":false},{"year":2025,"finding":"Rare heterozygous or compound heterozygous CACNG8 variants (including stop-gain p.Arg123Ter and missense p.Leu96Val, p.Val102Met) severely reduce stability (ΔΔG > 20 kcal/mol) of AMPAR-associated postsynaptic complexes containing auxiliary subunits (CACNG2-7, CNIH2/3), scaffolding proteins (PSD93, PSD95), and regulators (PPP3CA, RIMBPs), and increase structural disorder as shown by molecular dynamics simulations.","method":"Whole Exome Sequencing; molecular docking; MM-PBSA/MM-GBSA free energy calculations; molecular dynamics simulations; GIST and PCA/TICA analyses","journal":"Computational and structural biotechnology journal","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational structural modeling only, no in vitro or in vivo functional validation of the specific variants","pmids":["41127817"],"is_preprint":false}],"current_model":"CACNG8 encodes TARP γ-8, an auxiliary AMPA receptor regulatory protein that physically interacts with the pore-forming AMPAR subunit to regulate receptor trafficking, gating, and synaptic localization, particularly in hippocampal and prefrontal cortical neurons; disruption of this interaction (by partial uncoupling compounds, loss-of-function mutations, or knockout) impairs synaptic AMPAR complex integrity, reduces fast glutamatergic transmission, and produces behavioral deficits reversible by methylphenidate."},"narrative":{"mechanistic_narrative":"CACNG8 encodes TARP γ-8, an auxiliary AMPA receptor regulatory protein that physically associates with the pore-forming AMPAR subunit to govern synaptic glutamatergic signaling [PMID:26989142]. Novel AMPAR modulators act through TARP γ-8 by partially disrupting its interaction with the channel pore subunit, an effect dependent on intact TARP γ-8 and mapped using mutant constructs in calcium flux, radioligand binding, and electrophysiological assays [PMID:26989142]. In vivo, loss of TARP γ-8 disrupts the synaptic AMPAR complex in hippocampal synaptosomes and dysregulates dopaminergic and glutamatergic transmission in the prefrontal cortex, producing behavioral deficits rescuable by methylphenidate [PMID:36031768]. Its expression is sensitive to a transcription-suppressing SNP (rs10420324G) acting through a local G-quadruplex structure, and reduced gene dosage in heterozygous mice impairs synaptic AMPAR function in layer 2–3 prefrontal pyramidal neurons [PMID:34099816].","teleology":[{"year":2016,"claim":"Established that TARP γ-8 physically engages the AMPAR pore-forming subunit and that this interface is pharmacologically targetable, defining the molecular basis for its modulatory role.","evidence":"Calcium flux, radioligand binding, and electrophysiology with wild-type and mutant TARP γ-8 constructs plus in vivo occupancy","pmids":["26989142"],"confidence":"High","gaps":["No structural model of the TARP γ-8–pore subunit interface resolved here","Endogenous physiological consequence of disrupting the interaction not assessed in vivo","Specific residues mediating the interaction not fully mapped"]},{"year":2021,"claim":"Linked CACNG8 gene dosage and a transcription-regulatory SNP to AMPAR function in defined cortical neurons, connecting expression control to synaptic physiology.","evidence":"Reporter gene assay for transcriptional effect plus electrophysiology in knockout and heterozygous mice","pmids":["34099816"],"confidence":"Medium","gaps":["G-quadruplex mechanism inferred, not directly demonstrated at the endogenous locus","Single lab, two methods","Behavioral relevance of the SNP in humans not established"]},{"year":2022,"claim":"Demonstrated that whole-animal loss of TARP γ-8 disrupts the synaptic AMPAR complex and broader neurotransmission, with a pharmacological rescue defining a tractable circuit-level deficit.","evidence":"Knockout mice with synaptosomal proteomics, behavioral phenotyping, and methylphenidate rescue","pmids":["36031768"],"confidence":"Medium","gaps":["Mechanism connecting AMPAR complex loss to dopaminergic dysregulation unresolved","Single lab","Cell-type specificity of the proteomic changes not dissected"]},{"year":2025,"claim":"Proposed that rare human CACNG8 variants destabilize the postsynaptic AMPAR-associated complex, extending the gene's role to potential human disease.","evidence":"Whole exome sequencing with molecular docking, free-energy calculations, and molecular dynamics simulations","pmids":["41127817"],"confidence":"Low","gaps":["Computational modeling only, no in vitro or in vivo functional validation of variants","Stability predictions not confirmed by biochemical measurement","Causal genotype-phenotype link in patients not established"]},{"year":null,"claim":"How TARP γ-8 dosage and complex integrity mechanistically couple to prefrontal dopaminergic regulation and human neuropsychiatric phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experimental validation of disease-associated variants","Structural mechanism of complex stabilization uncharacterized in the corpus","Direct partners beyond the AMPAR pore subunit not biochemically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1]}],"complexes":["synaptic AMPA receptor complex"],"partners":["GRIA (AMPAR PORE-FORMING SUBUNIT)"],"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/CACNG8","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/CACNG8","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"},{"mim_id":"606404","title":"CALCIUM CHANNEL, VOLTAGE-DEPENDENT, GAMMA-4 SUBUNIT; CACNG4","url":"https://www.omim.org/entry/606404"},{"mim_id":"605366","title":"OLFACTOMEDIN 1; OLFM1","url":"https://www.omim.org/entry/605366"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"brain","ntpm":34.0}],"url":"https://www.proteinatlas.org/search/CACNG8"},"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=CACNG8","jax_strain_url":"https://www.jax.org/strain/search?query=CACNG8"},"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":"26989142","id":"PMC_26989142","title":"Discovery and Characterization of AMPA Receptor Modulators Selective for TARP-γ8.","date":"2016","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/26989142","citation_count":89,"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":"36490268","id":"PMC_36490268","title":"The impact of modifier genes on cone-rod dystrophy heterogeneity: An explorative familial pilot study and a hypothesis on neurotransmission impairment.","date":"2022","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/36490268","citation_count":38,"is_preprint":false},{"pmid":"38663526","id":"PMC_38663526","title":"Baicalin restore intestinal damage after early-life antibiotic therapy: the role of the MAPK signaling pathway.","date":"2024","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/38663526","citation_count":22,"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":"36031768","id":"PMC_36031768","title":"Deficiency of transmembrane AMPA receptor regulatory protein γ-8 leads to attention-deficit hyperactivity disorder-like behavior in mice.","date":"2022","source":"Zoological research","url":"https://pubmed.ncbi.nlm.nih.gov/36031768","citation_count":18,"is_preprint":false},{"pmid":"31192134","id":"PMC_31192134","title":"Somatic Mutations Profile of a Young Patient With Metastatic Urothelial Carcinoma Reveals Mutations in Genes Involved in Ion Channels.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31192134","citation_count":14,"is_preprint":false},{"pmid":"26710323","id":"PMC_26710323","title":"Patients with Dilated Cardiomyopathy and Sustained Monomorphic Ventricular Tachycardia Show Up-Regulation of KCNN3 and KCNJ2 Genes and CACNG8-Linked Left Ventricular Dysfunction.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26710323","citation_count":13,"is_preprint":false},{"pmid":"34099816","id":"PMC_34099816","title":"SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34099816","citation_count":12,"is_preprint":false},{"pmid":"36624125","id":"PMC_36624125","title":"Patient-specific identification of genome-wide DNA-methylation differences between intracranial and extracranial melanoma metastases.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36624125","citation_count":11,"is_preprint":false},{"pmid":"39564730","id":"PMC_39564730","title":"Blood Plasma Methylated DNA Markers in the Detection of Lymphoma: Discovery, Validation, and Clinical Pilot.","date":"2024","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/39564730","citation_count":9,"is_preprint":false},{"pmid":"32391085","id":"PMC_32391085","title":"Whole-genome mate-pair sequencing of apparently balanced chromosome rearrangements reveals complex structural variations: two case studies.","date":"2020","source":"Molecular cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/32391085","citation_count":8,"is_preprint":false},{"pmid":"39329756","id":"PMC_39329756","title":"Cannabinol (CBN) Influences the Ion Channels and Synaptic-Related Genes in NSC-34 Cell Line: A Transcriptomic Study.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/39329756","citation_count":6,"is_preprint":false},{"pmid":"38649401","id":"PMC_38649401","title":"Exploration of lncRNA/circRNA-miRNA-mRNA network in patients with chronic atrophic gastritis in Tibetan plateau areas based on DNBSEQ-G99 RNA sequencing.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38649401","citation_count":5,"is_preprint":false},{"pmid":"36744178","id":"PMC_36744178","title":"Identification of miRNA-mediated gene regulatory networks in L-methionine exposure counteracts cocaine-conditioned place preference in mice.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36744178","citation_count":4,"is_preprint":false},{"pmid":"41127817","id":"PMC_41127817","title":"Multifaceted disruption of AMPA receptor signaling by CACNG8 variants: Integrated evidence from human genetics and molecular simulation.","date":"2025","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/41127817","citation_count":2,"is_preprint":false},{"pmid":"41342963","id":"PMC_41342963","title":"Proteomic Analysis of Mouse Cerebral Cortex Following Experimental Ischemic Stroke: Identifying Novel Biomarkers of Damage and Repair.","date":"2025","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/41342963","citation_count":0,"is_preprint":false},{"pmid":"41327336","id":"PMC_41327336","title":"Dysregulated circRNA-miRNA-mRNA networks reveal stage-specific mRNA expression changes in Parkinson's disease.","date":"2025","source":"Molecular brain","url":"https://pubmed.ncbi.nlm.nih.gov/41327336","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12902,"output_tokens":1185,"usd":0.028241,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7827,"output_tokens":1821,"usd":0.04233,"stage2_stop_reason":"end_turn"},"total_usd":0.070571,"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\": 2016,\n      \"finding\": \"CACNG8 (TARP-γ8) acts as an accessory protein required for the activity of novel AMPA receptor modulators; these compounds partially disrupt the interaction between TARP-γ8 and the pore-forming subunit of the AMPA receptor channel, as demonstrated using wild-type and mutant forms of TARP-γ8 in calcium flux, radioligand binding, and electrophysiological assays.\",\n      \"method\": \"Calcium flux assay, radioligand binding, electrophysiology using wild-type and mutant TARP-γ8 constructs; pharmacological occupancy studies in vivo\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 / Moderate — multiple orthogonal biochemical and electrophysiological assays with mutant forms directly testing the TARP–pore-subunit interaction, single lab but rigorous multimethod study\",\n      \"pmids\": [\"26989142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockout of TARP γ-8 (CACNG8) in mice leads to dysfunction of the synaptic AMPA receptor complex in hippocampal synaptosomes and dysregulation of dopaminergic and glutamatergic transmission in the prefrontal cortex, establishing TARP γ-8 as a regulator of AMPAR complex function at synapses.\",\n      \"method\": \"TARP γ-8 knockout mice; synaptosomal proteomic analysis; behavioral phenotyping; methylphenidate rescue experiments\",\n      \"journal\": \"Zoological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined synaptosomal proteomic readout and pharmacological rescue, single lab with two orthogonal methods\",\n      \"pmids\": [\"36031768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A SNP (rs10420324G) in the CACNG8 gene suppresses transcription, likely through modulation of a local G-quadruplex DNA structure; reduced TARP γ-8 expression in heterozygous knockout mice impairs synaptic AMPAR function in layer 2–3 pyramidal neurons of the prefrontal cortex.\",\n      \"method\": \"Reporter gene expression assay in vitro; behavioral characterization of TARP γ-8 knockout and heterozygous mice; electrophysiological recording of prefrontal cortex neurons\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay for transcriptional mechanism plus electrophysiology in knockout mice, single lab with two orthogonal methods\",\n      \"pmids\": [\"34099816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rare heterozygous or compound heterozygous CACNG8 variants (including stop-gain p.Arg123Ter and missense p.Leu96Val, p.Val102Met) severely reduce stability (ΔΔG > 20 kcal/mol) of AMPAR-associated postsynaptic complexes containing auxiliary subunits (CACNG2-7, CNIH2/3), scaffolding proteins (PSD93, PSD95), and regulators (PPP3CA, RIMBPs), and increase structural disorder as shown by molecular dynamics simulations.\",\n      \"method\": \"Whole Exome Sequencing; molecular docking; MM-PBSA/MM-GBSA free energy calculations; molecular dynamics simulations; GIST and PCA/TICA analyses\",\n      \"journal\": \"Computational and structural biotechnology journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational structural modeling only, no in vitro or in vivo functional validation of the specific variants\",\n      \"pmids\": [\"41127817\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CACNG8 encodes TARP γ-8, an auxiliary AMPA receptor regulatory protein that physically interacts with the pore-forming AMPAR subunit to regulate receptor trafficking, gating, and synaptic localization, particularly in hippocampal and prefrontal cortical neurons; disruption of this interaction (by partial uncoupling compounds, loss-of-function mutations, or knockout) impairs synaptic AMPAR complex integrity, reduces fast glutamatergic transmission, and produces behavioral deficits reversible by methylphenidate.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CACNG8 encodes TARP γ-8, an auxiliary AMPA receptor regulatory protein that physically associates with the pore-forming AMPAR subunit to govern synaptic glutamatergic signaling [#0]. Novel AMPAR modulators act through TARP γ-8 by partially disrupting its interaction with the channel pore subunit, an effect dependent on intact TARP γ-8 and mapped using mutant constructs in calcium flux, radioligand binding, and electrophysiological assays [#0]. In vivo, loss of TARP γ-8 disrupts the synaptic AMPAR complex in hippocampal synaptosomes and dysregulates dopaminergic and glutamatergic transmission in the prefrontal cortex, producing behavioral deficits rescuable by methylphenidate [#1]. Its expression is sensitive to a transcription-suppressing SNP (rs10420324G) acting through a local G-quadruplex structure, and reduced gene dosage in heterozygous mice impairs synaptic AMPAR function in layer 2–3 prefrontal pyramidal neurons [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that TARP γ-8 physically engages the AMPAR pore-forming subunit and that this interface is pharmacologically targetable, defining the molecular basis for its modulatory role.\",\n      \"evidence\": \"Calcium flux, radioligand binding, and electrophysiology with wild-type and mutant TARP γ-8 constructs plus in vivo occupancy\",\n      \"pmids\": [\"26989142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of the TARP γ-8–pore subunit interface resolved here\",\n        \"Endogenous physiological consequence of disrupting the interaction not assessed in vivo\",\n        \"Specific residues mediating the interaction not fully mapped\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked CACNG8 gene dosage and a transcription-regulatory SNP to AMPAR function in defined cortical neurons, connecting expression control to synaptic physiology.\",\n      \"evidence\": \"Reporter gene assay for transcriptional effect plus electrophysiology in knockout and heterozygous mice\",\n      \"pmids\": [\"34099816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"G-quadruplex mechanism inferred, not directly demonstrated at the endogenous locus\",\n        \"Single lab, two methods\",\n        \"Behavioral relevance of the SNP in humans not established\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that whole-animal loss of TARP γ-8 disrupts the synaptic AMPAR complex and broader neurotransmission, with a pharmacological rescue defining a tractable circuit-level deficit.\",\n      \"evidence\": \"Knockout mice with synaptosomal proteomics, behavioral phenotyping, and methylphenidate rescue\",\n      \"pmids\": [\"36031768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism connecting AMPAR complex loss to dopaminergic dysregulation unresolved\",\n        \"Single lab\",\n        \"Cell-type specificity of the proteomic changes not dissected\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed that rare human CACNG8 variants destabilize the postsynaptic AMPAR-associated complex, extending the gene's role to potential human disease.\",\n      \"evidence\": \"Whole exome sequencing with molecular docking, free-energy calculations, and molecular dynamics simulations\",\n      \"pmids\": [\"41127817\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Computational modeling only, no in vitro or in vivo functional validation of variants\",\n        \"Stability predictions not confirmed by biochemical measurement\",\n        \"Causal genotype-phenotype link in patients not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TARP γ-8 dosage and complex integrity mechanistically couple to prefrontal dopaminergic regulation and human neuropsychiatric phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No experimental validation of disease-associated variants\",\n        \"Structural mechanism of complex stabilization uncharacterized in the corpus\",\n        \"Direct partners beyond the AMPAR pore subunit not biochemically mapped\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"synaptic AMPA receptor complex\"\n    ],\n    \"partners\": [\n      \"GRIA (AMPAR pore-forming subunit)\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}