{"gene":"COG6","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2012,"finding":"COG6 interacts with a subset of Golgi SNAREs (STX5, STX6, GS27, and SNAP29) via a universal SNARE-binding motif. COG6 overexpression or depletion disrupts Golgi complex integrity. A COG6 mutant lacking the SNARE-binding domain fails to localize to the Golgi and cannot induce Golgi fragmentation when overexpressed, indicating that COG6-SNARE interactions are required for both COG6 Golgi localization and maintenance of Golgi integrity.","method":"Yeast two-hybrid, co-immunoprecipitation, overexpression/depletion assays, domain-deletion mutagenesis","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal Co-IP plus yeast two-hybrid plus domain mutagenesis with functional phenotypic readout in a single focused study","pmids":["23057818"],"is_preprint":false},{"year":2013,"finding":"COG6 deficiency in patient cells results in pronounced reduction of STX6 protein, consistent with an established stabilizing role of COG6 on STX6. Additionally, no detectable abnormality in transferrin glycosylation was observed in these COG6-deficient patients, contrasting with a previously reported COG6-CDG patient.","method":"Expression analysis of patient-derived cells (protein level assessment of STX6; transferrin isoelectrofocusing)","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, patient cell-based functional study; stabilization of STX6 by COG6 confirmed by protein-level measurement in patient cells","pmids":["23606727"],"is_preprint":false},{"year":2025,"finding":"COG6 supports influenza A virus (IAV) replication via two distinct mechanisms: (1) it is required for proper presentation of cell-surface sialic acids (the primary IAV entry receptor), consistent with its role in Golgi homeostasis; and (2) COG6 deficiency leads to lysosome-dependent degradation of viral proteins, as rescued by lysosomal inhibitors. Protein interaction analysis showed that COG6-mediated viral protein stabilization does not involve direct COG6–viral protein interaction. Knockout of other COG subunits produced similar antiviral effects, indicating that an intact COG complex is required for IAV replication.","method":"Genome-wide CRISPR/Cas9 knockout screen, COG6 KO cell lines, lysosomal inhibitor rescue assays, protein interaction (co-IP/pulldown) analysis, surface sialic acid assays","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple orthogonal mechanistic assays (sialic acid presentation, lysosomal rescue, protein interaction) in a single study; not yet independently replicated","pmids":["40910953"],"is_preprint":false},{"year":2025,"finding":"Complete loss of COG6 protein (due to a frameshift variant) impairs two other cooperating COG subunits and delays retrograde Golgi transport, demonstrating that COG6 is required for retrograde trafficking and for stability of partner COG subunits. Aberrant combined N- and O-glycosylation defects are a functional consequence of COG6 loss.","method":"Functional studies assessing COG6 subunit expression, cooperating subunit levels, retrograde transport assay, MALDI mass spectrometry glycan analysis, HPLC-FLD and ESI-Orbitrap glycoprofiling","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, multiple orthogonal methods (transport assay, subunit stability, glycan analysis) but not independently replicated","pmids":["41362306"],"is_preprint":false}],"current_model":"COG6 is a subunit of the Conserved Oligomeric Golgi (COG) complex that localizes to the Golgi via its SNARE-binding motif, directly interacts with Golgi SNAREs (STX5, STX6, GS27, SNAP29) to tether retrograde intra-Golgi vesicles, stabilizes partner COG subunits and STX6, maintains Golgi integrity and retrograde transport, and thereby supports proper N- and O-glycosylation; additionally, COG6 is required for surface sialic acid presentation and protects viral proteins from lysosomal degradation, revealing a functional link between the Golgi and lysosomal proteostasis."},"narrative":{"mechanistic_narrative":"COG6 is a subunit of the Conserved Oligomeric Golgi (COG) complex that supports Golgi-based vesicle tethering and the maintenance of Golgi architecture [PMID:23057818]. It binds a subset of Golgi SNAREs (STX5, STX6, GS27, SNAP29) through a SNARE-binding motif that is itself required for COG6 Golgi localization, such that loss of this motif both mislocalizes COG6 and abolishes its ability to perturb Golgi integrity [PMID:23057818]. COG6 stabilizes its binding partners, including STX6, whose protein level drops sharply in COG6-deficient patient cells, and it is required for the stability of cooperating COG subunits and for normal retrograde intra-Golgi transport [PMID:23606727, PMID:41362306]. Through these trafficking and tethering functions, COG6 sustains proper combined N- and O-glycosylation, and complete COG6 loss produces aberrant glycosylation as a functional consequence, defining a COG6-associated congenital disorder of glycosylation [PMID:41362306]. COG6, as part of an intact COG complex, is also required for influenza A virus replication, contributing both to cell-surface sialic acid presentation and to protection of viral proteins from lysosome-dependent degradation, the latter occurring without a direct COG6–viral protein interaction [PMID:40910953].","teleology":[{"year":2012,"claim":"Established the molecular basis for how COG6 engages the membrane fusion machinery and why it is needed for Golgi structure, by identifying its SNARE partners and a localization-determining SNARE-binding motif.","evidence":"Yeast two-hybrid, reciprocal co-immunoprecipitation, and domain-deletion mutagenesis with overexpression/depletion phenotypic readouts","pmids":["23057818"],"confidence":"High","gaps":["Does not define the stoichiometry or structural arrangement of COG6 within the assembled COG complex","Which SNARE interaction is rate-limiting for tethering versus localization is not resolved"]},{"year":2013,"claim":"Showed that COG6 acts as a stabilizer of its partner STX6 in vivo, while revealing that glycosylation phenotypes of COG6 deficiency can be variable across patients.","evidence":"Protein-level analysis and transferrin isoelectrofocusing in COG6-deficient patient-derived cells","pmids":["23606727"],"confidence":"Medium","gaps":["Single-lab patient study not independently replicated","Mechanism of STX6 destabilization (degradation pathway) not defined","Basis for the discordant transferrin glycosylation phenotype unexplained"]},{"year":2025,"claim":"Demonstrated that complete COG6 loss destabilizes cooperating COG subunits, delays retrograde Golgi transport, and causes combined N- and O-glycosylation defects, linking COG6 trafficking function to disease-relevant glycosylation outcomes.","evidence":"Patient frameshift variant with subunit expression analysis, retrograde transport assay, and MALDI/HPLC-FLD/ESI-Orbitrap glycoprofiling","pmids":["41362306"],"confidence":"Medium","gaps":["Single-lab study not independently replicated","Does not establish which specific glycosyltransferase mislocalization drives the glycan defects"]},{"year":2025,"claim":"Extended COG6 function beyond glycosylation by showing an intact COG complex is required for influenza A virus replication, via sialic acid receptor presentation and protection of viral proteins from lysosomal degradation.","evidence":"Genome-wide CRISPR/Cas9 screen, COG subunit KO cell lines, surface sialic acid assays, lysosomal inhibitor rescue, and co-IP/pulldown interaction analysis","pmids":["40910953"],"confidence":"Medium","gaps":["Not independently replicated","The indirect route by which COG6 loss diverts viral proteins to lysosomes is undefined","Whether the lysosomal proteostasis effect generalizes to host cargo is unknown"]},{"year":null,"claim":"How COG6 assembles within the full COG complex structurally, and the precise mechanism coupling its SNARE-tethering activity to selective cargo glycosylation and lysosomal routing, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of COG6 within the complex in the corpus","No direct demonstration of which cargo glycosyltransferases depend on COG6 tethering","Mechanism linking Golgi dysfunction to lysosomal degradation not elucidated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3]}],"complexes":["COG complex"],"partners":["STX5","STX6","GS27","SNAP29"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y2V7","full_name":"Conserved oligomeric Golgi complex subunit 6","aliases":["Component of oligomeric Golgi complex 6"],"length_aa":657,"mass_kda":73.3,"function":"Required for normal Golgi function","subcellular_location":"Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y2V7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COG6","classification":"Not Classified","n_dependent_lines":306,"n_total_lines":1208,"dependency_fraction":0.2533112582781457},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/COG6","total_profiled":1310},"omim":[{"mim_id":"619286","title":"NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, CATARACTS, AND CEREBELLAR ATROPHY; NEDSCAC","url":"https://www.omim.org/entry/619286"},{"mim_id":"619008","title":"LONG INTERGENIC NONCODING RNA 598; LINC00598","url":"https://www.omim.org/entry/619008"},{"mim_id":"615328","title":"SHAHEEN SYNDROME; SHNS","url":"https://www.omim.org/entry/615328"},{"mim_id":"614576","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIl; CDG2L","url":"https://www.omim.org/entry/614576"},{"mim_id":"606977","title":"COMPONENT OF OLIGOMERIC GOLGI COMPLEX 6; COG6","url":"https://www.omim.org/entry/606977"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COG6"},"hgnc":{"alias_symbol":["COD2","KIAA1134"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y2V7","domains":[{"cath_id":"-","chopping":"237-415","consensus_level":"medium","plddt":92.9675,"start":237,"end":415},{"cath_id":"1.20.1280","chopping":"536-655","consensus_level":"high","plddt":88.8509,"start":536,"end":655},{"cath_id":"1.20.5","chopping":"74-160","consensus_level":"medium","plddt":89.2521,"start":74,"end":160},{"cath_id":"1.10.287","chopping":"163-228","consensus_level":"medium","plddt":85.8329,"start":163,"end":228}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2V7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2V7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2V7-F1-predicted_aligned_error_v6.png","plddt_mean":85.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COG6","jax_strain_url":"https://www.jax.org/strain/search?query=COG6"},"sequence":{"accession":"Q9Y2V7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y2V7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y2V7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2V7"}},"corpus_meta":[{"pmid":"27193031","id":"PMC_27193031","title":"A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus.","date":"2016","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/27193031","citation_count":46,"is_preprint":false},{"pmid":"23606727","id":"PMC_23606727","title":"A novel syndrome of hypohidrosis and intellectual disability is linked to COG6 deficiency.","date":"2013","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23606727","citation_count":43,"is_preprint":false},{"pmid":"23057818","id":"PMC_23057818","title":"COG6 interacts with a subset of the Golgi SNAREs and is important for the Golgi complex integrity.","date":"2012","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/23057818","citation_count":40,"is_preprint":false},{"pmid":"23430903","id":"PMC_23430903","title":"Deficiency of Subunit 6 of the Conserved Oligomeric Golgi Complex (COG6-CDG): Second Patient, Different Phenotype.","date":"2011","source":"JIMD reports","url":"https://pubmed.ncbi.nlm.nih.gov/23430903","citation_count":34,"is_preprint":false},{"pmid":"29445937","id":"PMC_29445937","title":"Secondary Hemophagocytic Syndrome Associated with COG6 Gene Defect: Report and Review.","date":"2018","source":"JIMD reports","url":"https://pubmed.ncbi.nlm.nih.gov/29445937","citation_count":25,"is_preprint":false},{"pmid":"29709711","id":"PMC_29709711","title":"Compound heterozygous variants of the COG6 gene in a Chinese patient with deficiency of subunit 6 of the conserved oligomeric Golgi complex (COG6-CDG).","date":"2018","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29709711","citation_count":16,"is_preprint":false},{"pmid":"25264125","id":"PMC_25264125","title":"Investigating the genetic association of HCP5, SPATA2, TNIP1, TNFAIP3 and COG6 with psoriasis in Chinese population.","date":"2014","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/25264125","citation_count":16,"is_preprint":false},{"pmid":"32905044","id":"PMC_32905044","title":"Neonatal presentation of COG6-CDG with prominent skin phenotype.","date":"2020","source":"JIMD reports","url":"https://pubmed.ncbi.nlm.nih.gov/32905044","citation_count":12,"is_preprint":false},{"pmid":"37149673","id":"PMC_37149673","title":"Decrease of lethal infectious complications in the context of causes of death (COD) after hematopoietic cell transplantation: COD-2 and COD-1 study of the Infectious Diseases Working Party EBMT.","date":"2023","source":"Bone marrow transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/37149673","citation_count":11,"is_preprint":false},{"pmid":"35068072","id":"PMC_35068072","title":"COG6-CDG: Novel variants and novel malformation.","date":"2022","source":"Birth defects research","url":"https://pubmed.ncbi.nlm.nih.gov/35068072","citation_count":9,"is_preprint":false},{"pmid":"33394555","id":"PMC_33394555","title":"Disorder of sex development associated with a novel homozygous nonsense mutation in COG6 expands the phenotypic spectrum of COG6-CDG.","date":"2021","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/33394555","citation_count":8,"is_preprint":false},{"pmid":"35048409","id":"PMC_35048409","title":"Lethal COG6-CDG in neonatal patient with arachnodactyly, joint contractures, and skin manifestations: Founder mutation in the Southeastern European population?","date":"2022","source":"Pediatric dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/35048409","citation_count":4,"is_preprint":false},{"pmid":"40910953","id":"PMC_40910953","title":"COG6 is an essential host factor for influenza A virus infection.","date":"2025","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/40910953","citation_count":1,"is_preprint":false},{"pmid":"39528286","id":"PMC_39528286","title":"[Clinical features and genetic analysis of a child with Congenital disorder of glycosylation due to novel variants of COG6 gene].","date":"2024","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39528286","citation_count":0,"is_preprint":false},{"pmid":"40213872","id":"PMC_40213872","title":"COG6-related prenatal phenotype (CDG2L): Clinico-pathological report and review of the literature.","date":"2025","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40213872","citation_count":0,"is_preprint":false},{"pmid":"41362306","id":"PMC_41362306","title":"Insights Into the Pathological Glycosylation Associated With COG6-CDG.","date":"2025","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/41362306","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9963,"output_tokens":1281,"usd":0.024552,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7917,"output_tokens":2088,"usd":0.045893,"stage2_stop_reason":"end_turn"},"total_usd":0.070445,"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\": 2012,\n      \"finding\": \"COG6 interacts with a subset of Golgi SNAREs (STX5, STX6, GS27, and SNAP29) via a universal SNARE-binding motif. COG6 overexpression or depletion disrupts Golgi complex integrity. A COG6 mutant lacking the SNARE-binding domain fails to localize to the Golgi and cannot induce Golgi fragmentation when overexpressed, indicating that COG6-SNARE interactions are required for both COG6 Golgi localization and maintenance of Golgi integrity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, overexpression/depletion assays, domain-deletion mutagenesis\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal Co-IP plus yeast two-hybrid plus domain mutagenesis with functional phenotypic readout in a single focused study\",\n      \"pmids\": [\"23057818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"COG6 deficiency in patient cells results in pronounced reduction of STX6 protein, consistent with an established stabilizing role of COG6 on STX6. Additionally, no detectable abnormality in transferrin glycosylation was observed in these COG6-deficient patients, contrasting with a previously reported COG6-CDG patient.\",\n      \"method\": \"Expression analysis of patient-derived cells (protein level assessment of STX6; transferrin isoelectrofocusing)\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, patient cell-based functional study; stabilization of STX6 by COG6 confirmed by protein-level measurement in patient cells\",\n      \"pmids\": [\"23606727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"COG6 supports influenza A virus (IAV) replication via two distinct mechanisms: (1) it is required for proper presentation of cell-surface sialic acids (the primary IAV entry receptor), consistent with its role in Golgi homeostasis; and (2) COG6 deficiency leads to lysosome-dependent degradation of viral proteins, as rescued by lysosomal inhibitors. Protein interaction analysis showed that COG6-mediated viral protein stabilization does not involve direct COG6–viral protein interaction. Knockout of other COG subunits produced similar antiviral effects, indicating that an intact COG complex is required for IAV replication.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 knockout screen, COG6 KO cell lines, lysosomal inhibitor rescue assays, protein interaction (co-IP/pulldown) analysis, surface sialic acid assays\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple orthogonal mechanistic assays (sialic acid presentation, lysosomal rescue, protein interaction) in a single study; not yet independently replicated\",\n      \"pmids\": [\"40910953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Complete loss of COG6 protein (due to a frameshift variant) impairs two other cooperating COG subunits and delays retrograde Golgi transport, demonstrating that COG6 is required for retrograde trafficking and for stability of partner COG subunits. Aberrant combined N- and O-glycosylation defects are a functional consequence of COG6 loss.\",\n      \"method\": \"Functional studies assessing COG6 subunit expression, cooperating subunit levels, retrograde transport assay, MALDI mass spectrometry glycan analysis, HPLC-FLD and ESI-Orbitrap glycoprofiling\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, multiple orthogonal methods (transport assay, subunit stability, glycan analysis) but not independently replicated\",\n      \"pmids\": [\"41362306\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COG6 is a subunit of the Conserved Oligomeric Golgi (COG) complex that localizes to the Golgi via its SNARE-binding motif, directly interacts with Golgi SNAREs (STX5, STX6, GS27, SNAP29) to tether retrograde intra-Golgi vesicles, stabilizes partner COG subunits and STX6, maintains Golgi integrity and retrograde transport, and thereby supports proper N- and O-glycosylation; additionally, COG6 is required for surface sialic acid presentation and protects viral proteins from lysosomal degradation, revealing a functional link between the Golgi and lysosomal proteostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COG6 is a subunit of the Conserved Oligomeric Golgi (COG) complex that supports Golgi-based vesicle tethering and the maintenance of Golgi architecture [#0]. It binds a subset of Golgi SNAREs (STX5, STX6, GS27, SNAP29) through a SNARE-binding motif that is itself required for COG6 Golgi localization, such that loss of this motif both mislocalizes COG6 and abolishes its ability to perturb Golgi integrity [#0]. COG6 stabilizes its binding partners, including STX6, whose protein level drops sharply in COG6-deficient patient cells, and it is required for the stability of cooperating COG subunits and for normal retrograde intra-Golgi transport [#1, #3]. Through these trafficking and tethering functions, COG6 sustains proper combined N- and O-glycosylation, and complete COG6 loss produces aberrant glycosylation as a functional consequence, defining a COG6-associated congenital disorder of glycosylation [#3]. COG6, as part of an intact COG complex, is also required for influenza A virus replication, contributing both to cell-surface sialic acid presentation and to protection of viral proteins from lysosome-dependent degradation, the latter occurring without a direct COG6\\u2013viral protein interaction [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the molecular basis for how COG6 engages the membrane fusion machinery and why it is needed for Golgi structure, by identifying its SNARE partners and a localization-determining SNARE-binding motif.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-immunoprecipitation, and domain-deletion mutagenesis with overexpression/depletion phenotypic readouts\",\n      \"pmids\": [\n        \"23057818\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not define the stoichiometry or structural arrangement of COG6 within the assembled COG complex\",\n        \"Which SNARE interaction is rate-limiting for tethering versus localization is not resolved\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that COG6 acts as a stabilizer of its partner STX6 in vivo, while revealing that glycosylation phenotypes of COG6 deficiency can be variable across patients.\",\n      \"evidence\": \"Protein-level analysis and transferrin isoelectrofocusing in COG6-deficient patient-derived cells\",\n      \"pmids\": [\n        \"23606727\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab patient study not independently replicated\",\n        \"Mechanism of STX6 destabilization (degradation pathway) not defined\",\n        \"Basis for the discordant transferrin glycosylation phenotype unexplained\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that complete COG6 loss destabilizes cooperating COG subunits, delays retrograde Golgi transport, and causes combined N- and O-glycosylation defects, linking COG6 trafficking function to disease-relevant glycosylation outcomes.\",\n      \"evidence\": \"Patient frameshift variant with subunit expression analysis, retrograde transport assay, and MALDI/HPLC-FLD/ESI-Orbitrap glycoprofiling\",\n      \"pmids\": [\n        \"41362306\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study not independently replicated\",\n        \"Does not establish which specific glycosyltransferase mislocalization drives the glycan defects\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended COG6 function beyond glycosylation by showing an intact COG complex is required for influenza A virus replication, via sialic acid receptor presentation and protection of viral proteins from lysosomal degradation.\",\n      \"evidence\": \"Genome-wide CRISPR/Cas9 screen, COG subunit KO cell lines, surface sialic acid assays, lysosomal inhibitor rescue, and co-IP/pulldown interaction analysis\",\n      \"pmids\": [\n        \"40910953\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Not independently replicated\",\n        \"The indirect route by which COG6 loss diverts viral proteins to lysosomes is undefined\",\n        \"Whether the lysosomal proteostasis effect generalizes to host cargo is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How COG6 assembles within the full COG complex structurally, and the precise mechanism coupling its SNARE-tethering activity to selective cargo glycosylation and lysosomal routing, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of COG6 within the complex in the corpus\",\n        \"No direct demonstration of which cargo glycosyltransferases depend on COG6 tethering\",\n        \"Mechanism linking Golgi dysfunction to lysosomal degradation not elucidated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0060090\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005794\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-5653656\",\n        \"supporting_discovery_ids\": [\n          0,\n          3\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-392499\",\n        \"supporting_discovery_ids\": [\n          3\n        ]\n      }\n    ],\n    \"complexes\": [\n      \"COG complex\"\n    ],\n    \"partners\": [\n      \"STX5\",\n      \"STX6\",\n      \"GS27\",\n      \"SNAP29\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}