{"gene":"CFAP418","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2016,"finding":"Knockdown of c8orf37 (CFAP418) in zebrafish resulted in impaired visual behavior and BBS-related phenotypes including defects in Kupffer's vesicle formation and delays in retrograde transport; rescue experiments confirmed specificity, and over-expression of human missense mutations also produced these phenotypes, establishing CFAP418 as a functional ciliopathy gene required for retrograde transport.","method":"Zebrafish gene knockdown, rescue experiments, over-expression of human missense mutations, visual behavior assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with rescue experiments and functional readouts in a vertebrate model, single lab","pmids":["27008867"],"is_preprint":false},{"year":2024,"finding":"CFAP418 protein binds to phosphatidic acid (PA) and mitochondrion-specific cardiolipin but does not form a tight static complex with proteins; loss of Cfap418 in mice disrupts membrane lipid homeostasis and membrane-protein associations, causes mitochondrial defects and membrane-remodeling abnormalities across vesicular trafficking pathways (especially ESCRT) in photoreceptors, and increases activity of PA-binding protein kinase Cα in the retina.","method":"Affinity purification coupled with mass spectrometry, quantitative lipidomics, proteomics, phosphoproteomics, Cfap418 knockout mouse model","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (lipidomics, proteomics, phosphoproteomics, AP-MS, KO mouse) in a single rigorous study establishing lipid-binding function and downstream pathway disruption","pmids":["37971880"],"is_preprint":false}],"current_model":"CFAP418 is a cilia-associated protein that binds membrane lipids phosphatidic acid and cardiolipin (but not a stable protein complex), and its loss disrupts membrane lipid homeostasis, ESCRT-mediated vesicular trafficking, and mitochondrial integrity in photoreceptors, while also impairing retrograde ciliary transport—collectively explaining its role in retinal degeneration and syndromic ciliopathies such as Bardet-Biedl syndrome."},"narrative":{"mechanistic_narrative":"CFAP418 is a cilia-associated protein required for normal ciliary transport and photoreceptor membrane homeostasis, and its disruption underlies retinal degeneration and Bardet-Biedl syndrome-related ciliopathy phenotypes [PMID:27008867]. Rather than acting as a stable subunit of a protein complex, CFAP418 binds membrane lipids—specifically phosphatidic acid and the mitochondrion-specific lipid cardiolipin—and its loss perturbs membrane lipid homeostasis and membrane-protein associations [PMID:37971880]. Through this lipid-binding activity, CFAP418 supports membrane-remodeling processes across vesicular trafficking pathways, notably ESCRT, maintains mitochondrial integrity, and restrains activity of the phosphatidic acid-binding kinase protein kinase Cα in the retina [PMID:37971880]. In vivo, CFAP418 is required for retrograde ciliary transport, consistent with its role as a functional ciliopathy gene [PMID:27008867].","teleology":[{"year":2016,"claim":"Established CFAP418 as a bona fide ciliopathy gene by showing its loss disrupts ciliary function in vivo, addressing whether the gene has a causal cellular role rather than mere disease association.","evidence":"Zebrafish knockdown with rescue and human missense over-expression, scored by visual behavior, Kupffer's vesicle formation, and retrograde transport assays","pmids":["27008867"],"confidence":"Medium","gaps":["did not define the molecular activity of CFAP418","mechanism linking the protein to retrograde transport unresolved","knockdown approach not confirmed with a genetic null"]},{"year":2024,"claim":"Defined CFAP418's biochemical activity as lipid binding rather than stable protein-complex assembly, explaining how its loss propagates into membrane, vesicular, and mitochondrial defects in photoreceptors.","evidence":"AP-MS, quantitative lipidomics, proteomics, phosphoproteomics, and a Cfap418 knockout mouse","pmids":["37971880"],"confidence":"High","gaps":["structural basis of phosphatidic acid and cardiolipin binding not resolved","direct mechanistic link between lipid binding and retrograde transport defect not established","whether PKCα activation is a direct or downstream consequence not determined"]},{"year":null,"claim":"How CFAP418 lipid binding mechanistically couples to ciliary retrograde transport and ESCRT-mediated membrane remodeling remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no structural model of the lipid-binding interface","molecular link between membrane lipid homeostasis and transport machinery undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96NL8","full_name":"Cilia- and flagella-associated protein 418","aliases":[],"length_aa":207,"mass_kda":23.4,"function":"May be involved in photoreceptor outer segment disk morphogenesis (By similarity)","subcellular_location":"Cytoplasm; Photoreceptor inner segment","url":"https://www.uniprot.org/uniprotkb/Q96NL8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFAP418","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/CFAP418","total_profiled":1310},"omim":[{"mim_id":"617406","title":"BARDET-BIEDL SYNDROME 21; BBS21","url":"https://www.omim.org/entry/617406"},{"mim_id":"615586","title":"CENTROSOMAL PROTEIN, 19-KD; CEP19","url":"https://www.omim.org/entry/615586"},{"mim_id":"614500","title":"CONE-ROD DYSTROPHY 16; CORD16","url":"https://www.omim.org/entry/614500"},{"mim_id":"614477","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 418; CFAP418","url":"https://www.omim.org/entry/614477"},{"mim_id":"209900","title":"BARDET-BIEDL SYNDROME 1; BBS1","url":"https://www.omim.org/entry/209900"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Primary cilium","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cell Junctions","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CFAP418"},"hgnc":{"alias_symbol":["MOT25","FLJ30600","CORD16","RP64","BBS21","FAP418","SMALLTALK"],"prev_symbol":["C8orf37"]},"alphafold":{"accession":"Q96NL8","domains":[{"cath_id":"-","chopping":"109-205","consensus_level":"medium","plddt":92.59,"start":109,"end":205}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96NL8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96NL8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96NL8-F1-predicted_aligned_error_v6.png","plddt_mean":74.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFAP418","jax_strain_url":"https://www.jax.org/strain/search?query=CFAP418"},"sequence":{"accession":"Q96NL8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96NL8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96NL8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96NL8"}},"corpus_meta":[{"pmid":"27008867","id":"PMC_27008867","title":"Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21).","date":"2016","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27008867","citation_count":85,"is_preprint":false},{"pmid":"29127258","id":"PMC_29127258","title":"Homozygous mutation in CEP19, a gene mutated in morbid obesity, in Bardet-Biedl syndrome with predominant postaxial polydactyly.","date":"2017","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29127258","citation_count":25,"is_preprint":false},{"pmid":"37971880","id":"PMC_37971880","title":"Disruption of CFAP418 interaction with lipids causes widespread abnormal membrane-associated cellular processes in retinal degenerations.","date":"2024","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/37971880","citation_count":3,"is_preprint":false},{"pmid":"41153400","id":"PMC_41153400","title":"Inherited Retinal Diseases with High Myopia: A Review.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/41153400","citation_count":2,"is_preprint":false},{"pmid":"41021661","id":"PMC_41021661","title":"Identifying genetic determinants of outer retinal function in mice using a large-scale gene-targeted screen.","date":"2025","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41021661","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4822,"output_tokens":642,"usd":0.012048,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7047,"output_tokens":1326,"usd":0.034193,"stage2_stop_reason":"end_turn"},"total_usd":0.046241,"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\": \"Knockdown of c8orf37 (CFAP418) in zebrafish resulted in impaired visual behavior and BBS-related phenotypes including defects in Kupffer's vesicle formation and delays in retrograde transport; rescue experiments confirmed specificity, and over-expression of human missense mutations also produced these phenotypes, establishing CFAP418 as a functional ciliopathy gene required for retrograde transport.\",\n      \"method\": \"Zebrafish gene knockdown, rescue experiments, over-expression of human missense mutations, visual behavior assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with rescue experiments and functional readouts in a vertebrate model, single lab\",\n      \"pmids\": [\"27008867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CFAP418 protein binds to phosphatidic acid (PA) and mitochondrion-specific cardiolipin but does not form a tight static complex with proteins; loss of Cfap418 in mice disrupts membrane lipid homeostasis and membrane-protein associations, causes mitochondrial defects and membrane-remodeling abnormalities across vesicular trafficking pathways (especially ESCRT) in photoreceptors, and increases activity of PA-binding protein kinase Cα in the retina.\",\n      \"method\": \"Affinity purification coupled with mass spectrometry, quantitative lipidomics, proteomics, phosphoproteomics, Cfap418 knockout mouse model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (lipidomics, proteomics, phosphoproteomics, AP-MS, KO mouse) in a single rigorous study establishing lipid-binding function and downstream pathway disruption\",\n      \"pmids\": [\"37971880\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CFAP418 is a cilia-associated protein that binds membrane lipids phosphatidic acid and cardiolipin (but not a stable protein complex), and its loss disrupts membrane lipid homeostasis, ESCRT-mediated vesicular trafficking, and mitochondrial integrity in photoreceptors, while also impairing retrograde ciliary transport—collectively explaining its role in retinal degeneration and syndromic ciliopathies such as Bardet-Biedl syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CFAP418 is a cilia-associated protein required for normal ciliary transport and photoreceptor membrane homeostasis, and its disruption underlies retinal degeneration and Bardet-Biedl syndrome-related ciliopathy phenotypes [#0]. Rather than acting as a stable subunit of a protein complex, CFAP418 binds membrane lipids—specifically phosphatidic acid and the mitochondrion-specific lipid cardiolipin—and its loss perturbs membrane lipid homeostasis and membrane-protein associations [#1]. Through this lipid-binding activity, CFAP418 supports membrane-remodeling processes across vesicular trafficking pathways, notably ESCRT, maintains mitochondrial integrity, and restrains activity of the phosphatidic acid-binding kinase protein kinase Cα in the retina [#1]. In vivo, CFAP418 is required for retrograde ciliary transport, consistent with its role as a functional ciliopathy gene [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established CFAP418 as a bona fide ciliopathy gene by showing its loss disrupts ciliary function in vivo, addressing whether the gene has a causal cellular role rather than mere disease association.\",\n      \"evidence\": \"Zebrafish knockdown with rescue and human missense over-expression, scored by visual behavior, Kupffer's vesicle formation, and retrograde transport assays\",\n      \"pmids\": [\"27008867\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"single-lab in vivo knockdown model\",\n      \"gaps\": [\n        \"did not define the molecular activity of CFAP418\",\n        \"mechanism linking the protein to retrograde transport unresolved\",\n        \"knockdown approach not confirmed with a genetic null\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined CFAP418's biochemical activity as lipid binding rather than stable protein-complex assembly, explaining how its loss propagates into membrane, vesicular, and mitochondrial defects in photoreceptors.\",\n      \"evidence\": \"AP-MS, quantitative lipidomics, proteomics, phosphoproteomics, and a Cfap418 knockout mouse\",\n      \"pmids\": [\"37971880\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"multiple orthogonal methods in one rigorous study\",\n      \"gaps\": [\n        \"structural basis of phosphatidic acid and cardiolipin binding not resolved\",\n        \"direct mechanistic link between lipid binding and retrograde transport defect not established\",\n        \"whether PKCα activation is a direct or downstream consequence not determined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CFAP418 lipid binding mechanistically couples to ciliary retrograde transport and ESCRT-mediated membrane remodeling remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"no structural model of the lipid-binding interface\",\n        \"molecular link between membrane lipid homeostasis and transport machinery undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}