{"gene":"CPLANE2","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2017,"finding":"RSG1 (CPLANE2) is a small GTPase that localizes to the mother centriole and is required for a final maturation step enabling axonemal microtubule elongation during cilia initiation; its centriolar localization depends on TTBK2, the CPLANE complex protein Inturned (INTU), and its own GTPase activity.","method":"Mouse knockout embryos, live imaging, immunofluorescence localization, genetic epistasis with TTBK2 and INTU","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, direct localization experiments, genetic epistasis across multiple components, replicated in vivo","pmids":["29038301"],"is_preprint":false},{"year":2013,"finding":"Rsg1 (CPLANE2) is required for apical trafficking/localization of basal bodies, axonemal intraflagellar transport (IFT) dynamics in multiciliated cells, and cytoplasmic localization of the retrograde IFT-A protein IFT43.","method":"Xenopus loss-of-function (morpholino knockdown), live imaging of IFT dynamics, immunofluorescence of basal body positioning","journal":"Cilia","confidence":"Medium","confidence_rationale":"Tier 2 — defined cellular phenotypes with IFT imaging, single lab","pmids":["24192041"],"is_preprint":false},{"year":2025,"finding":"RSG1 (CPLANE2) binds the CPLANE complex and the transition zone protein FAM92 in a GTP-dependent manner, as revealed by affinity purification mass spectrometry (APMS); disease-causing variants disrupt basal body docking and IFT protein recruitment; CPLANE is required for normal transition zone architecture.","method":"APMS (affinity purification mass spectrometry), patient-derived variant functional analysis, ciliogenesis assays (basal body docking, IFT recruitment)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — APMS with GTP-dependence validation, patient variants with functional readouts, multiple orthogonal methods in single study","pmids":["40593758"],"is_preprint":false},{"year":2024,"finding":"A point mutation in the GTP-binding pocket (G1 domain) of RSG1 (CPLANE2) disrupts axonemal elongation without affecting basal body maturation or localization of RSG1 or other centrosomal/IFT proteins to the basal body, indicating that RSG1 GTPase activity is specifically required for a downstream step after basal body docking.","method":"Forward genetic screen in mouse, point mutation mapping, immunofluorescence of centrosomal/IFT protein localization","journal":"Genesis (New York, N.Y. : 2000)","confidence":"Medium","confidence_rationale":"Tier 2 — active-site point mutation with specific cellular phenotype, single lab","pmids":["38721990"],"is_preprint":false},{"year":2025,"finding":"Folic acid-regulated reactive oxygen species (ROS) modulate ROS-sensitive GTPase activity of RSG1 required for ciliogenesis; moderate folic acid levels preserve RSG1 GTPase activity and cilia formation, while high fortified FA levels reduce basal ROS and impair RSG1-dependent ciliogenesis.","method":"Mouse NTD models with Rsg1 mutation, ROS measurement, cilia formation assays under varying folic acid supplementation","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo model with pharmacological intervention and cilia readout, single lab","pmids":["39755226"],"is_preprint":false},{"year":2024,"finding":"Patient variants in CPLANE2/RSG1 cause Oral-Facial-Digital Syndrome ciliopathy; in silico structural analysis predicts that the FUZ variant p.Arg186His alters interactions between FUZ and CPLANE2/RSG1, potentially disrupting ciliogenesis.","method":"Patient variant identification, in silico 3D structural modeling of FUZ–RSG1 interaction","journal":"Clinical genetics","confidence":"Low","confidence_rationale":"Tier 4 — computational structural prediction only for the FUZ–RSG1 interaction; patient genetics without in vitro validation","pmids":["41952398"],"is_preprint":false},{"year":2022,"finding":"The CPLANE complex, composed of INTU, FUZ, WDPCP (which bind JBTS17 and RSG1/CPLANE2), is required for intraflagellar transport and planar cell polarity; bioinformatic analysis identifies INTU/FUZ as a novel member of HerMon (Hermansky-Pudlak/MON1-CCZ1) complexes with triplication of Longin domains, suggesting INTU/FUZ acts as a GEF for Rab GTPases during ciliogenesis, with RSG1 as a binding partner.","method":"Evolutionary coevolution-based contact prediction and sequence conservation analysis; review/bioinformatics","journal":"Biomolecules","confidence":"Low","confidence_rationale":"Tier 4 — computational/evolutionary inference, no direct biochemical validation of GEF activity","pmids":["35740972","31562761"],"is_preprint":false},{"year":2024,"finding":"RSG1 binds the CPLANE complex (INTU, FUZ, WDPCP, JBTS17) and the transition zone protein FAM92 in a GTP-dependent manner (preprint version of the published Nature Communications paper).","method":"APMS, GTP-dependence assay","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 2 — APMS with GTP-dependence, replicated in peer-reviewed version","pmids":["39386566"],"is_preprint":true}],"current_model":"RSG1 (CPLANE2) is a small GTPase that acts as a component of the CPLANE complex, localizing to the mother centriole in a manner dependent on TTBK2 and INTU, where its GTP-dependent GTPase activity is required for a final step of axonemal elongation after basal body docking; RSG1 also binds the transition zone protein FAM92 in a GTP-dependent manner and governs IFT protein recruitment and basal body trafficking, with loss-of-function causing ciliopathic phenotypes including Oral-Facial-Digital Syndrome in humans."},"narrative":{"teleology":[{"year":2013,"claim":"Establishing that RSG1 is required for ciliogenesis answered whether this uncharacterized small GTPase has a ciliary role, revealing its necessity for basal body apical trafficking, IFT dynamics, and cytoplasmic localization of the retrograde IFT-A protein IFT43.","evidence":"Morpholino knockdown in Xenopus multiciliated cells with live IFT imaging and basal body immunofluorescence","pmids":["24192041"],"confidence":"Medium","gaps":["Morpholino-based knockdown requires genetic confirmation","Whether RSG1 GTPase activity is required was not tested","Mechanism linking RSG1 to IFT-A localization not defined"]},{"year":2017,"claim":"Demonstrating that RSG1 localizes to the mother centriole and is required for a final maturation step enabling axonemal elongation resolved its site of action and placed it in a genetic pathway downstream of TTBK2 and INTU.","evidence":"Mouse Rsg1 knockout embryos with live imaging, immunofluorescence, and epistasis analysis with TTBK2 and INTU","pmids":["29038301"],"confidence":"High","gaps":["Biochemical GTPase activity not directly measured","Direct physical interactions with CPLANE subunits not demonstrated","Whether the centriolar localization defect is the proximate cause of axonemal failure was not resolved"]},{"year":2024,"claim":"A G1-domain point mutation that disrupts axonemal elongation without affecting basal body docking or IFT protein recruitment to the basal body demonstrated that RSG1 GTPase activity is specifically required for a post-docking step, separating its GTP-dependent function from its scaffolding role.","evidence":"Forward genetic screen in mouse; point mutation mapping with immunofluorescence of centrosomal and IFT proteins","pmids":["38721990"],"confidence":"Medium","gaps":["In vitro GTPase activity and GTP/GDP binding kinetics not measured biochemically","Identity of the effector engaged by GTP-bound RSG1 at the basal body remains unknown","Single lab finding"]},{"year":2024,"claim":"Identification of patient variants in CPLANE2 causing Oral-Facial-Digital Syndrome established a direct human disease link, though the structural basis of pathogenicity relied on in silico modeling.","evidence":"Patient variant identification with in silico 3D structural modeling of FUZ–RSG1 interaction","pmids":["41952398"],"confidence":"Low","gaps":["No in vitro or cell-based validation of the predicted FUZ–RSG1 interaction disruption","Genotype-phenotype correlation not established across a patient cohort","Functional rescue experiments not performed"]},{"year":2025,"claim":"APMS demonstrated that RSG1 binds the CPLANE complex and the transition zone protein FAM92 in a GTP-dependent manner, and that disease-causing variants disrupt basal body docking and IFT recruitment, unifying the GTPase-dependent interaction network with ciliopathy pathogenesis.","evidence":"Affinity purification mass spectrometry with GTP-dependence controls, patient-derived variant functional analysis, ciliogenesis assays","pmids":["40593758"],"confidence":"High","gaps":["Direct structural basis of GTP-dependent FAM92 binding not resolved","Whether RSG1 acts catalytically (multiple GTP cycles) or as a molecular switch remains untested","Downstream effectors linking RSG1–FAM92 binding to axonemal elongation not identified"]},{"year":2025,"claim":"Demonstration that folic acid-regulated reactive oxygen species modulate RSG1 GTPase activity and ciliogenesis connected a metabolic/environmental input to RSG1-dependent cilia formation, expanding the regulatory context.","evidence":"Mouse neural tube defect models with Rsg1 mutation, ROS measurements, and cilia formation assays under varying folic acid levels","pmids":["39755226"],"confidence":"Medium","gaps":["Direct biochemical demonstration of ROS-mediated RSG1 GTPase modulation not shown","Relevant cysteine residues or redox-sensitive sites on RSG1 not identified","Specificity of the ROS effect to RSG1 versus other GTPases not established"]},{"year":null,"claim":"The identity of the downstream effector(s) through which GTP-bound RSG1 drives axonemal elongation after basal body docking, and whether RSG1 functions as a canonical molecular switch or has additional catalytic roles, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No effector protein identified downstream of GTP-bound RSG1","No in vitro GTPase kinetics or structural data for RSG1","Mechanism by which transition zone architecture depends on CPLANE/RSG1 is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,3,4]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,2,3]}],"complexes":["CPLANE complex"],"partners":["INTU","FUZ","WDPCP","JBTS17","FAM92","TTBK2"],"other_free_text":[]},"mechanistic_narrative":"CPLANE2 (RSG1) is a small GTPase that functions as a core component of the CPLANE ciliogenesis complex, governing basal body maturation, intraflagellar transport (IFT) protein recruitment, and axonemal microtubule elongation during cilia initiation. It localizes to the mother centriole in a manner dependent on TTBK2, the CPLANE subunit INTU, and its own GTPase activity, and it binds the CPLANE complex components (INTU, FUZ, WDPCP, JBTS17) and the transition zone protein FAM92 in a GTP-dependent manner [PMID:29038301, PMID:40593758]. A point mutation in the RSG1 GTP-binding pocket specifically blocks axonemal elongation without disrupting basal body docking or IFT protein localization, establishing that GTPase activity is required for a discrete downstream step after basal body maturation [PMID:38721990]. Loss-of-function variants in CPLANE2 cause Oral-Facial-Digital Syndrome, a ciliopathy, with disease-associated mutations disrupting basal body docking and IFT recruitment [PMID:40593758, PMID:41952398]."},"prefetch_data":{"uniprot":{"accession":"Q9BU20","full_name":"Ciliogenesis and planar polarity effector 2","aliases":["REM2- and Rab-like small GTPase 1"],"length_aa":258,"mass_kda":28.5,"function":"Required for efficient primary cilia initiation, regulating a late step in cilia initiation. Plays a role in the final maturation of the mother centriole and ciliary vesicle that allows extension of the ciliary axoneme","subcellular_location":"Cytoplasm, cytoskeleton, cilium basal body; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/Q9BU20/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CPLANE2","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CPLANE2","total_profiled":1310},"omim":[{"mim_id":"620487","title":"CILIOGENESIS AND PLANAR POLARITY EFFECTOR COMPLEX, SUBUNIT 2; CPLANE2","url":"https://www.omim.org/entry/620487"},{"mim_id":"613580","title":"WD REPEAT-CONTAINING PLANAR CELL POLARITY EFFECTOR; WDPCP","url":"https://www.omim.org/entry/613580"},{"mim_id":"610622","title":"FUZZY PLANAR CELL POLARITY PROTEIN; FUZ","url":"https://www.omim.org/entry/610622"},{"mim_id":"610621","title":"INTURNED PLANAR CELL POLARITY PROTEIN; INTU","url":"https://www.omim.org/entry/610621"},{"mim_id":"610501","title":"NEUROBLASTOMA BREAKPOINT FAMILY, MEMBER 1; NBPF1","url":"https://www.omim.org/entry/610501"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CPLANE2"},"hgnc":{"alias_symbol":["MGC10731"],"prev_symbol":["C1orf89","RSG1"]},"alphafold":{"accession":"Q9BU20","domains":[{"cath_id":"3.40.50.300","chopping":"16-247","consensus_level":"high","plddt":92.4233,"start":16,"end":247}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BU20","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BU20-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BU20-F1-predicted_aligned_error_v6.png","plddt_mean":90.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CPLANE2","jax_strain_url":"https://www.jax.org/strain/search?query=CPLANE2"},"sequence":{"accession":"Q9BU20","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BU20.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BU20/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BU20"}},"corpus_meta":[{"pmid":"14634138","id":"PMC_14634138","title":"Placental 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its centriolar localization depends on TTBK2, the CPLANE complex protein Inturned (INTU), and its own GTPase activity.\",\n      \"method\": \"Mouse knockout embryos, live imaging, immunofluorescence localization, genetic epistasis with TTBK2 and INTU\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, direct localization experiments, genetic epistasis across multiple components, replicated in vivo\",\n      \"pmids\": [\"29038301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rsg1 (CPLANE2) is required for apical trafficking/localization of basal bodies, axonemal intraflagellar transport (IFT) dynamics in multiciliated cells, and cytoplasmic localization of the retrograde IFT-A protein IFT43.\",\n      \"method\": \"Xenopus loss-of-function (morpholino knockdown), live imaging of IFT dynamics, immunofluorescence of basal body positioning\",\n      \"journal\": \"Cilia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotypes with IFT imaging, single lab\",\n      \"pmids\": [\"24192041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RSG1 (CPLANE2) binds the CPLANE complex and the transition zone protein FAM92 in a GTP-dependent manner, as revealed by affinity purification mass spectrometry (APMS); disease-causing variants disrupt basal body docking and IFT protein recruitment; CPLANE is required for normal transition zone architecture.\",\n      \"method\": \"APMS (affinity purification mass spectrometry), patient-derived variant functional analysis, ciliogenesis assays (basal body docking, IFT recruitment)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — APMS with GTP-dependence validation, patient variants with functional readouts, multiple orthogonal methods in single study\",\n      \"pmids\": [\"40593758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A point mutation in the GTP-binding pocket (G1 domain) of RSG1 (CPLANE2) disrupts axonemal elongation without affecting basal body maturation or localization of RSG1 or other centrosomal/IFT proteins to the basal body, indicating that RSG1 GTPase activity is specifically required for a downstream step after basal body docking.\",\n      \"method\": \"Forward genetic screen in mouse, point mutation mapping, immunofluorescence of centrosomal/IFT protein localization\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — active-site point mutation with specific cellular phenotype, single lab\",\n      \"pmids\": [\"38721990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Folic acid-regulated reactive oxygen species (ROS) modulate ROS-sensitive GTPase activity of RSG1 required for ciliogenesis; moderate folic acid levels preserve RSG1 GTPase activity and cilia formation, while high fortified FA levels reduce basal ROS and impair RSG1-dependent ciliogenesis.\",\n      \"method\": \"Mouse NTD models with Rsg1 mutation, ROS measurement, cilia formation assays under varying folic acid supplementation\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo model with pharmacological intervention and cilia readout, single lab\",\n      \"pmids\": [\"39755226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Patient variants in CPLANE2/RSG1 cause Oral-Facial-Digital Syndrome ciliopathy; in silico structural analysis predicts that the FUZ variant p.Arg186His alters interactions between FUZ and CPLANE2/RSG1, potentially disrupting ciliogenesis.\",\n      \"method\": \"Patient variant identification, in silico 3D structural modeling of FUZ–RSG1 interaction\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational structural prediction only for the FUZ–RSG1 interaction; patient genetics without in vitro validation\",\n      \"pmids\": [\"41952398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The CPLANE complex, composed of INTU, FUZ, WDPCP (which bind JBTS17 and RSG1/CPLANE2), is required for intraflagellar transport and planar cell polarity; bioinformatic analysis identifies INTU/FUZ as a novel member of HerMon (Hermansky-Pudlak/MON1-CCZ1) complexes with triplication of Longin domains, suggesting INTU/FUZ acts as a GEF for Rab GTPases during ciliogenesis, with RSG1 as a binding partner.\",\n      \"method\": \"Evolutionary coevolution-based contact prediction and sequence conservation analysis; review/bioinformatics\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational/evolutionary inference, no direct biochemical validation of GEF activity\",\n      \"pmids\": [\"35740972\", \"31562761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RSG1 binds the CPLANE complex (INTU, FUZ, WDPCP, JBTS17) and the transition zone protein FAM92 in a GTP-dependent manner (preprint version of the published Nature Communications paper).\",\n      \"method\": \"APMS, GTP-dependence assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — APMS with GTP-dependence, replicated in peer-reviewed version\",\n      \"pmids\": [\"39386566\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RSG1 (CPLANE2) is a small GTPase that acts as a component of the CPLANE complex, localizing to the mother centriole in a manner dependent on TTBK2 and INTU, where its GTP-dependent GTPase activity is required for a final step of axonemal elongation after basal body docking; RSG1 also binds the transition zone protein FAM92 in a GTP-dependent manner and governs IFT protein recruitment and basal body trafficking, with loss-of-function causing ciliopathic phenotypes including Oral-Facial-Digital Syndrome in humans.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CPLANE2 (RSG1) is a small GTPase that functions as a core component of the CPLANE ciliogenesis complex, governing basal body maturation, intraflagellar transport (IFT) protein recruitment, and axonemal microtubule elongation during cilia initiation. It localizes to the mother centriole in a manner dependent on TTBK2, the CPLANE subunit INTU, and its own GTPase activity, and it binds the CPLANE complex components (INTU, FUZ, WDPCP, JBTS17) and the transition zone protein FAM92 in a GTP-dependent manner [PMID:29038301, PMID:40593758]. A point mutation in the RSG1 GTP-binding pocket specifically blocks axonemal elongation without disrupting basal body docking or IFT protein localization, establishing that GTPase activity is required for a discrete downstream step after basal body maturation [PMID:38721990]. Loss-of-function variants in CPLANE2 cause Oral-Facial-Digital Syndrome, a ciliopathy, with disease-associated mutations disrupting basal body docking and IFT recruitment [PMID:40593758, PMID:41952398].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing that RSG1 is required for ciliogenesis answered whether this uncharacterized small GTPase has a ciliary role, revealing its necessity for basal body apical trafficking, IFT dynamics, and cytoplasmic localization of the retrograde IFT-A protein IFT43.\",\n      \"evidence\": \"Morpholino knockdown in Xenopus multiciliated cells with live IFT imaging and basal body immunofluorescence\",\n      \"pmids\": [\"24192041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Morpholino-based knockdown requires genetic confirmation\",\n        \"Whether RSG1 GTPase activity is required was not tested\",\n        \"Mechanism linking RSG1 to IFT-A localization not defined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that RSG1 localizes to the mother centriole and is required for a final maturation step enabling axonemal elongation resolved its site of action and placed it in a genetic pathway downstream of TTBK2 and INTU.\",\n      \"evidence\": \"Mouse Rsg1 knockout embryos with live imaging, immunofluorescence, and epistasis analysis with TTBK2 and INTU\",\n      \"pmids\": [\"29038301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Biochemical GTPase activity not directly measured\",\n        \"Direct physical interactions with CPLANE subunits not demonstrated\",\n        \"Whether the centriolar localization defect is the proximate cause of axonemal failure was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A G1-domain point mutation that disrupts axonemal elongation without affecting basal body docking or IFT protein recruitment to the basal body demonstrated that RSG1 GTPase activity is specifically required for a post-docking step, separating its GTP-dependent function from its scaffolding role.\",\n      \"evidence\": \"Forward genetic screen in mouse; point mutation mapping with immunofluorescence of centrosomal and IFT proteins\",\n      \"pmids\": [\"38721990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vitro GTPase activity and GTP/GDP binding kinetics not measured biochemically\",\n        \"Identity of the effector engaged by GTP-bound RSG1 at the basal body remains unknown\",\n        \"Single lab finding\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of patient variants in CPLANE2 causing Oral-Facial-Digital Syndrome established a direct human disease link, though the structural basis of pathogenicity relied on in silico modeling.\",\n      \"evidence\": \"Patient variant identification with in silico 3D structural modeling of FUZ–RSG1 interaction\",\n      \"pmids\": [\"41952398\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No in vitro or cell-based validation of the predicted FUZ–RSG1 interaction disruption\",\n        \"Genotype-phenotype correlation not established across a patient cohort\",\n        \"Functional rescue experiments not performed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"APMS demonstrated that RSG1 binds the CPLANE complex and the transition zone protein FAM92 in a GTP-dependent manner, and that disease-causing variants disrupt basal body docking and IFT recruitment, unifying the GTPase-dependent interaction network with ciliopathy pathogenesis.\",\n      \"evidence\": \"Affinity purification mass spectrometry with GTP-dependence controls, patient-derived variant functional analysis, ciliogenesis assays\",\n      \"pmids\": [\"40593758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct structural basis of GTP-dependent FAM92 binding not resolved\",\n        \"Whether RSG1 acts catalytically (multiple GTP cycles) or as a molecular switch remains untested\",\n        \"Downstream effectors linking RSG1–FAM92 binding to axonemal elongation not identified\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstration that folic acid-regulated reactive oxygen species modulate RSG1 GTPase activity and ciliogenesis connected a metabolic/environmental input to RSG1-dependent cilia formation, expanding the regulatory context.\",\n      \"evidence\": \"Mouse neural tube defect models with Rsg1 mutation, ROS measurements, and cilia formation assays under varying folic acid levels\",\n      \"pmids\": [\"39755226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical demonstration of ROS-mediated RSG1 GTPase modulation not shown\",\n        \"Relevant cysteine residues or redox-sensitive sites on RSG1 not identified\",\n        \"Specificity of the ROS effect to RSG1 versus other GTPases not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the downstream effector(s) through which GTP-bound RSG1 drives axonemal elongation after basal body docking, and whether RSG1 functions as a canonical molecular switch or has additional catalytic roles, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No effector protein identified downstream of GTP-bound RSG1\",\n        \"No in vitro GTPase kinetics or structural data for RSG1\",\n        \"Mechanism by which transition zone architecture depends on CPLANE/RSG1 is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"complexes\": [\n      \"CPLANE complex\"\n    ],\n    \"partners\": [\n      \"INTU\",\n      \"FUZ\",\n      \"WDPCP\",\n      \"JBTS17\",\n      \"FAM92\",\n      \"TTBK2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}