{"gene":"RABL2B","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2017,"finding":"CEP19 specifically captures GTP-bound RABL2B at the ciliary base; RABL2B is activated via its intrinsic nucleotide exchange. Activated RABL2B then captures and releases the IFT-B holocomplex from the pool of pre-docked IFT-B complexes, thereby initiating ciliary entry of IFT. The upstream module consists of CEP350 and FOP recruiting CEP19 to the centriole, which then binds GTP-RABL2B.","method":"Affinity-purification mass spectrometry (AP-MS), Co-immunoprecipitation, GTPase nucleotide-state mutant analysis, functional ciliary entry assays","journal":"Developmental Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal AP-MS, GTPase activation-state mutants, multiple orthogonal methods in a single rigorous study establishing the full pathway","pmids":["28625565"],"is_preprint":false},{"year":2019,"finding":"RABL2 (RABL2A/RABL2B) recruitment to the mother centriole depends on distal appendage proteins CEP164 and CEP83. RABL2 physically associates with ciliary GPCRs (GPR161 and HTR6) and positively controls their localization to primary cilia. This function is independent of TULP3 but requires CEP19 and the IFT-B complex.","method":"siRNA silencing with mis-localization readout, overexpression rescue, Co-immunoprecipitation (RABL2 with GPCRs), epistasis with CEP19/IFT-B knockdown","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus KD phenotype, single lab, multiple orthogonal methods","pmids":["30578315"],"is_preprint":false},{"year":1999,"finding":"RABL2B encodes a small GTPase with similarity to the RAB family, located in the subtelomeric region of 22q13.3. It is expressed ubiquitously (2.5-kb transcript in all tissues) and in a muscle-specific isoform (1.4-kb transcript) generated by differential splicing of an intron in the 3' UTR.","method":"Northern analysis, genomic mapping, sequence analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Northern blot and sequence analysis replicated in subsequent studies; establishes expression and basic gene structure","pmids":["10444334"],"is_preprint":false},{"year":2011,"finding":"RABL2B pre-mRNA undergoes alternative splicing with constant splice-isoform ratios across genetically diverse lymphoblastoid cell lines, independent of gene expression level; subtle splicing at tandem acceptor splice sites is highly constrained and strongly depends on upstream donor sequence content.","method":"Pyrosequencing of splice isoforms across multiple cell lines, quantitative splice ratio analysis","journal":"Genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (quantitative RT-PCR/pyrosequencing), no functional consequence demonstrated for the splicing regulation","pmids":["21220357"],"is_preprint":false},{"year":2017,"finding":"An intronic deletion variant (rs144944885, 50776482 delC) in RABL2B is predicted by bioinformatics to modify splicing of RABL2B pre-mRNA and was found at significantly higher frequency in infertile men with oligoasthenoteratozoospermia compared to controls.","method":"PCR/Sanger sequencing of exons 4-5 and flanking introns in patient cohort; bioinformatics splice-site prediction","journal":"Journal of Assisted Reproduction and Genetics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — splicing effect inferred by bioinformatics only, no functional splicing assay performed; association study with small cohort","pmids":["28138870"],"is_preprint":false},{"year":2017,"finding":"A SNP (c.125G>A) within an exonic splicing enhancer (ESE) motif of bovine RABL2B causes exon 2 skipping and production of an aberrant splice variant (RABL2B-TV). This was demonstrated by constructing pSPL3 exon-capture vectors with different genotypes and transfecting into MLTC-1 cells; the AA genotype was associated with higher sperm deformity and lower motility.","method":"pSPL3 exon-trapping reporter assay in MLTC-1 cells, RT-PCR splice variant detection, association analysis in bulls","journal":"Reproduction, Fertility and Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional splicing demonstrated by exon-trapping reporter assay with genotype-specific constructs; bovine ortholog","pmids":["28553998"],"is_preprint":false}],"current_model":"RABL2B is an atypical RAB-family GTPase that, when activated (GTP-bound) via intrinsic nucleotide exchange, is captured by the centrosomal scaffold protein CEP19 (itself recruited by CEP350/FOP) at the ciliary base, where it binds and releases the IFT-B holocomplex to initiate intraflagellar transport and ciliary entry; it also physically associates with ciliary GPCRs (GPR161, HTR6) to promote their trafficking into primary cilia, in a manner dependent on CEP19, IFT-B, and distal appendage proteins CEP164/CEP83 but independent of TULP3."},"narrative":{"mechanistic_narrative":"RABL2B is an atypical RAB-family small GTPase that initiates intraflagellar transport and controls protein delivery into the primary cilium [PMID:28625565, PMID:30578315]. When loaded with GTP through its intrinsic nucleotide exchange, RABL2B is specifically captured at the ciliary base by the centrosomal scaffold CEP19, which is itself recruited to the centriole by the CEP350/FOP module; activated RABL2B then engages and releases the IFT-B holocomplex from a pool of pre-docked complexes to license ciliary entry of intraflagellar transport [PMID:28625565]. Beyond launching IFT, RABL2 physically associates with the ciliary GPCRs GPR161 and HTR6 and promotes their trafficking into primary cilia in a manner that depends on its recruitment to the mother centriole by the distal appendage proteins CEP164 and CEP83 and on CEP19 and IFT-B, but is independent of TULP3 [PMID:30578315]. The gene is expressed ubiquitously with a muscle-specific isoform arising from differential 3' UTR splicing [PMID:10444334], and splicing variants of the orthologous gene that disrupt the transcript are associated with defects in sperm morphology and motility [PMID:28553998].","teleology":[{"year":1999,"claim":"Established RABL2B as a RAB-like small GTPase gene with defined chromosomal location and expression pattern, providing the molecular starting point before any function was known.","evidence":"Northern analysis, genomic mapping, and sequence analysis of the 22q13.3 subtelomeric locus","pmids":["10444334"],"confidence":"Medium","gaps":["No biochemical activity or interaction partner identified","Functional role of the muscle-specific 3' UTR isoform undefined"]},{"year":2011,"claim":"Showed that RABL2B alternative splicing is tightly constrained and constant across genetic backgrounds, but did not link the splicing regulation to any functional output.","evidence":"Pyrosequencing of splice isoforms and quantitative splice-ratio analysis across lymphoblastoid cell lines","pmids":["21220357"],"confidence":"Low","gaps":["No functional consequence demonstrated for the splicing regulation","Single method/single lab","No protein-level readout"]},{"year":2017,"claim":"Defined the core mechanism: how RABL2B is activated and how it triggers ciliary entry of IFT, answering what this GTPase actually does at the ciliary base.","evidence":"AP-MS, reciprocal Co-IP, GTPase nucleotide-state mutants, and ciliary entry assays establishing the CEP350/FOP→CEP19→GTP-RABL2B→IFT-B pathway","pmids":["28625565"],"confidence":"High","gaps":["GAP/GEF regulating the RABL2B nucleotide cycle in cells not identified","Structural basis of IFT-B capture and release not resolved","Quantitative dynamics of IFT initiation not measured"]},{"year":2017,"claim":"Linked RABL2B sequence variation to a physiological phenotype, suggesting splicing disruption impairs reproductive function.","evidence":"pSPL3 exon-trapping reporter assay in MLTC-1 cells with genotype-specific constructs plus bull sperm-quality association (bovine ortholog); and a human cohort splice-prediction association in oligoasthenoteratozoospermia (bioinformatics only)","pmids":["28553998","28138870"],"confidence":"Medium","gaps":["Human variant splicing effect inferred bioinformatically without a functional assay","Small association cohorts","Mechanistic link between aberrant splice product and sperm defect not established"]},{"year":2019,"claim":"Extended RABL2 function beyond IFT initiation to selective cargo delivery, defining how specific ciliary GPCRs reach the cilium and which upstream factors recruit RABL2.","evidence":"siRNA silencing with mislocalization readout, overexpression rescue, reciprocal Co-IP of RABL2 with GPR161/HTR6, and epistasis with CEP19/IFT-B and distal appendage proteins","pmids":["30578315"],"confidence":"Medium","gaps":["Direct vs indirect nature of the RABL2–GPCR association not fully resolved","Single lab","Generality across other ciliary GPCRs untested"]},{"year":null,"claim":"How the RABL2B GTPase cycle is regulated in vivo (its GEF beyond intrinsic exchange and any GAP) and the structural basis of IFT-B engagement remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No GAP identified","No high-resolution structure of RABL2B–IFT-B or RABL2B–CEP19 complexes","Direct GPCR binding interface uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0]}],"complexes":[],"partners":["CEP19","GPR161","HTR6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UNT1","full_name":"Rab-like protein 2B","aliases":[],"length_aa":228,"mass_kda":26.1,"function":"Small GTPase required for ciliation. Activated in a guanine nucleotide exchange factor (GEF)-independent manner via its intrinsic GDP for GTP nucleotide exchange ability (PubMed:28625565). Involved in ciliary assembly by binding the intraflagellar transport (IFT) complex B from the large pool pre-docked at the base of the cilium and thus triggers its entry into the cilia (PubMed:28428259, PubMed:28625565)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm, cytoskeleton, cilium basal body; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UNT1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RABL2B","classification":"Not Classified","n_dependent_lines":35,"n_total_lines":1165,"dependency_fraction":0.030042918454935622},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RABL2B","total_profiled":1310},"omim":[{"mim_id":"617870","title":"CENTROSOMAL PROTEIN 350; CEP350","url":"https://www.omim.org/entry/617870"},{"mim_id":"615586","title":"CENTROSOMAL PROTEIN, 19-KD; CEP19","url":"https://www.omim.org/entry/615586"},{"mim_id":"606232","title":"PHELAN-MCDERMID SYNDROME; PHMDS","url":"https://www.omim.org/entry/606232"},{"mim_id":"606230","title":"SH3 AND MULTIPLE ANKYRIN REPEAT DOMAINS 3; SHANK3","url":"https://www.omim.org/entry/606230"},{"mim_id":"605413","title":"RAB, MEMBER OF RAS ONCOGENE FAMILY-LIKE 2B; RABL2B","url":"https://www.omim.org/entry/605413"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Basal body","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"epididymis","ntpm":84.8}],"url":"https://www.proteinatlas.org/search/RABL2B"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9UNT1","domains":[{"cath_id":"3.40.50.300","chopping":"17-184","consensus_level":"high","plddt":88.0478,"start":17,"end":184}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UNT1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UNT1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UNT1-F1-predicted_aligned_error_v6.png","plddt_mean":79.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RABL2B","jax_strain_url":"https://www.jax.org/strain/search?query=RABL2B"},"sequence":{"accession":"Q9UNT1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UNT1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UNT1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UNT1"}},"corpus_meta":[{"pmid":"28625565","id":"PMC_28625565","title":"The CEP19-RABL2 GTPase Complex Binds IFT-B to Initiate Intraflagellar Transport at the Ciliary Base.","date":"2017","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/28625565","citation_count":94,"is_preprint":false},{"pmid":"12073014","id":"PMC_12073014","title":"FISH-mapping of a 100-kb terminal 22q13 deletion.","date":"2002","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12073014","citation_count":65,"is_preprint":false},{"pmid":"32699331","id":"PMC_32699331","title":"Gene biomarker discovery at different stages of Alzheimer using gene co-expression network approach.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32699331","citation_count":47,"is_preprint":false},{"pmid":"19454329","id":"PMC_19454329","title":"Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3.","date":"2009","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19454329","citation_count":43,"is_preprint":false},{"pmid":"10444334","id":"PMC_10444334","title":"Two novel human RAB genes with near identical sequence each map to a telomere-associated region: the subtelomeric region of 22q13.3 and the ancestral telomere band 2q13.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10444334","citation_count":33,"is_preprint":false},{"pmid":"30578315","id":"PMC_30578315","title":"RABL2 positively controls localization of GPCRs in mammalian primary cilia.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30578315","citation_count":25,"is_preprint":false},{"pmid":"28138870","id":"PMC_28138870","title":"The impact of RABL2B gene (rs144944885) on human male infertility in patients with oligoasthenoteratozoospermia and immotile short tail sperm defects.","date":"2017","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28138870","citation_count":18,"is_preprint":false},{"pmid":"20635403","id":"PMC_20635403","title":"Fulminant hepatic failure requiring liver transplantation in 22q13.3 deletion syndrome.","date":"2010","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/20635403","citation_count":11,"is_preprint":false},{"pmid":"21220357","id":"PMC_21220357","title":"Constant splice-isoform ratios in human lymphoblastoid cells support the concept of a splico-stat.","date":"2011","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21220357","citation_count":10,"is_preprint":false},{"pmid":"20138207","id":"PMC_20138207","title":"Analysis of relative gene dosage and expression differences of the paralogs RABL2A and RABL2B by Pyrosequencing.","date":"2010","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/20138207","citation_count":9,"is_preprint":false},{"pmid":"28553998","id":"PMC_28553998","title":"Splicing-related single nucleotide polymorphism of RAB, member of RAS oncogene family like 2B (RABL2B) jeopardises semen quality in Chinese Holstein bulls.","date":"2017","source":"Reproduction, fertility, and development","url":"https://pubmed.ncbi.nlm.nih.gov/28553998","citation_count":5,"is_preprint":false},{"pmid":"28018439","id":"PMC_28018439","title":"Phelan-McDermid syndrome presenting with developmental delays and facial dysmorphisms.","date":"2016","source":"Korean journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/28018439","citation_count":4,"is_preprint":false},{"pmid":"38927965","id":"PMC_38927965","title":"Transcript-Level Biomarkers of Early Lung Carcinogenesis in Bronchial Lesions.","date":"2024","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38927965","citation_count":0,"is_preprint":false},{"pmid":"41249621","id":"PMC_41249621","title":"Meta single-cell atlas and xQTL post-GWAS analysis revealed the pathogenic features of thyroid cancer for target therapy: A multi-omics study.","date":"2025","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41249621","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8742,"output_tokens":1605,"usd":0.02515,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8350,"output_tokens":2151,"usd":0.047762,"stage2_stop_reason":"end_turn"},"total_usd":0.072912,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"CEP19 specifically captures GTP-bound RABL2B at the ciliary base; RABL2B is activated via its intrinsic nucleotide exchange. Activated RABL2B then captures and releases the IFT-B holocomplex from the pool of pre-docked IFT-B complexes, thereby initiating ciliary entry of IFT. The upstream module consists of CEP350 and FOP recruiting CEP19 to the centriole, which then binds GTP-RABL2B.\",\n      \"method\": \"Affinity-purification mass spectrometry (AP-MS), Co-immunoprecipitation, GTPase nucleotide-state mutant analysis, functional ciliary entry assays\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal AP-MS, GTPase activation-state mutants, multiple orthogonal methods in a single rigorous study establishing the full pathway\",\n      \"pmids\": [\"28625565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RABL2 (RABL2A/RABL2B) recruitment to the mother centriole depends on distal appendage proteins CEP164 and CEP83. RABL2 physically associates with ciliary GPCRs (GPR161 and HTR6) and positively controls their localization to primary cilia. This function is independent of TULP3 but requires CEP19 and the IFT-B complex.\",\n      \"method\": \"siRNA silencing with mis-localization readout, overexpression rescue, Co-immunoprecipitation (RABL2 with GPCRs), epistasis with CEP19/IFT-B knockdown\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus KD phenotype, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30578315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RABL2B encodes a small GTPase with similarity to the RAB family, located in the subtelomeric region of 22q13.3. It is expressed ubiquitously (2.5-kb transcript in all tissues) and in a muscle-specific isoform (1.4-kb transcript) generated by differential splicing of an intron in the 3' UTR.\",\n      \"method\": \"Northern analysis, genomic mapping, sequence analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Northern blot and sequence analysis replicated in subsequent studies; establishes expression and basic gene structure\",\n      \"pmids\": [\"10444334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RABL2B pre-mRNA undergoes alternative splicing with constant splice-isoform ratios across genetically diverse lymphoblastoid cell lines, independent of gene expression level; subtle splicing at tandem acceptor splice sites is highly constrained and strongly depends on upstream donor sequence content.\",\n      \"method\": \"Pyrosequencing of splice isoforms across multiple cell lines, quantitative splice ratio analysis\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (quantitative RT-PCR/pyrosequencing), no functional consequence demonstrated for the splicing regulation\",\n      \"pmids\": [\"21220357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"An intronic deletion variant (rs144944885, 50776482 delC) in RABL2B is predicted by bioinformatics to modify splicing of RABL2B pre-mRNA and was found at significantly higher frequency in infertile men with oligoasthenoteratozoospermia compared to controls.\",\n      \"method\": \"PCR/Sanger sequencing of exons 4-5 and flanking introns in patient cohort; bioinformatics splice-site prediction\",\n      \"journal\": \"Journal of Assisted Reproduction and Genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — splicing effect inferred by bioinformatics only, no functional splicing assay performed; association study with small cohort\",\n      \"pmids\": [\"28138870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A SNP (c.125G>A) within an exonic splicing enhancer (ESE) motif of bovine RABL2B causes exon 2 skipping and production of an aberrant splice variant (RABL2B-TV). This was demonstrated by constructing pSPL3 exon-capture vectors with different genotypes and transfecting into MLTC-1 cells; the AA genotype was associated with higher sperm deformity and lower motility.\",\n      \"method\": \"pSPL3 exon-trapping reporter assay in MLTC-1 cells, RT-PCR splice variant detection, association analysis in bulls\",\n      \"journal\": \"Reproduction, Fertility and Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional splicing demonstrated by exon-trapping reporter assay with genotype-specific constructs; bovine ortholog\",\n      \"pmids\": [\"28553998\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RABL2B is an atypical RAB-family GTPase that, when activated (GTP-bound) via intrinsic nucleotide exchange, is captured by the centrosomal scaffold protein CEP19 (itself recruited by CEP350/FOP) at the ciliary base, where it binds and releases the IFT-B holocomplex to initiate intraflagellar transport and ciliary entry; it also physically associates with ciliary GPCRs (GPR161, HTR6) to promote their trafficking into primary cilia, in a manner dependent on CEP19, IFT-B, and distal appendage proteins CEP164/CEP83 but independent of TULP3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RABL2B is an atypical RAB-family small GTPase that initiates intraflagellar transport and controls protein delivery into the primary cilium [#0, #1]. When loaded with GTP through its intrinsic nucleotide exchange, RABL2B is specifically captured at the ciliary base by the centrosomal scaffold CEP19, which is itself recruited to the centriole by the CEP350/FOP module; activated RABL2B then engages and releases the IFT-B holocomplex from a pool of pre-docked complexes to license ciliary entry of intraflagellar transport [#0]. Beyond launching IFT, RABL2 physically associates with the ciliary GPCRs GPR161 and HTR6 and promotes their trafficking into primary cilia in a manner that depends on its recruitment to the mother centriole by the distal appendage proteins CEP164 and CEP83 and on CEP19 and IFT-B, but is independent of TULP3 [#1]. The gene is expressed ubiquitously with a muscle-specific isoform arising from differential 3' UTR splicing [#2], and splicing variants of the orthologous gene that disrupt the transcript are associated with defects in sperm morphology and motility [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established RABL2B as a RAB-like small GTPase gene with defined chromosomal location and expression pattern, providing the molecular starting point before any function was known.\",\n      \"evidence\": \"Northern analysis, genomic mapping, and sequence analysis of the 22q13.3 subtelomeric locus\",\n      \"pmids\": [\"10444334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical activity or interaction partner identified\", \"Functional role of the muscle-specific 3' UTR isoform undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed that RABL2B alternative splicing is tightly constrained and constant across genetic backgrounds, but did not link the splicing regulation to any functional output.\",\n      \"evidence\": \"Pyrosequencing of splice isoforms and quantitative splice-ratio analysis across lymphoblastoid cell lines\",\n      \"pmids\": [\"21220357\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional consequence demonstrated for the splicing regulation\", \"Single method/single lab\", \"No protein-level readout\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the core mechanism: how RABL2B is activated and how it triggers ciliary entry of IFT, answering what this GTPase actually does at the ciliary base.\",\n      \"evidence\": \"AP-MS, reciprocal Co-IP, GTPase nucleotide-state mutants, and ciliary entry assays establishing the CEP350/FOP\\u2192CEP19\\u2192GTP-RABL2B\\u2192IFT-B pathway\",\n      \"pmids\": [\"28625565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GAP/GEF regulating the RABL2B nucleotide cycle in cells not identified\", \"Structural basis of IFT-B capture and release not resolved\", \"Quantitative dynamics of IFT initiation not measured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked RABL2B sequence variation to a physiological phenotype, suggesting splicing disruption impairs reproductive function.\",\n      \"evidence\": \"pSPL3 exon-trapping reporter assay in MLTC-1 cells with genotype-specific constructs plus bull sperm-quality association (bovine ortholog); and a human cohort splice-prediction association in oligoasthenoteratozoospermia (bioinformatics only)\",\n      \"pmids\": [\"28553998\", \"28138870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human variant splicing effect inferred bioinformatically without a functional assay\", \"Small association cohorts\", \"Mechanistic link between aberrant splice product and sperm defect not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended RABL2 function beyond IFT initiation to selective cargo delivery, defining how specific ciliary GPCRs reach the cilium and which upstream factors recruit RABL2.\",\n      \"evidence\": \"siRNA silencing with mislocalization readout, overexpression rescue, reciprocal Co-IP of RABL2 with GPR161/HTR6, and epistasis with CEP19/IFT-B and distal appendage proteins\",\n      \"pmids\": [\"30578315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect nature of the RABL2\\u2013GPCR association not fully resolved\", \"Single lab\", \"Generality across other ciliary GPCRs untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the RABL2B GTPase cycle is regulated in vivo (its GEF beyond intrinsic exchange and any GAP) and the structural basis of IFT-B engagement remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No GAP identified\", \"No high-resolution structure of RABL2B\\u2013IFT-B or RABL2B\\u2013CEP19 complexes\", \"Direct GPCR binding interface uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CEP19\", \"GPR161\", \"HTR6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}