KIAA0586

Summary

KIAA0586 (HGNC:19960) is a protein-coding gene on chromosome 14q23.1, encoding Protein TALPID3 (Q9BVV6). Required for ciliogenesis and sonic hedgehog/SHH signaling.

This gene encodes a conserved centrosomal protein that functions in ciliogenesis and responds to hedgehog signaling. Mutations in this gene causes Joubert syndrome 23. Alternative splicing results in multiple transcript variants and protein isoforms.

Source: NCBI Gene 9786 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Joubert syndrome 23 (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 1,649 total — 103 pathogenic, 50 likely-pathogenic
• Phenotypes (HPO): 135
• MANE Select transcript: NM_001329943

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19960
Approved symbol	KIAA0586
Name	KIAA0586
Location	14q23.1
Locus type	gene with protein product
Status	Approved
Aliases	Talpid3, JBTS23
Ensembl gene	ENSG00000100578
Ensembl biotype	protein_coding
OMIM	610178
Entrez	9786

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 12 protein_coding, 5 protein_coding_CDS_not_defined, 5 retained_intron, 4 nonsense_mediated_decay

ENST00000261244, ENST00000354386, ENST00000423743, ENST00000538571, ENST00000554463, ENST00000555203, ENST00000555397, ENST00000555833, ENST00000556235, ENST00000557192, ENST00000557392, ENST00000557590, ENST00000619416, ENST00000619722, ENST00000650845, ENST00000650904, ENST00000651596, ENST00000651759, ENST00000651852, ENST00000651937, ENST00000652120, ENST00000652326, ENST00000652414, ENST00000652732, ENST00000674802, ENST00000676447

RefSeq mRNA: 13 — MANE Select: NM_001329943 NM_001244189, NM_001244190, NM_001244191, NM_001244192, NM_001244193, NM_001329943, NM_001329944, NM_001329945, NM_001329946, NM_001329947, NM_001364700, NM_001364701, NM_014749

CCDS: CCDS45115, CCDS58320, CCDS58321, CCDS58322, CCDS73639, CCDS91882

Canonical transcript exons

ENST00000652326 — 31 exons

Exon	Start	End
ENSE00001094688	58540071	58540136
ENSE00003459834	58458473	58458545
ENSE00003467629	58490164	58490240
ENSE00003473799	58457759	58457979
ENSE00003475018	58477123	58477241
ENSE00003488855	58470613	58470723
ENSE00003491671	58488621	58488874
ENSE00003494991	58512522	58512627
ENSE00003504620	58430648	58430717
ENSE00003514651	58498783	58498960
ENSE00003515380	58442706	58442880
ENSE00003525938	58456702	58456810
ENSE00003527170	58474607	58474797
ENSE00003545754	58487007	58487166
ENSE00003546302	58465835	58466029
ENSE00003557894	58432388	58432457
ENSE00003570652	58460986	58461160
ENSE00003599900	58472199	58472279
ENSE00003607194	58482513	58482712
ENSE00003610072	58492144	58492275
ENSE00003620803	58448340	58448493
ENSE00003639747	58459843	58460070
ENSE00003642505	58443954	58444175
ENSE00003645941	58453350	58453473
ENSE00003662912	58467735	58467922
ENSE00003665131	58450579	58450746
ENSE00003681081	58487887	58488109
ENSE00003685247	58508555	58508709
ENSE00003691021	58429363	58429433
ENSE00003847938	58427719	58428463
ENSE00003893728	58547781	58551297

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 92.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.1475 / max 287.0723, expressed in 1759 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139829	13.6446	1757
139831	0.2862	137
139827	0.1476	34
139828	0.0691	10

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.38	gold quality
right testis	UBERON:0004534	90.07	gold quality
left testis	UBERON:0004533	89.90	gold quality
testis	UBERON:0000473	88.92	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.52	gold quality
ventricular zone	UBERON:0003053	88.42	gold quality
calcaneal tendon	UBERON:0003701	87.47	gold quality
ganglionic eminence	UBERON:0004023	86.79	gold quality
adrenal tissue	UBERON:0018303	85.60	gold quality
colonic epithelium	UBERON:0000397	84.58	gold quality
cortical plate	UBERON:0005343	84.25	gold quality
sperm	CL:0000019	83.29	gold quality
corpus callosum	UBERON:0002336	82.59	gold quality
cerebellar hemisphere	UBERON:0002245	82.41	gold quality
male germ cell	CL:0000015	82.40	gold quality
cerebellar cortex	UBERON:0002129	82.33	gold quality
adenohypophysis	UBERON:0002196	82.24	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.07	gold quality
secondary oocyte	CL:0000655	81.94	gold quality
embryo	UBERON:0000922	81.90	gold quality
bone marrow cell	CL:0002092	81.68	gold quality
islet of Langerhans	UBERON:0000006	81.62	gold quality
pituitary gland	UBERON:0000007	81.31	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	81.22	gold quality
right coronary artery	UBERON:0001625	81.08	gold quality
cerebellum	UBERON:0002037	81.07	gold quality
right lobe of liver	UBERON:0001114	80.99	gold quality
tendon	UBERON:0000043	80.89	gold quality
hindlimb stylopod muscle	UBERON:0004252	80.86	gold quality
stromal cell of endometrium	CL:0002255	80.61	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.57
E-CURD-112	no	2.59

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

56 targeting KIAA0586, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-548AJ-5P	99.78	71.12	3085

Literature-anchored findings (GeneRIF, showing 15)

• The chicken ortholog functions in regulation of the Gli repressor and activator proteins in the Hedgehog signaling pathway. (PMID:16702409)
• Talpid3 and Cep290 play overlapping and distinct roles in ciliary vesicle formation through regulation of centriolar satellite accretion and Rab8a (PMID:24421332)
• Intersection of this data with whole exome results from 145 individuals with unexplained Joubert syndrome identified six families with predominantly compound heterozygous mutations in KIAA0586. (PMID:26026149)
• we show that biallelic KIAA0586 mutations are associated with relatively mild JS in square2.5% of families with JS. (PMID:26096313)
• Mutations in KIAA0586 cause lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly syndrome. (PMID:26166481)
• biallelic deleterious mutations in KIAA0586 lead to Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. (PMID:26386044)
• The authors demonstrate KIAA0586 protein localization at the basal body in human and mouse photoreceptors, as is common for Joubert syndrome proteins, and also in pericentriolar locations. (PMID:26386247)
• In the absence of PCM1, Mib1 destabilizes Talpid3 through poly-ubiquitylation and suppresses cilium assembly. (PMID:27146717)
• Considering this and the high allele frequency of 0.003117 in the gnomAD database, we conclude that c.428delG represents a JBTS disease-causing variant only if present in compound heterozygous state with a more severe KIAA0586 variant, but not in a homozygous situation. (PMID:30120217)
• Talpid3, C2CD3, and OFD1 differentially regulate the assembly of centriole sub-distal appendages, the CEP350/FOP/CEP19 module, centriolar satellites, and actin networks. (PMID:30258116)
• CEP120 interacts with C2CD3 and Talpid3 and is required for centriole appendage assembly and ciliogenesis. (PMID:30988386)
• Loss of KIAA0586 protein (TALPID3) function can cause both severe lethal and mild cilia-related developmental disorders [Review] (PMID:31326647)
• This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. (PMID:32381069)
• Talpid3-Mediated Centrosome Integrity Restrains Neural Progenitor Delamination to Sustain Neurogenesis by Stabilizing Adherens Junctions. (PMID:33326788)
• Compound heterozygous splicing variants in KIAA0586 cause fetal short-rib thoracic dysplasia and cerebellar malformation: Use of exome sequencing in prenatal diagnosis. (PMID:36538006)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-185a18.2	ENSDARG00000097772
mus_musculus	2700049A03Rik	ENSMUSG00000034601
rattus_norvegicus	Kiaa0586	ENSRNOG00000008244

Protein

Protein identifiers

Protein TALPID3 — Q9BVV6 (reviewed: Q9BVV6)

All UniProt accessions (13): Q9BVV6, A0A087WYM5, A0A494C058, A0A494C075, A0A494C0M8, A0A494C0Z1, A0A494C110, A0A494C133, A0A494C171, A0A494C1C3, G3V2T5, G3V4J0, H0YJF0

UniProt curated annotations — full annotation on UniProt →

Function. Required for ciliogenesis and sonic hedgehog/SHH signaling. Required for the centrosomal recruitment of RAB8A and for the targeting of centriole satellite proteins to centrosomes such as of PCM1. May play a role in early ciliogenesis in the disappearance of centriolar satellites that preceeds ciliary vesicle formation. Involved in regulation of cell intracellular organization. Involved in regulation of cell polarity. Required for asymmetrical localization of CEP120 to daughter centrioles.

Subunit / interactions. Interacts with CCP110, CEP290, CEP97, KIF24.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Photoreceptor inner segment. Centriole. Cilium basal body.

Tissue specificity. Ubiquitously expressed. Expressed in photoreceptor cells (at protein level).

Disease relevance. Joubert syndrome 23 (JBTS23) [MIM:616490] A mild form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. The disease is caused by variants affecting the gene represented in this entry. Some patients with biallelic KIAA0586 mutations manifest a disease phenotype with features of Joubert syndrome and additional findings of a small thorax and respiratory problems consistent with Jeune syndrome (Joubert-Jeune ciliopathy). Short-rib thoracic dysplasia 14 with polydactyly (SRTD14) [MIM:616546] A form of short-rib thoracic dysplasia, a group of autosomal recessive ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a ’trident’ appearance of the acetabular roof. Polydactyly is variably present. Non-skeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of the disease are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Disease spectrum encompasses Ellis-van Creveld syndrome, asphyxiating thoracic dystrophy (Jeune syndrome), Mainzer-Saldino syndrome, and short rib-polydactyly syndrome. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TALPID3 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9BVV6-1	1	yes
Q9BVV6-2	2
Q9BVV6-3	3
Q9BVV6-4	4

RefSeq proteins (13): NP_001231118, NP_001231119, NP_001231120, NP_001231121, NP_001231122, NP_001316872, NP_001316873, NP_001316874, NP_001316875, NP_001316876, NP_001351629, NP_001351630, NP_055564 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029246	TALPID3	Family

Pfam: PF15324

UniProt features (29 total): region of interest 6, modified residue 6, splice variant 6, compositionally biased region 3, sequence variant 3, sequence conflict 2, coiled-coil region 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BVV6-F1	47.61	0.09

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (6): 406, 1042, 1046, 1050, 1063, 1066

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 440 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE45365_NK_CELL_VS_CD8_TCELL_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, MORF_MSH3, RORA1_01, MORF_BRCA1, MORF_ATRX, TGACCTY_ERR1_Q2, MORF_ESR1, GGGTGGRR_PAX4_03, GOCC_MICROTUBULE_ORGANIZING_CENTER, MODULE_379, FREAC3_01, MORF_PPP5C

GO Biological Process (4): smoothened signaling pathway (GO:0007224), cilium assembly (GO:0060271), regulation of establishment of protein localization (GO:0070201), cell projection organization (GO:0030030)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (7): photoreceptor inner segment (GO:0001917), centrosome (GO:0005813), centriole (GO:0005814), ciliary basal body (GO:0036064), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
microtubule organizing center	3
intracellular membraneless organelle	2
cell surface receptor signaling pathway	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
regulation of protein localization	1
establishment of protein localization	1
cellular component organization	1
binding	1
centriole	1
cilium	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1344 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KIAA0586	CEP120	Q8N960	869
KIAA0586	CCP110	O43303	812
KIAA0586	SHH	Q15465	711
KIAA0586	CEP290	O15078	663
KIAA0586	OFD1	O75665	654
KIAA0586	CNTLN	Q9NXG0	653
KIAA0586	C2CD3	Q4AC94	620
KIAA0586	DYNC2I2	Q96EX3	603
KIAA0586	CEP164	Q9UPV0	597
KIAA0586	IFT88	Q13099	592
KIAA0586	CPLANE1	Q9H799	583
KIAA0586	DYNC2H1	Q8NCM8	577
KIAA0586	DYNC2I1	Q8WVS4	575
KIAA0586	TMEM67	Q5HYA8	572
KIAA0586	IFT172	Q9UG01	570
KIAA0586	CEP97	Q8IW35	570

IntAct

29 interactions, top by confidence:

A	B	Type	Score
CCP110	CEP290	psi-mi:“MI:0914”(association)	0.890
CEP290	CCP110	psi-mi:“MI:0914”(association)	0.890
KIF24	CCP110	psi-mi:“MI:0914”(association)	0.810
CEP97	CEP290	psi-mi:“MI:0914”(association)	0.740
CEP76	CEP290	psi-mi:“MI:0914”(association)	0.740
PCM1	CEP290	psi-mi:“MI:0914”(association)	0.660
KIAA0586	CCP110	psi-mi:“MI:0915”(physical association)	0.560
KIAA0586	CCP110	psi-mi:“MI:0914”(association)	0.560
CEP76	KIAA0586	psi-mi:“MI:0915”(physical association)	0.500
KIAA0586	RAB8A	psi-mi:“MI:0915”(physical association)	0.400
PA	KIAA0586	psi-mi:“MI:0915”(physical association)	0.370
KIAA0586	CEP290	psi-mi:“MI:0914”(association)	0.350
CEP63	CIBAR1	psi-mi:“MI:0914”(association)	0.350
CDC16	IFT56	psi-mi:“MI:0914”(association)	0.350
PIPSL	C1orf226	psi-mi:“MI:0914”(association)	0.350
TRIM52	MEIOC	psi-mi:“MI:0914”(association)	0.350
C6orf141	KRBA1	psi-mi:“MI:0914”(association)	0.350
NCAPH2	MYO9A	psi-mi:“MI:0914”(association)	0.350
NEK10	MYO9A	psi-mi:“MI:0914”(association)	0.350
SNAPC4	PIK3C2A	psi-mi:“MI:0914”(association)	0.350
PRKAR1B	DNAJC13	psi-mi:“MI:0914”(association)	0.350
TCTE1	DVL2	psi-mi:“MI:2364”(proximity)	0.270
CEP120	CCDC66	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (32): KIAA0586 (Proximity Label-MS), KIAA0586 (Proximity Label-MS), KIAA0586 (Proximity Label-MS), KIAA0586 (Proximity Label-MS), KIAA0586 (Affinity Capture-MS), KIAA0586 (Two-hybrid), KIAA0586 (Affinity Capture-MS), KIAA0586 (Affinity Capture-MS), KIAA0586 (Affinity Capture-MS), KIAA0586 (Affinity Capture-MS), KIAA0586 (Affinity Capture-MS), KIAA0586 (Affinity Capture-RNA), KIAA0586 (Affinity Capture-MS), KIAA0586 (Proximity Label-MS), KIAA0586 (Proximity Label-MS)

ESM2 similar proteins: A0A1W2P884, A2RUB6, A7E3D8, A8MT70, B0CM36, B2RYR0, F1PZQ5, O95447, Q0IIM1, Q0P5X1, Q2KHM9, Q2T9X8, Q4KLH6, Q4R3Q7, Q4R6Q9, Q5NVK0, Q5R7F8, Q5RBD6, Q5RBY6, Q5RC32, Q5RD75, Q5SZL2, Q5TB80, Q5TID7, Q5VX52, Q5XI03, Q6A000, Q6NS45, Q6NZK5, Q6ZPR1, Q6ZQ06, Q7Z4H7, Q80VP2, Q80XJ2, Q80ZU5, Q86T90, Q86YF9, Q8BMD2, Q8IYW5, Q8N0Z3

Diamond homologs: E9PV87, H6D7E6, Q1G7G9, Q9BVV6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MIB1	“down-regulates quantity by destabilization”	KIAA0586	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Anchoring of the basal body to the plasma membrane	8	53.2×	1e-10
Loss of Nlp from mitotic centrosomes	5	46.6×	2e-06
Loss of proteins required for interphase microtubule organization from the centrosome	5	46.6×	2e-06
Regulation of PLK1 Activity at G2/M Transition	6	44.8×	2e-07
AURKA Activation by TPX2	5	44.8×	2e-06
Recruitment of mitotic centrosome proteins and complexes	5	40.0×	3e-06
Recruitment of NuMA to mitotic centrosomes	5	34.3×	5e-06
Cilium Assembly	5	32.0×	6e-06

GO biological processes:

GO term	Partners	Fold	FDR
cilium assembly	7	22.4×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

1649 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	103
Likely pathogenic	50
Uncertain significance	740
Likely benign	563
Benign	88

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068589	NM_001329943.3(KIAA0586):c.1466_1476del (p.Lys489fs)	Pathogenic
1070138	NM_001329943.3(KIAA0586):c.1935del (p.Val646fs)	Pathogenic
1070838	NM_001329943.3(KIAA0586):c.4495+3755del	Pathogenic
1072185	NM_001329943.3(KIAA0586):c.1667dup (p.Arg557fs)	Pathogenic
1073545	NM_001329943.3(KIAA0586):c.1075_1076del (p.Lys359fs)	Pathogenic
1175094	NM_001329943.3(KIAA0586):c.2536del (p.Val846fs)	Pathogenic
1323139	NM_001329943.3(KIAA0586):c.506C>A (p.Ser169Ter)	Pathogenic
1323140	NM_001329943.3(KIAA0586):c.2875C>T (p.Gln959Ter)	Pathogenic
1350774	NM_001329943.3(KIAA0586):c.25G>T (p.Glu9Ter)	Pathogenic
1357141	NM_001329943.3(KIAA0586):c.4456C>T (p.Gln1486Ter)	Pathogenic
1359882	NM_001329943.3(KIAA0586):c.622dup (p.Thr208fs)	Pathogenic
1369714	NM_001329943.3(KIAA0586):c.3353del (p.Pro1118fs)	Pathogenic
1379251	NM_001329943.3(KIAA0586):c.126T>A (p.Cys42Ter)	Pathogenic
1429932	NM_001329943.3(KIAA0586):c.3700del (p.Val1234fs)	Pathogenic
1435532	NM_001329943.3(KIAA0586):c.1872del (p.Glu625fs)	Pathogenic
1435732	NM_001329943.3(KIAA0586):c.411-1371G>A	Pathogenic
1452576	NM_001329943.3(KIAA0586):c.3638del (p.Pro1213fs)	Pathogenic
1453326	NM_001329943.3(KIAA0586):c.938del (p.Tyr313fs)	Pathogenic
1453478	NM_001329943.3(KIAA0586):c.4495+3777del	Pathogenic
1453784	NM_001329943.3(KIAA0586):c.4225del (p.Glu1409fs)	Pathogenic
1453816	NM_001329943.3(KIAA0586):c.4495+3785A>T	Pathogenic
1456969	NM_001329943.3(KIAA0586):c.3580C>T (p.Gln1194Ter)	Pathogenic
1457512	NM_001329943.3(KIAA0586):c.4495+3767A>T	Pathogenic
1457530	NM_001329943.3(KIAA0586):c.2047_2048del (p.Glu683fs)	Pathogenic
1457538	NM_001329943.3(KIAA0586):c.1093del (p.Glu365fs)	Pathogenic
1683813	NM_001329943.3(KIAA0586):c.3097dup (p.Ala1033fs)	Pathogenic
1899465	NM_001329943.3(KIAA0586):c.653_663del (p.Asp218fs)	Pathogenic
1938645	NM_001329943.3(KIAA0586):c.3718_3719del (p.Leu1240fs)	Pathogenic
1976272	NM_001329943.3(KIAA0586):c.411-1455_411-1454insGG	Pathogenic
1984603	NM_001329943.3(KIAA0586):c.1743dup (p.Ile582fs)	Pathogenic

SpliceAI

5796 predictions. Top by Δscore:

Variant	Effect	Δscore
14:58429432:GT:G	donor_gain	1.0000
14:58429434:G:GG	donor_gain	1.0000
14:58430637:A:AG	acceptor_gain	1.0000
14:58430639:A:AG	acceptor_gain	1.0000
14:58430640:T:G	acceptor_gain	1.0000
14:58430644:AAAG:A	acceptor_gain	1.0000
14:58430646:A:G	acceptor_gain	1.0000
14:58430715:AAGGT:A	donor_loss	1.0000
14:58430716:AGG:A	donor_loss	1.0000
14:58430719:T:A	donor_loss	1.0000
14:58432377:T:A	acceptor_gain	1.0000
14:58432384:GCAGC:G	acceptor_loss	1.0000
14:58432386:A:AC	acceptor_loss	1.0000
14:58432386:A:AG	acceptor_gain	1.0000
14:58432387:G:GG	acceptor_gain	1.0000
14:58432387:GC:G	acceptor_gain	1.0000
14:58432387:GCA:G	acceptor_gain	1.0000
14:58432387:GCAA:G	acceptor_gain	1.0000
14:58432387:GCAAA:G	acceptor_gain	1.0000
14:58432454:AAAAG:A	donor_loss	1.0000
14:58432455:AAA:A	donor_gain	1.0000
14:58432455:AAAG:A	donor_loss	1.0000
14:58432456:AA:A	donor_gain	1.0000
14:58432456:AAGT:A	donor_loss	1.0000
14:58432457:AGT:A	donor_loss	1.0000
14:58432458:G:GG	donor_gain	1.0000
14:58432459:TAAG:T	donor_loss	1.0000
14:58442698:A:AG	acceptor_gain	1.0000
14:58442699:T:G	acceptor_gain	1.0000
14:58442701:TATAG:T	acceptor_gain	1.0000

AlphaMissense

10210 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:58442845:G:C	A169P	0.997
14:58442846:C:A	A169D	0.997
14:58442851:G:C	A171P	0.997
14:58442852:C:A	A171D	0.997
14:58442848:G:C	A170P	0.995
14:58442849:C:A	A170D	0.994
14:58442857:G:C	A173P	0.994
14:58442834:C:A	A165D	0.993
14:58442855:T:A	I172N	0.993
14:58442839:G:C	A167P	0.992
14:58457910:T:C	L490P	0.992
14:58442863:G:C	A175P	0.991
14:58443972:G:C	A187P	0.986
14:58442836:G:C	A166P	0.985
14:58450647:C:A	R329S	0.985
14:58443988:T:A	V192D	0.984
14:58442833:G:C	A165P	0.980
14:58458508:T:A	V525E	0.980
14:58442873:T:C	L178S	0.979
14:58442855:T:G	I172S	0.978
14:58442867:C:A	A176D	0.978
14:58444141:T:C	L243P	0.976
14:58442866:G:C	A176P	0.975
14:58442858:C:A	A173E	0.974
14:58457915:G:C	A492P	0.974
14:58442840:C:A	A167E	0.973
14:58457898:T:C	L486P	0.973
14:58457855:G:C	A472P	0.972
14:58458541:T:G	I536S	0.972
14:58443967:T:C	L185S	0.970

dbSNP variants (sampled 300 via entrez): RS1000001712 (14:58525677 A>G), RS1000004481 (14:58560003 T>C), RS1000011149 (14:58451990 A>G,T), RS1000053862 (14:58475828 A>G), RS1000089006 (14:58435285 C>T), RS1000095563 (14:58556790 G>C), RS1000125868 (14:58550869 C>A), RS1000205567 (14:58526724 T>C), RS1000205918 (14:58500740 A>C,G), RS1000210399 (14:58476958 A>G), RS1000216660 (14:58519339 A>G), RS1000227625 (14:58457514 T>G), RS1000254871 (14:58464532 T>G), RS1000302908 (14:58507887 C>G,T), RS1000303570 (14:58549139 TC>T)

Disease associations

OMIM: gene MIM:610178 | disease phenotypes: MIM:616490, MIM:616546, MIM:244400, MIM:213000, MIM:213300, MIM:249000, MIM:208500

GenCC curated gene-disease

Disease	Classification	Inheritance
Joubert syndrome 23	Definitive	Autosomal recessive
short-rib thoracic dysplasia 14 with polydactyly	Strong	Autosomal recessive
Joubert syndrome with Jeune asphyxiating thoracic dystrophy	Supportive	Autosomal recessive
Joubert syndrome	Supportive	Autosomal recessive

Mondo (13): Joubert syndrome 23 (MONDO:0014664), short-rib thoracic dysplasia 14 with polydactyly (MONDO:0014688), ciliopathy (MONDO:0005308), primary ciliary dyskinesia (MONDO:0016575), Joubert syndrome and related disorders (MONDO:0015369), intellectual disability (MONDO:0001071), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), Joubert syndrome (MONDO:0018772), inherited retinal dystrophy (MONDO:0019118), neurodevelopmental disorder (MONDO:0700092), Meckel syndrome (MONDO:0018921), Jeune syndrome (MONDO:0018770), Joubert syndrome with Jeune asphyxiating thoracic dystrophy (MONDO:0018342)

Orphanet (11): Joubert syndrome with Jeune asphyxiating thoracic dystrophy (Orphanet:397715), Isolated Joubert syndrome (Orphanet:475), Ciliopathy (Orphanet:363250), Primary ciliary dyskinesia (Orphanet:244), Joubert syndrome and related disorders (Orphanet:140874), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Meckel syndrome (Orphanet:564), Jeune syndrome (Orphanet:474), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

135 total (30 of 135 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000083	Renal insufficiency
HP:0000110	Renal dysplasia
HP:0000113	Polycystic kidney dysplasia
HP:0000175	Cleft palate
HP:0000191	Accessory oral frenulum
HP:0000202	Orofacial cleft
HP:0000238	Hydrocephalus
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000396	Overfolded helix
HP:0000407	Sensorineural hearing impairment
HP:0000426	Prominent nasal bridge
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000480	Retinal coloboma
HP:0000486	Strabismus
HP:0000496	Abnormality of eye movement
HP:0000508	Ptosis
HP:0000545	Myopia
HP:0000556	Retinal dystrophy
HP:0000572	Visual loss
HP:0000589	Coloboma
HP:0000612	Iris coloboma

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST008158_127	Body mass index	8.000000e-06
GCST009391_155	Metabolite levels	6.000000e-06
GCST009391_1930	Metabolite levels	9.000000e-06
GCST009391_516	Metabolite levels	1.000000e-06
GCST010703_93	Brain morphology (MOSTest)	6.000000e-54
GCST011616_22	Cortical volume	1.000000e-15
GCST011617_38	Cortical surface area	5.000000e-18
GCST011618_3	Cortical thickness	9.000000e-21
GCST011618_5	Cortical thickness	6.000000e-18
GCST90020025_427	Waist-to-hip ratio adjusted for BMI	2.000000e-09
GCST90020027_680	Waist-hip index	2.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0010486	glucuronate measurement
EFO:0010461	argininosuccinate measurement
EFO:0010117	pyruvate measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D002925	Ciliary Motility Disorders	C08.200; C09.150; C16.131.077.245.500; C16.320.184.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D007619	Kartagener Syndrome	C08.127.384.500; C08.200.531; C08.695.501; C09.150.531; C14.240.400.280.500; C14.280.400.280.500; C16.131.077.245.500.531; C16.131.240.400.280.500; C16.131.740.501; C16.131.810.250.500; C16.320.184.500.531; C16.320.480
D065886	Neurodevelopmental Disorders	F03.625
D058499	Retinal Dystrophies	C11.768.585.658
C562568	Cerebellar Hypoplasia (supp.)
C537571	Jeune syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression, decreases methylation	2
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenite	affects expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Atrazine	decreases expression	1
Vehicle Emissions	increases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Caffeine	increases phosphorylation	1
Coumestrol	increases expression	1
Doxorubicin	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Lead	affects expression	1
Dronabinol	increases expression	1
Tretinoin	decreases expression	1
Urethane	increases expression	1
Cyclosporine	increases methylation	1
Copper Sulfate	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

299 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT02871778	PHASE2	COMPLETED	Clearing Lungs With ENaC Inhibition in Primary Ciliary Dyskinesia
NCT07318974	PHASE2	ACTIVE_NOT_RECRUITING	Melatonin Therapy for Improving ICSI Outcomes in Women With Diminished Ovarian Reserve
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05737485	PHASE1	COMPLETED	Study Evaluating the Safety and Tolerability of RCT1100 in Healthy and PCD Subjects
NCT06600425	PHASE1	COMPLETED	A Study to Assess the Safety, Tolerability, Ciliary Rescue, and Pharmacodynamics of RCT1100 in Adults With PCD
NCT06633757	PHASE1	COMPLETED	Study of Inhaled RCT1100 in Adults With PCD Caused by Pathogenic Mutations in the DNAI1 Gene to Measure Mucociliary Clearance
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT00873678	Not specified	COMPLETED	Assessment of the Prevalence of Genes AHI1, NPHP1 and CEP290 in Joubert Syndrome
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)
NCT00068224	Not specified	COMPLETED	Clinical and Molecular Investigations Into Ciliopathies
NCT04901715	EARLY_PHASE1	COMPLETED	Functional Studies of Novel Genes Mutated in Primary Ciliary Dyskinesia II: Genotype to Phenotype
NCT00005650	Not specified	COMPLETED	Genetic Study of Patients With Primary Ciliary Dyskinesia
NCT00323167	Not specified	COMPLETED	Rare Genetic Disorders of the Breathing Airways
NCT00368446	Not specified	COMPLETED	Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease
NCT00450918	Not specified	COMPLETED	Evaluating Progression of and Diagnostic Tools for Primary Ciliary Dyskinesia in Children and Adolescents
NCT00608556	Not specified	COMPLETED	Dyskinesia, Heterotaxy and Congenital Heart Disease
NCT00686309	Not specified	UNKNOWN	Comparison of On-line and Off-line Measurements of Exhaled Nitric Oxide (NO)
NCT00722878	Not specified	COMPLETED	Long-term Lung Function and Disease Progression in Children With Early Onset Primary Ciliary Dyskinesia Lung Disease
NCT00739817	Not specified	UNKNOWN	Screening for Primary Ciliary Dyskinesia Using Nasal Nitric Oxide