C2CD3

Summary

C2CD3 (C2 domain containing 3 centriole elongation regulator, HGNC:24564) is a protein-coding gene on chromosome 11q13.4, encoding C2 domain-containing protein 3 (Q4AC94). Component of the centrioles that acts as a positive regulator of centriole elongation.

This gene encodes a protein that functions as a regulator of centriole elongation. Studies of the orthologous mouse protein show that it promotes centriolar distal appendage assembly and is also required for the recruitment of other ciliogenic proteins, including intraflagellar transport proteins. Mutations in this gene cause orofaciodigital syndrome XIV (OFD14), a ciliopathy resulting in malformations of the oral cavity, face and digits. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 26005 — RefSeq curated summary.

At a glance

• Gene–disease (curated): orofaciodigital syndrome type 14 (Definitive, ClinGen)
• Clinical variants (ClinVar): 1,230 total — 55 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 67
• MANE Select transcript: NM_001286577

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24564
Approved symbol	C2CD3
Name	C2 domain containing 3 centriole elongation regulator
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP586P0123
Ensembl gene	ENSG00000168014
Ensembl biotype	protein_coding
OMIM	615944
Entrez	26005

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 13 protein_coding, 11 nonsense_mediated_decay, 10 retained_intron, 6 protein_coding_CDS_not_defined

ENST00000313663, ENST00000334126, ENST00000366334, ENST00000414160, ENST00000415191, ENST00000436679, ENST00000442398, ENST00000535954, ENST00000537285, ENST00000538361, ENST00000538625, ENST00000539061, ENST00000540057, ENST00000541922, ENST00000542452, ENST00000542484, ENST00000542930, ENST00000544293, ENST00000679415, ENST00000679906, ENST00000679940, ENST00000680173, ENST00000680231, ENST00000680306, ENST00000680645, ENST00000680665, ENST00000680718, ENST00000680839, ENST00000681000, ENST00000681143, ENST00000681233, ENST00000681291, ENST00000681310, ENST00000681345, ENST00000681385, ENST00000681609, ENST00000681811, ENST00000681829, ENST00000681924, ENST00000923534

RefSeq mRNA: 2 — MANE Select: NM_001286577 NM_001286577, NM_015531

CCDS: CCDS31636, CCDS66167

Canonical transcript exons

ENST00000334126 — 33 exons

Exon	Start	End
ENSE00001600275	74074253	74074600
ENSE00001617374	74078115	74078717
ENSE00001630163	74049337	74049542
ENSE00001633364	74048205	74048338
ENSE00001653574	74113780	74113892
ENSE00001688205	74092416	74092588
ENSE00001695191	74093816	74093999
ENSE00001755772	74085618	74085886
ENSE00001758412	74100525	74100676
ENSE00001786545	74095228	74095408
ENSE00001792992	74012718	74013525
ENSE00001803083	74098009	74098255
ENSE00002705508	74042054	74042218
ENSE00003464779	74037478	74037698
ENSE00003471357	74161399	74161556
ENSE00003481235	74138720	74138967
ENSE00003522621	74109034	74109152
ENSE00003526074	74139605	74139828
ENSE00003538158	74122988	74123135
ENSE00003547010	74133425	74133557
ENSE00003553692	74028287	74028398
ENSE00003554111	74103131	74103625
ENSE00003568854	74114384	74114593
ENSE00003584714	74057406	74057544
ENSE00003585481	74054607	74054671
ENSE00003590699	74106371	74106493
ENSE00003593871	74132844	74132972
ENSE00003612592	74090813	74090936
ENSE00003619528	74118228	74118382
ENSE00003661128	74168344	74168613
ENSE00003667375	74033351	74034278
ENSE00003677324	74084881	74084970
ENSE00003909727	74170738	74171002

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 91.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.9210 / max 119.1143, expressed in 1727 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121307	2.0220	914
121306	1.4029	844
121302	1.2220	803
121309	1.0538	508
121303	0.6360	388
121310	0.5459	258
121304	0.5409	334
121305	0.2752	125
121308	0.1859	76
121301	0.0279	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	91.42	gold quality
right uterine tube	UBERON:0001302	90.88	gold quality
bronchial epithelial cell	CL:0002328	89.66	gold quality
colonic epithelium	UBERON:0000397	88.98	gold quality
epithelium of bronchus	UBERON:0002031	88.76	gold quality
right testis	UBERON:0004534	88.61	gold quality
left testis	UBERON:0004533	88.23	gold quality
ventricular zone	UBERON:0003053	88.20	gold quality
bronchus	UBERON:0002185	88.17	gold quality
cortical plate	UBERON:0005343	87.38	gold quality
sperm	CL:0000019	87.30	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.23	gold quality
ganglionic eminence	UBERON:0004023	87.07	gold quality
testis	UBERON:0000473	86.92	gold quality
bone marrow cell	CL:0002092	86.28	gold quality
mucosa of paranasal sinus	UBERON:0005030	86.27	gold quality
adenohypophysis	UBERON:0002196	86.11	gold quality
male germ cell	CL:0000015	86.03	gold quality
secondary oocyte	CL:0000655	85.96	gold quality
pituitary gland	UBERON:0000007	85.83	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.69	gold quality
stromal cell of endometrium	CL:0002255	85.67	gold quality
primary visual cortex	UBERON:0002436	85.60	gold quality
right lobe of thyroid gland	UBERON:0001119	85.51	gold quality
left lobe of thyroid gland	UBERON:0001120	85.05	gold quality
thyroid gland	UBERON:0002046	84.81	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.42	gold quality
granulocyte	CL:0000094	84.34	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.19	gold quality
blood	UBERON:0000178	84.06	gold quality

Single-cell (SCXA)

Detected in 43 experiment(s), a significant marker in 20.

Experiment	Marker?	Max mean expression
E-MTAB-8894	yes	6494.27
E-HCAD-56	yes	4922.26
E-GEOD-137537	yes	4168.18
E-MTAB-6701	yes	3850.18
E-CURD-79	yes	3634.81
E-MTAB-8884	yes	3361.51
E-CURD-88	yes	3048.70
E-MTAB-10018	yes	2422.21
E-MTAB-9154	yes	1941.53
E-MTAB-10485	yes	1924.15
E-MTAB-8142	yes	1026.94
E-MTAB-8060	yes	678.72
E-GEOD-76312	yes	249.41
E-HCAD-1	yes	81.76
E-MTAB-8410	yes	28.43

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting C2CD3, 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-576-5P	99.84	70.46	2582
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-4751	98.80	64.95	525
HSA-MIR-4752	98.71	68.04	833
HSA-MIR-767-3P	98.61	67.69	1192
HSA-MIR-7114-5P	98.51	67.87	1349
HSA-MIR-6847-5P	97.93	66.74	1808
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280
HSA-MIR-6828-3P	96.06	67.61	1155
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002

Literature-anchored findings (GeneRIF, showing 7)

• Loss of C2CD3 results in short centrioles without subdistal and distal appendages. (PMID:24997988)
• we uncover that SAS-1 is related to C2CD3, a protein required for complete centriole formation in human cells and affected in a type of oral-facial-digital (OFD) syndrome (PMID:25412110)
• Our data provide further evidence that mutations in C2CD3 cause a ciliopathy in humans and expand the previously reported phenotype resulting from C2CD3 dysfunction. (PMID:27094867)
• Biallelic C2CD3 variants lead to a broad spectrum of ciliopathy phenotypes. (PMID:30097616)
• 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)
• Evolutionary conservation of centriole rotational asymmetry in the human centrosome. (PMID:35319462)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	c2cd3	ENSDARG00000074137
mus_musculus	C2cd3	ENSMUSG00000047248
rattus_norvegicus	C2cd3	ENSRNOG00000017608
drosophila_melanogaster	CG32425	FBGN0052425

Protein

Protein identifiers

C2 domain-containing protein 3 — Q4AC94 (reviewed: Q4AC94)

All UniProt accessions (19): A0A7P0T831, Q4AC94, A0A7P0T883, A0A7P0T8E9, A0A7P0T8H7, A0A7P0T8V8, A0A7P0T995, A0A7P0T9H1, A0A7P0TAM9, A0A7P0TAU6, A0A7P0Z464, A0A7P0Z475, A0A7P0Z4H1, A0A7P0Z4J2, F5H0U2, H0YFM6, H0YG44, H7BZB4, H7C288

UniProt curated annotations — full annotation on UniProt →

Function. Component of the centrioles that acts as a positive regulator of centriole elongation. Promotes assembly of centriolar distal appendage, a structure at the distal end of the mother centriole that acts as an anchor of the cilium, and is required for recruitment of centriolar distal appendages proteins CEP83, SCLT1, CEP89, FBF1 and CEP164. Not required for centriolar satellite integrity or RAB8 activation. Required for primary cilium formation. Required for sonic hedgehog/SHH signaling and for proteolytic processing of GLI3.

Subunit / interactions. Interacts with IFT88, BBS4 and PCM1. Interacts with OFD1; OFD1 may act as a negative regulator of C2CD3. Associates with the BBSome complex.

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

Disease relevance. Orofaciodigital syndrome 14 (OFD14) [MIM:615948] A form of orofaciodigital syndrome, a group of heterogeneous disorders characterized by malformations of the oral cavity, face and digits, and associated phenotypic abnormalities that lead to the delineation of various subtypes. OFD14 patients show severe microcephaly, cerebral malformations the molar tooth sign, and intellectual disability in addition to canonical OFDS features. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (5)

UniProt ID	Names	Canonical?
Q4AC94-5	5	yes
Q4AC94-1	1
Q4AC94-2	2
Q4AC94-3	3
Q4AC94-4	4

RefSeq proteins (2): NP_001273506, NP_056346 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR037775	C2_C2CD3	Domain
IPR057537	C2_C2CD3_N	Domain

Pfam: PF00168, PF25339

UniProt features (54 total): region of interest 9, splice variant 9, sequence variant 9, sequence conflict 8, compositionally biased region 7, domain 6, modified residue 5, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q4AC94-F1	55.65	0.03

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 (5): 466, 728, 1891, 2114, 2132

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5620912	Anchoring of the basal body to the plasma membrane
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-5617833	Cilium Assembly

MSigDB gene sets: 356 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GCM_MAP4K4, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_PROTEIN_LOCALIZATION_TO_CYTOSKELETON, GOBP_AXIS_SPECIFICATION, GOBP_EMBRYONIC_AXIS_SPECIFICATION, GOBP_EMBRYONIC_DIGIT_MORPHOGENESIS, GCM_ZNF198, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_NEURAL_TUBE_DEVELOPMENT, chr11q13, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (16): in utero embryonic development (GO:0001701), heart looping (GO:0001947), brain development (GO:0007420), regulation of smoothened signaling pathway (GO:0008589), protein processing (GO:0016485), neural tube development (GO:0021915), neural plate axis specification (GO:0021997), regulation of proteolysis (GO:0030162), embryonic digit morphogenesis (GO:0042733), cilium assembly (GO:0060271), centriole elongation (GO:0061511), protein localization to centrosome (GO:0071539), non-motile cilium assembly (GO:1905515), pattern specification process (GO:0007389), cell projection organization (GO:0030030), embryonic limb morphogenesis (GO:0030326)

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

GO Cellular Component (9): centrosome (GO:0005813), centriole (GO:0005814), microtubule organizing center (GO:0005815), cytosol (GO:0005829), centriolar satellite (GO:0034451), ciliary basal body (GO:0036064), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Assembly of the 9+0 primary cilium	1
Organelle biogenesis and maintenance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
microtubule organizing center	3
chordate embryonic development	2
proteolysis	2
intracellular membraneless organelle	2
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
central nervous system development	1
animal organ development	1
head development	1
smoothened signaling pathway	1
regulation of signal transduction	1
protein maturation	1
nervous system development	1
tube development	1
epithelium development	1
embryonic axis specification	1
neural plate development	1
neural plate pattern specification	1
regulation of protein metabolic process	1
embryonic limb morphogenesis	1
embryonic morphogenesis	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
centriole replication	1
cell cycle process	1
protein localization to microtubule organizing center	1
cilium assembly	1
multicellular organism development	1
multicellular organismal process	1
cellular component organization	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
binding	1

Protein interactions and networks

STRING

726 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C2CD3	CEP164	Q9UPV0	785
C2CD3	CEP89	Q96ST8	745
C2CD3	IFT88	Q13099	733
C2CD3	CEP120	Q8N960	732
C2CD3	SCLT1	Q96NL6	727
C2CD3	CEP83	Q9Y592	720
C2CD3	OFD1	O75665	696
C2CD3	FBF1	Q8TES7	670
C2CD3	KIAA0586	Q9BVV6	620
C2CD3	TCTN3	Q6NUS6	609
C2CD3	CPLANE1	Q9H799	606
C2CD3	ARL13B	Q3SXY8	604
C2CD3	NPHP4	O75161	594
C2CD3	CCP110	O43303	584
C2CD3	CC2D2A	Q9P2K1	578

IntAct

34 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
C2CD3	OFD1	psi-mi:“MI:0915”(physical association)	0.640
BBS1	C2CD3	psi-mi:“MI:0915”(physical association)	0.400
BBS2	C2CD3	psi-mi:“MI:0915”(physical association)	0.400
BBS4	C2CD3	psi-mi:“MI:0915”(physical association)	0.400
TTC8	C2CD3	psi-mi:“MI:0915”(physical association)	0.400
BBS5	C2CD3	psi-mi:“MI:0915”(physical association)	0.400
BBS9	C2CD3	psi-mi:“MI:0915”(physical association)	0.400
C2CD3	BBS7	psi-mi:“MI:0915”(physical association)	0.400
PLEC	C2CD3	psi-mi:“MI:0915”(physical association)	0.400
C2CD3	H2AC12	psi-mi:“MI:0915”(physical association)	0.400
C2CD3	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
Cep135		psi-mi:“MI:0914”(association)	0.350
Cep120	TBC1D31	psi-mi:“MI:0914”(association)	0.350
Cep131	WBP2	psi-mi:“MI:0914”(association)	0.350
OFD1	CCDC14	psi-mi:“MI:0914”(association)	0.350
Cep43	TBC1D31	psi-mi:“MI:0914”(association)	0.350
CEP162	IPO5	psi-mi:“MI:0914”(association)	0.350
RYBP	FAM186A	psi-mi:“MI:0914”(association)	0.350
CEP63	CIBAR1	psi-mi:“MI:0914”(association)	0.350
CEP128	CCDC66	psi-mi:“MI:2364”(proximity)	0.270
PCM1	CCDC66	psi-mi:“MI:2364”(proximity)	0.270
CEP135	CCDC66	psi-mi:“MI:2364”(proximity)	0.270
CNTRL	CCDC85C	psi-mi:“MI:2364”(proximity)	0.270
SPICE1	CCDC66	psi-mi:“MI:2364”(proximity)	0.270
CEP89	CCDC66	psi-mi:“MI:2364”(proximity)	0.270
CDC14A	CEP290	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (59): C2CD3 (Proximity Label-MS), C2CD3 (Proximity Label-MS), C2CD3 (Proximity Label-MS), C2CD3 (Affinity Capture-MS), C2CD3 (Proximity Label-MS), C2CD3 (Proximity Label-MS), C2CD3 (Proximity Label-MS), C2CD3 (Proximity Label-MS), C2CD3 (Proximity Label-MS), C2CD3 (Proximity Label-MS), C2CD3 (Affinity Capture-MS), C2CD3 (Affinity Capture-MS), C2CD3 (Affinity Capture-MS), C2CD3 (Affinity Capture-MS), C2CD3 (Affinity Capture-MS)

ESM2 similar proteins: A0JM13, A1A4L4, A2RRS8, B0DOB4, D4A039, O00750, O70167, O70173, Q08EC4, Q1LXR6, Q3ULW6, Q3UQI9, Q3V0L5, Q3ZAV8, Q4AC94, Q4G0A6, Q52KB6, Q5DTU0, Q5F479, Q5JV73, Q5SUS0, Q5T0N1, Q5XIR4, Q5XIZ9, Q6IFT4, Q6IRN0, Q6IRU7, Q6P1H6, Q6P4K6, Q6PF55, Q6REY9, Q6ZPF3, Q7TP65, Q7Z2Z1, Q80TQ5, Q80VH0, Q8C008, Q8IWE5, Q8N4X5, Q8N5R6

Diamond homologs: A0JM13, Q4AC94, Q52KB6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 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
BBSome-mediated cargo-targeting to cilium	7	124.1×	5e-12
Cargo trafficking to the periciliary membrane	5	44.3×	1e-06
Loss of Nlp from mitotic centrosomes	7	39.6×	1e-08
Loss of proteins required for interphase microtubule organization from the centrosome	7	39.6×	1e-08
Cilium Assembly	10	38.8×	5e-12
AURKA Activation by TPX2	7	38.1×	1e-08
Anchoring of the basal body to the plasma membrane	9	36.3×	9e-11
Recruitment of mitotic centrosome proteins and complexes	7	34.0×	2e-08

GO biological processes:

GO term	Partners	Fold	FDR
non-motile cilium assembly	8	62.8×	6e-11
cilium assembly	16	31.8×	2e-18
fat cell differentiation	6	29.4×	4e-06
intracellular protein localization	6	17.0×	6e-05
visual perception	6	12.9×	2e-04
protein transport	7	8.3×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1230 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	55
Likely pathogenic	23
Uncertain significance	523
Likely benign	377
Benign	144

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070295	NM_001286577.2(C2CD3):c.5405del (p.Tyr1802fs)	Pathogenic
1424462	NM_001286577.2(C2CD3):c.52dup (p.Arg18fs)	Pathogenic
144038	NM_001286577.2(C2CD3):c.184C>T (p.Arg62Ter)	Pathogenic
144039	NM_001286577.2(C2CD3):c.3085T>G (p.Cys1029Gly)	Pathogenic
1451467	NM_001286577.2(C2CD3):c.1957A>T (p.Lys653Ter)	Pathogenic
1454437	NM_001286577.2(C2CD3):c.2842C>T (p.Arg948Ter)	Pathogenic
1456017	NM_001286577.2(C2CD3):c.2070dup (p.Phe691fs)	Pathogenic
1905561	NM_001286577.2(C2CD3):c.441dup (p.Thr148fs)	Pathogenic
1910492	NM_001286577.2(C2CD3):c.5749dup (p.Thr1917fs)	Pathogenic
1954802	NM_001286577.2(C2CD3):c.4684del (p.Ser1562fs)	Pathogenic
1980454	NM_001286577.2(C2CD3):c.4808_4824del (p.His1603fs)	Pathogenic
1999885	NM_001286577.2(C2CD3):c.197G>A (p.Trp66Ter)	Pathogenic
2027190	NM_001286577.2(C2CD3):c.2401_2402del (p.Ser801fs)	Pathogenic
2028489	NM_001286577.2(C2CD3):c.4278dup (p.Asn1427fs)	Pathogenic
2028571	NM_001286577.2(C2CD3):c.1898_1899dup (p.Glu634Ter)	Pathogenic
2036491	NM_001286577.2(C2CD3):c.195G>T (p.Trp65Cys)	Pathogenic
2072037	NM_001286577.2(C2CD3):c.5036_5039del (p.Thr1679fs)	Pathogenic
2084925	NM_001286577.2(C2CD3):c.3685del (p.Val1229fs)	Pathogenic
217559	NM_001286577.2(C2CD3):c.4951+1G>T	Pathogenic
2693230	NM_001286577.2(C2CD3):c.3049dup (p.Ala1017fs)	Pathogenic
2694905	NM_001286577.2(C2CD3):c.1141_1142insA (p.Leu381fs)	Pathogenic
2696541	NM_001286577.2(C2CD3):c.5497del (p.Ser1833fs)	Pathogenic
2699103	NM_001286577.2(C2CD3):c.3459del (p.Phe1153fs)	Pathogenic
2720824	NM_001286577.2(C2CD3):c.3459_3460dup (p.Asn1154fs)	Pathogenic
2762861	NM_001286577.2(C2CD3):c.3340del (p.Cys1114fs)	Pathogenic
2769651	NM_001286577.2(C2CD3):c.281dup (p.Tyr94Ter)	Pathogenic
2788409	NM_001286577.2(C2CD3):c.519C>G (p.Tyr173Ter)	Pathogenic
2794446	NM_001286577.2(C2CD3):c.1423A>T (p.Lys475Ter)	Pathogenic
2796140	NM_001286577.2(C2CD3):c.4657C>T (p.Arg1553Ter)	Pathogenic
2802669	NM_001286577.2(C2CD3):c.3535del (p.Gly1178_Leu1179insTer)	Pathogenic

SpliceAI

5033 predictions. Top by Δscore:

Variant	Effect	Δscore
11:74037695:CTTC:C	acceptor_gain	1.0000
11:74042132:C:CA	donor_gain	1.0000
11:74042214:CACTT:C	acceptor_gain	1.0000
11:74042216:CTT:C	acceptor_gain	1.0000
11:74042217:TT:T	acceptor_gain	1.0000
11:74042218:TCT:T	acceptor_loss	1.0000
11:74042219:C:CC	acceptor_gain	1.0000
11:74042220:T:A	acceptor_loss	1.0000
11:74042223:C:CT	acceptor_gain	1.0000
11:74042224:A:T	acceptor_gain	1.0000
11:74048203:ACCT:A	donor_gain	1.0000
11:74048203:ACCTC:A	donor_gain	1.0000
11:74048204:CCTC:C	donor_gain	1.0000
11:74048204:CCTCC:C	donor_gain	1.0000
11:74048339:C:CC	acceptor_gain	1.0000
11:74049334:TA:T	donor_loss	1.0000
11:74049335:A:AC	donor_gain	1.0000
11:74049335:A:AG	donor_loss	1.0000
11:74049336:C:CC	donor_gain	1.0000
11:74049540:CAT:C	acceptor_gain	1.0000
11:74049543:C:CC	acceptor_gain	1.0000
11:74054608:T:TA	donor_gain	1.0000
11:74057543:CC:C	acceptor_gain	1.0000
11:74057544:CC:C	acceptor_gain	1.0000
11:74084875:CCTTA:C	donor_loss	1.0000
11:74084876:CTTA:C	donor_loss	1.0000
11:74084877:TTAC:T	donor_loss	1.0000
11:74084878:TACCA:T	donor_loss	1.0000
11:74084879:A:AC	donor_gain	1.0000
11:74084879:A:T	donor_loss	1.0000

AlphaMissense

15374 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:74049468:A:G	W1744R	0.999
11:74049468:A:T	W1744R	0.999
11:74168476:A:G	W65R	0.999
11:74168476:A:T	W65R	0.999
11:74057428:A:G	W1690R	0.998
11:74057428:A:T	W1690R	0.998
11:74049466:C:A	W1744C	0.997
11:74049466:C:G	W1744C	0.997
11:74054627:A:G	F1712S	0.997
11:74078235:A:G	W1495R	0.997
11:74078235:A:T	W1495R	0.997
11:74078706:A:G	W1338R	0.997
11:74078706:A:T	W1338R	0.997
11:74098128:C:G	G954R	0.997
11:74168349:A:G	L107P	0.997
11:74168471:C:A	W66C	0.997
11:74168471:C:G	W66C	0.997
11:74168473:A:G	W66R	0.997
11:74168473:A:T	W66R	0.997
11:74057426:C:A	W1690C	0.996
11:74057426:C:G	W1690C	0.996
11:74098133:G:T	A952D	0.996
11:74161403:A:G	L160P	0.996
11:74168353:A:C	Y106D	0.996
11:74168474:C:A	W65C	0.996
11:74168474:C:G	W65C	0.996
11:74049417:C:G	A1761P	0.995
11:74049419:A:T	V1760D	0.995
11:74078171:G:T	A1516D	0.995
11:74078630:A:G	L1363P	0.995

dbSNP variants (sampled 300 via entrez): RS1000068959 (11:74100354 A>G), RS1000091628 (11:74055503 C>T), RS1000099395 (11:74074110 G>A,C), RS1000142315 (11:74079226 C>T), RS1000151756 (11:74167698 G>A), RS1000156300 (11:74012431 G>T), RS1000176623 (11:74068303 C>T), RS1000225552 (11:74013690 C>G), RS1000258875 (11:74026718 C>A,T), RS1000288219 (11:74120027 A>G,T), RS1000324096 (11:74133640 G>C), RS1000368019 (11:74138681 C>A,T), RS1000460262 (11:74067846 T>C), RS1000480357 (11:74113056 G>C), RS1000495380 (11:74157338 T>A,C)

Disease associations

OMIM: gene MIM:615944 | disease phenotypes: MIM:615948, MIM:213300, MIM:208500

GenCC curated gene-disease

Disease	Classification	Inheritance
orofaciodigital syndrome type 14	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
orofaciodigital syndrome type 14	Definitive	AR

Mondo (4): orofaciodigital syndrome type 14 (MONDO:0014413), Joubert syndrome (MONDO:0018772), congenital portosystemic shunt (MONDO:0018811), Jeune syndrome (MONDO:0018770)

Orphanet (4): Orofaciodigital syndrome type 14 (Orphanet:434179), Isolated Joubert syndrome (Orphanet:475), Congenital portosystemic shunt (Orphanet:480531), Jeune syndrome (Orphanet:474)

HPO phenotypes

67 total (30 of 67 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000039	Epispadias
HP:0000054	Micropenis
HP:0000175	Cleft palate
HP:0000180	Lobulated tongue
HP:0000191	Accessory oral frenulum
HP:0000243	Trigonocephaly
HP:0000252	Microcephaly
HP:0000308	Microretrognathia
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000414	Bulbous nose
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000480	Retinal coloboma
HP:0000506	Telecanthus
HP:0000582	Upslanted palpebral fissure
HP:0000588	Optic disc coloboma
HP:0000695	Natal tooth
HP:0000773	Short ribs
HP:0001162	Postaxial hand polydactyly
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001305	Dandy-Walker malformation
HP:0001320	Cerebellar vermis hypoplasia

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
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

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, affects expression	2
Cadmium Chloride	increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases reaction, affects binding	1
Ethyl Methanesulfonate	increases expression	1
Methotrexate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases methylation	1
Vanadates	decreases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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)
NCT06041906	Not specified	ENROLLING_BY_INVITATION	International Registry of Congenital Portosystemic Shunt (IRCPSS)
NCT07314814	Not specified	NOT_YET_RECRUITING	Genetic Hallmarks of Patients With Congenital Portosystemic Shunts and Portopulmonary Hypertension
NCT00948376	Not specified	COMPLETED	Natural History of Asphyxiating Thoracic Dystrophy (DTJ)
NCT04143841	Not specified	TERMINATED	Viveye Ocular Magnetic Neurostimulation System (OMNS) for the Management of Severe Dry Eye Disease