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): 1,251 total — 56 pathogenic, 26 likely-pathogenic (top 2% of genes corpus-wide)
• GTEx eGene: eQTL in 35 tissues, sQTL in 14 (q < 0.05)
• Phenotypes (HPO): 67
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.64 (unconstrained)
• 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: 47 — 18 protein_coding, 13 nonsense_mediated_decay, 10 retained_intron, 6 protein_coding_CDS_not_defined

MANE Select: ENST00000334126

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 5, TSL 3: 6, TSL 4: 2, TSL 5: 3

ENST00000334126, ENST00000313663, 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, ENST00001036028, ENST00001067208, ENST00001067209, ENST00001067210, ENST00001067211, ENST00001067212, ENST00001108793

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.

Highest expression (Bgee): sural nerve, uterine tube, bronchial epithelial cell, colonic epithelium, epithelium of bronchus.

Genetic regulation across tissues (GTEx eQTL / sQTL)

C2CD3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 35 tissues and its splicing (sQTL) in 14 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 49 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	1.3e-36	+0.40	11:74162691:C:A
Cells Cultured fibroblasts	sqtl	3.4e-19	+0.57	11:74137508:G:A
Testis	sqtl	1.1e-15	+0.80	11:74099852:T:C
Skin Sun Exposed Lower leg	sqtl	2.7e-12	-1.21	11:74008929:G:A
Testis	eqtl	2.4e-11	+0.70	11:74057009:AC:A
Thyroid	eqtl	8.6e-11	+0.26	11:74075040:C:T
Brain Cerebellum	eqtl	2.6e-09	+0.50	11:74099826:A:G
Thyroid	sqtl	2.3e-08	+1.02	11:74008929:G:A
Colon Sigmoid	eqtl	1.5e-07	+0.34	11:74056452:G:A
Brain Spinal cord cervical c-1	eqtl	9.4e-07	+0.47	11:74099826:A:G
Cells EBV-transformed lymphocytes	sqtl	1.0e-06	+0.59	11:74111647:T:C
Nerve Tibial	sqtl	2.6e-06	+0.92	11:74008929:G:A
Adrenal Gland	eqtl	5.0e-06	-0.33	11:74089842:C:T
Esophagus Muscularis	eqtl	6.3e-06	+0.23	11:74111647:T:C
Brain Cortex	eqtl	2.2e-05	+0.37	11:74061728:T:C
Artery Aorta	eqtl	6.3e-05	-0.24	11:74002084:T:C
Brain Frontal Cortex BA9	eqtl	8.8e-05	-0.29	11:74128752:C:G
Adipose Visceral Omentum	eqtl	1.0e-04	+0.19	11:74111647:T:C
Brain Cerebellar Hemisphere	eqtl	1.0e-04	+0.29	11:74111647:T:C
Brain Caudate basal ganglia	eqtl	1.2e-04	+0.28	11:74108105:C:T

FANTOM5 promoters

showing 10 of 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

showing 100 of 293 tissues 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
cerebellar hemisphere	UBERON:0002245	84.02	gold quality
gastrocnemius	UBERON:0001388	84.01	gold quality
cerebellar cortex	UBERON:0002129	83.99	gold quality
tonsil	UBERON:0002372	83.45	gold quality
oocyte	CL:0000023	83.38	gold quality
cerebellum	UBERON:0002037	83.25	gold quality
adrenal tissue	UBERON:0018303	83.18	gold quality
right adrenal gland cortex	UBERON:0035827	83.15	gold quality
muscle of leg	UBERON:0001383	83.14	gold quality
apex of heart	UBERON:0002098	83.04	gold quality
embryo	UBERON:0000922	82.89	gold quality
buccal mucosa cell	CL:0002336	82.78	gold quality
metanephros cortex	UBERON:0010533	82.70	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.47	gold quality
endothelial cell	CL:0000115	82.39	gold quality
left adrenal gland	UBERON:0001234	82.38	gold quality
body of uterus	UBERON:0009853	82.37	gold quality
tibial nerve	UBERON:0001323	82.33	gold quality
left adrenal gland cortex	UBERON:0035825	82.32	gold quality
right adrenal gland	UBERON:0001233	82.21	gold quality
adrenal gland	UBERON:0002369	82.21	gold quality
occipital lobe	UBERON:0002021	82.14	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.98	gold quality
right frontal lobe	UBERON:0002810	81.88	gold quality
left ovary	UBERON:0002119	81.86	gold quality
endocervix	UBERON:0000458	81.77	gold quality
corpus callosum	UBERON:0002336	81.76	gold quality
amniotic fluid	UBERON:0000173	81.74	gold quality
spleen	UBERON:0002106	81.69	gold quality
adrenal cortex	UBERON:0001235	81.66	gold quality
upper lobe of left lung	UBERON:0008952	81.61	gold quality
middle temporal gyrus	UBERON:0002771	81.60	gold quality
caput epididymis	UBERON:0004358	81.50	gold quality
right ovary	UBERON:0002118	81.44	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	81.32	gold quality
Brodmann (1909) area 10	UBERON:0013541	81.31	gold quality
prostate gland	UBERON:0002367	81.20	gold quality
lower esophagus muscularis layer	UBERON:0035833	81.14	gold quality
lower esophagus	UBERON:0013473	81.12	gold quality
mucosa of transverse colon	UBERON:0004991	81.10	gold quality
prefrontal cortex	UBERON:0000451	81.08	gold quality
ovary	UBERON:0000992	80.92	gold quality
muscle layer of sigmoid colon	UBERON:0035805	80.91	gold quality
rectum	UBERON:0001052	80.88	gold quality
skin of leg	UBERON:0001511	80.88	gold quality
upper lobe of lung	UBERON:0008948	80.82	gold quality
ectocervix	UBERON:0012249	80.78	gold quality
minor salivary gland	UBERON:0001830	80.77	gold quality
placenta	UBERON:0001987	80.77	gold quality
islet of Langerhans	UBERON:0000006	80.72	gold quality
calcaneal tendon	UBERON:0003701	80.71	gold quality
epithelium of nasopharynx	UBERON:0001951	80.65	gold quality
right lung	UBERON:0002167	80.63	gold quality
skin of abdomen	UBERON:0001416	80.55	gold quality
medial globus pallidus	UBERON:0002477	80.50	gold quality
lower esophagus mucosa	UBERON:0035834	80.47	gold quality
transverse colon	UBERON:0001157	80.32	gold quality
right atrium auricular region	UBERON:0006631	80.32	gold quality
neocortex	UBERON:0001950	80.31	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	80.30	gold quality
stomach	UBERON:0000945	80.28	gold quality
saliva-secreting gland	UBERON:0001044	80.27	gold quality
spinal cord	UBERON:0002240	80.23	gold quality
anatomical system	UBERON:0000467	80.19	gold quality
esophagus	UBERON:0001043	80.04	gold quality
material anatomical entity	UBERON:0000465	80.02	gold quality
multicellular organism	UBERON:0000468	80.01	gold quality
lymph node	UBERON:0000029	80.00	gold quality
female reproductive system	UBERON:0000474	79.93	gold quality
cingulate cortex	UBERON:0003027	79.92	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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	55.5
Hippocampus	tissue	49.5	low
Nucleus accumbens	tissue	47.5
Postcentral gyrus	tissue	43.7
Locus coeruleus	tissue	42.0
Cerebellum	tissue	12.1	low
Testis	tissue	10.1	high
Caudate putamen	tissue	10.1
Bone marrow	tissue	9.5	low
Corpus callosum	tissue	9.2
Olfactory bulb	tissue	9.2
Hippocampal formation	tissue	8.7
Ventral forebrain	tissue	8.4
Periaqueductal gray	tissue	8.4
Amygdala	tissue	8.3
Hypothalamus	tissue	8.3
Substantia nigra	tissue	8.3
Basal ganglia	tissue	8.2	low
Thalamus	tissue	8.2
Cerebral cortex	tissue	8.1	low
Septum	tissue	8.1
Retrosplenial cortex	tissue	8.1
Insular cortex	tissue	8.1
Putamen	tissue	8.0
Midbrain	tissue	7.9
Medulla oblongata	tissue	7.9
Superior colliculi	tissue	7.9
Entorhinal cortex	tissue	7.9
Pons	tissue	7.8
Occipital cortex	tissue	7.8
Retina	tissue	7.7
Somatosensory cortex	tissue	7.7
Prefrontal cortex	tissue	7.6
Retrosplenial and cingulate cortex	tissue	7.6
Motor cortex	tissue	7.5
Temporal cortex	tissue	7.5
Fallopian tube	tissue	7.4	medium
Frontal cortex	tissue	7.3
Spinal cord	tissue	7.3
Thymus	tissue	7.3
Thyroid gland	tissue	6.3	high
Skin 1	tissue	6.2	medium
Parathyroid gland	tissue	5.9	high
Spleen	tissue	5.8	medium
Placenta	tissue	5.7	high
Liver	tissue	5.3	medium
Tonsil	tissue	5.0	high
Lymph node	tissue	4.9	medium
Kidney	tissue	4.9	high
Rectum	tissue	4.8	high
Appendix	tissue	4.8	high
Endometrium 1	tissue	4.7	high
Adrenal gland	tissue	4.5	medium
Lung	tissue	4.3	high
Ovary	tissue	4.2	not detected
Salivary gland	tissue	4.2	high
Epididymis	tissue	4.2	medium
Cervix	tissue	4.1	medium
Stomach 1	tissue	4.1	high
Small intestine	tissue	4.1	high

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Flocculonodular lobe (65.8), Vermis (63.7), Temporal white matter (60.9), Parieto-temporal junction (white matter) (59.8), Hippocampus, CA3 (59.3).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting C2CD3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

15 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 1.88e-14, LOEUF 0.637, missense Z 2.62 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000334126 — one region, missense o/e 0.92.

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

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2142166) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 30 distinct phenotype terms.

Mouse phenotype (MP)	Records
exencephaly	2
pericardial edema	2
abnormal cranial flexure morphology	2
embryonic lethality during organogenesis, complete penetrance	2
delayed bone ossification	1
cleft palate	1
increased neutrophil cell number	1
abnormal heart looping	1
polydactyly	1
abnormal tongue morphology	1
abnormal floor plate morphology	1
abnormal uterus morphology	1
hyperactivity	1
abnormal embryo size	1
abnormal dorsal-ventral axis patterning	1
abnormal left-right axis patterning	1
abnormal skin morphology	1
abnormal developmental patterning	1
abnormal facial morphology	1
abnormal rostral-caudal body axis extension	1
embryonic growth retardation	1
absent embryonic cilia	1
abnormal direction of heart looping	1
decreased lymphocyte cell number	1
tongue hypoplasia	1

+5 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Xenopus tropicalis	A0JM13	45.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
UCP2	protein-coding	7351
UCP3	protein-coding	7352
P4HA3	protein-coding	283208
PPME1	protein-coding	51400
P4HA3-AS1	ncRNA	101928580
PGM2L1	protein-coding	283209

Protein

Protein identifiers

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

All UniProt accessions (19): Q4AC94, A0A7P0T831, 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

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Predicted intracellular proteins, Disease related genes, Human disease related genes, Congenital malformations, Other congenital malformations

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): basal body; centrosome; nucleoplasm; acrosome; equatorial segment; principal piece

Antibody reliability (HPA): IH approved · IF supported

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)

Type	Positions
Phosphoserine	466, 728, 1891, 2114, 2132

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

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

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 (5): cilium assembly (GO:0060271), centriole elongation (GO:0061511), protein localization to centrosome (GO:0071539), non-motile cilium assembly (GO:1905515), cell projection organization (GO:0030030)

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

GO Cellular Component (6): centrosome (GO:0005813), centriole (GO:0005814), microtubule organizing center (GO:0005815), cytosol (GO:0005829), centriolar satellite (GO:0034451), ciliary basal body (GO:0036064)

Reactome top-level categories

2 top-level categories:

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

GO top-level categories

22 GO namespaces:

Category	Terms
microtubule organizing center	3
cellular anatomical structure	3
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
cellular component organization	1
binding	1
centriole	1
intracellular membraneless organelle	1
microtubule cytoskeleton	1
cytoplasm	1
centrosome	1
cilium	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 12 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
centriole elongation	BP	direct assay
non-motile cilium assembly	BP	mutant phenotype
protein localization to centrosome	BP	direct assay
centriolar satellite	CC	direct assay
centriole	CC	direct assay
centrosome	CC	direct assay
ciliary basal body	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 862 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C2CD3	SCLT1	Q96NL6	725
C2CD3	CEP83	Q9Y592	720
C2CD3	CEP89	Q96ST8	709
C2CD3	CEP164	Q9UPV0	678
C2CD3	OFD1	O75665	677
C2CD3	FBF1	Q8TES7	624
C2CD3	KIAA0586	Q9BVV6	606
C2CD3	CEP120	Q8N960	595
C2CD3	CCP110	O43303	572
C2CD3	TCTN3	Q6NUS6	570
C2CD3	CPLANE1	Q9H799	568
C2CD3	ARL13B	Q3SXY8	556
C2CD3	IFT88	Q13099	528
C2CD3	NPHP4	O75161	528
C2CD3	RPGRIP1L	Q68CZ1	517

IntAct

Human interaction partners of C2CD3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

11 partners by confidence:

Partner	Interaction type	MIscore	Records
OFD1	physical association	0.640	2
BBS1	physical association	0.400	1
BBS2	physical association	0.400	1
BBS4	physical association	0.400	1
BBS5	physical association	0.400	1
BBS7	physical association	0.400	1
BBS9	physical association	0.400	1
H2AC12	physical association	0.400	1
H2BC21	physical association	0.400	1
PLEC	physical association	0.400	1
TTC8	physical association	0.400	1

BioGRID (57 interactions; top human partners by supporting records): AMBRA1 (Affinity Capture-MS; 2 records), CEP135 (Proximity Label-MS; 2 records), PCM1 (Proximity Label-MS; 2 records), AGBL4 (Proximity Label-MS), BICD1 (Proximity Label-MS), BICD2 (Proximity Label-MS), CDC14A (Proximity Label-MS), CENPJ (Proximity Label-MS), CEP128 (Proximity Label-MS), CEP162 (Affinity Capture-MS), CEP63 (Proximity Label-MS), CEP89 (Proximity Label-MS), CNTRL (Proximity Label-MS), CRBN (Proximity Label-MS), DCAF11 (Proximity Label-MS)

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
Distal appendage	12	SCLT1, C2CD3, CBY1, CEP164, CEP290, CEP83, CEP97, CCP110, CEP162, CEP89, FBF1, ODF2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 11 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	316.0×	1e-15
Cargo trafficking to the periciliary membrane	5	112.8×	1e-08
Cilium Assembly	5	49.4×	7e-07
Organelle biogenesis and maintenance	5	30.0×	6e-06

GO biological processes:

GO term	Partners	Fold	FDR
non-motile cilium assembly	5	132.1×	8e-09
fat cell differentiation	6	98.8×	7e-10
cilium assembly	8	53.5×	2e-11
visual perception	6	43.4×	4e-08
protein transport	5	19.9×	2e-05

Disease & clinical

Genetic variants

Variant evidence for C2CD3: 1,251 ClinVar records (82 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

1,251 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	56
Likely pathogenic	26
Uncertain significance	524
Likely benign	389
Benign	126

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 82 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3014634	NM_001286577.2(C2CD3):c.1996C>T (p.Arg666Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
418736	NM_001286577.2(C2CD3):c.708-2_708-1del	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
144038	NM_001286577.2(C2CD3):c.184C>T (p.Arg62Ter)	Pathogenic	criteria provided, single submitter	2
217559	NM_001286577.2(C2CD3):c.4951+1G>T	Pathogenic	criteria provided, single submitter	1
419541	NM_001286577.2(C2CD3):c.3910+1G>A	Pathogenic	criteria provided, single submitter	1
1070295	NM_001286577.2(C2CD3):c.5405del (p.Tyr1802fs)	Pathogenic	criteria provided, single submitter	1
1424462	NM_001286577.2(C2CD3):c.52dup (p.Arg18fs)	Pathogenic	criteria provided, single submitter	1
1451467	NM_001286577.2(C2CD3):c.1957A>T (p.Lys653Ter)	Pathogenic	criteria provided, single submitter	1
1454437	NM_001286577.2(C2CD3):c.2842C>T (p.Arg948Ter)	Pathogenic	criteria provided, single submitter	1
1456017	NM_001286577.2(C2CD3):c.2070dup (p.Phe691fs)	Pathogenic	criteria provided, single submitter	1
1905561	NM_001286577.2(C2CD3):c.441dup (p.Thr148fs)	Pathogenic	criteria provided, single submitter	1
1910492	NM_001286577.2(C2CD3):c.5749dup (p.Thr1917fs)	Pathogenic	criteria provided, single submitter	1
1954802	NM_001286577.2(C2CD3):c.4684del (p.Ser1562fs)	Pathogenic	criteria provided, single submitter	1
1980454	NM_001286577.2(C2CD3):c.4808_4824del (p.His1603fs)	Pathogenic	criteria provided, single submitter	1
1999885	NM_001286577.2(C2CD3):c.197G>A (p.Trp66Ter)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore C2CD3’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 38 predictions of 3,037):

Position(s)	Effect	Δscore	Sites
11:74037476–74037477	donor_loss	1.0000	4
11:74042219–74042220	acceptor_loss	1.0000	6
11:74042224	acceptor_gain	1.0000
11:74049335–74049336	donor_loss	1.0000	5
11:74084879–74084880	donor_loss	1.0000	6
11:74084971–74084972	acceptor_loss	1.0000	3
11:74084981	acceptor_gain	1.0000
11:74095226–74095227	donor_loss	1.0000	4
11:74095409–74095410	acceptor_loss	1.0000	6
11:74103626	acceptor_loss	1.0000	2

AlphaMissense

2,684 missense substitutions predicted likely pathogenic (of 15,374 scored), across 749 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M110	9	0.894	0.978
D1510	8	0.976	0.992
F1369	8	0.963	0.992
D109	8	0.957	0.987
F1712	8	0.933	0.997
D1028	8	0.932	0.977
F1261	8	0.925	0.993
F910	8	0.920	0.986
F75	8	0.918	0.993
F1738	8	0.911	0.976
F1073	8	0.910	0.980
F1726	8	0.900	0.991
D930	8	0.898	0.967
F1540	8	0.897	0.981
F1110	8	0.893	0.988
F1035	8	0.885	0.974
F103	8	0.881	0.995
F451	8	0.880	0.967
F906	8	0.874	0.991
F2345	8	0.858	0.969

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Testicular Germ Cell Tumor)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	5.87e-06
Kidney Chromophobe (TCGA)	unfavorable	0.000375

Disease associations

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

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
orofaciodigital syndrome type 14	Definitive	Autosomal recessive	4

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
orofaciodigital syndrome type 14	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (14 panels, 14 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

14 panels:

Panel	Rating
Clefting	green
DDG2P	green
Fetal anomalies	green
Hereditary ataxia and cerebellar anomalies, childhood onset	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Neurological ciliopathies	green
Paediatric disorders	green
Rare multisystem ciliopathy Super panel	green
Rare multisystem ciliopathy disorders	green
Skeletal ciliopathies	green
Skeletal dysplasia	green
Thoracic dystrophies	green

Mondo (2): orofaciodigital syndrome type 14 (MONDO:0014413), Joubert syndrome (MONDO:0018772)

Orphanet (2): Orofaciodigital syndrome type 14 (Orphanet:434179), Isolated Joubert syndrome (Orphanet:475)

HPO phenotypes

showing 60 of 67 phenotypes (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
HP:0001321	Cerebellar hypoplasia
HP:0001338	Partial agenesis of the corpus callosum
HP:0001344	Absent speech
HP:0001360	Holoprosencephaly
HP:0001545	Anteriorly placed anus
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001643	Patent ductus arteriosus
HP:0001830	Postaxial foot polydactyly
HP:0001999	Abnormal facial shape
HP:0002079	Hypoplasia of the corpus callosum
HP:0002085	Occipital encephalocele
HP:0002126	Polymicrogyria
HP:0002198	Dilated fourth ventricle
HP:0002419	Molar tooth sign on MRI
HP:0003429	CNS hypomyelination
HP:0003577	Congenital onset
HP:0007082	Dilated third ventricle
HP:0007165	Periventricular heterotopia
HP:0008689	Bilateral cryptorchidism
HP:0008753	Aplasia of the epiglottis
HP:0009879	Simplified gyral pattern
HP:0010051	Deviation of the hallux
HP:0010055	Broad hallux
HP:0010066	Duplication of phalanx of hallux
HP:0010297	Bifid tongue
HP:0010535	Sleep apnea
HP:0010864	Severe intellectual disability
HP:0011069	Supernumerary tooth
HP:0011471	Gastrostomy tube feeding in infancy

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects expression, affects methylation	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)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	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	affects binding, increases reaction	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)

Via MONDO — disease-level, not drug-specific.

7 trials:

NCT	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