CCDC88C

Summary

CCDC88C (coiled-coil and HOOK domain protein 88C, HGNC:19967) is a protein-coding gene on chromosome 14q32.11-q32.12, encoding Protein Daple (Q9P219). Required for activation of guanine nucleotide-binding proteins (G-proteins) during non-canonical Wnt signaling.

This gene encodes a ubiquitously expressed coiled-coil domain-containing protein that interacts with the dishevelled protein and is a negative regulator of the Wnt signalling pathway. The protein encoded by this gene has a PDZ-domain binding motif in its C-terminus with which it interacts with the dishevelled protein. Dishevelled is a scaffold protein involved in the regulation of the Wnt signaling pathway. The Wnt signaling pathway plays an important role in embryonic development, tissue maintenance, and cancer progression. Mutations in this gene cause autosomal recessive, primary non-syndromic congenital hydrocephalus; a condition characterized by excessive accumulation of cerebrospinal fluid in the ventricles of the brain.

Source: NCBI Gene 440193 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hydrocephalus, nonsyndromic, autosomal recessive 1 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 12
• Clinical variants (ClinVar): 1,881 total — 64 pathogenic, 52 likely-pathogenic
• Phenotypes (HPO): 26
• MANE Select transcript: NM_001080414

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19967
Approved symbol	CCDC88C
Name	coiled-coil and HOOK domain protein 88C
Location	14q32.11-q32.12
Locus type	gene with protein product
Status	Approved
Aliases	DAPLE, HkRP2, SCA40
Ensembl gene	ENSG00000015133
Ensembl biotype	protein_coding
OMIM	611204
Entrez	440193

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 retained_intron, 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000334448, ENST00000389856, ENST00000389857, ENST00000553403, ENST00000553437, ENST00000554051, ENST00000554165, ENST00000554872, ENST00000555995, ENST00000556726, ENST00000556767, ENST00000557455, ENST00000557507

RefSeq mRNA: 1 — MANE Select: NM_001080414 NM_001080414

CCDS: CCDS45151

Canonical transcript exons

ENST00000389857 — 30 exons

Exon	Start	End
ENSE00001507103	91289105	91289343
ENSE00001507104	91290995	91291084
ENSE00001507105	91294173	91294318
ENSE00001507106	91297305	91297491
ENSE00001507107	91299927	91300070
ENSE00001507108	91303701	91303978
ENSE00001507109	91305765	91305926
ENSE00001507110	91307038	91307226
ENSE00001507112	91308351	91308492
ENSE00001507113	91309859	91309986
ENSE00001507114	91313080	91314150
ENSE00001507115	91315650	91315787
ENSE00001507116	91321120	91321304
ENSE00001507117	91324779	91324923
ENSE00001507118	91325910	91326056
ENSE00001507119	91338005	91338163
ENSE00001507120	91338489	91338570
ENSE00001507121	91339278	91339462
ENSE00002438905	91417631	91417820
ENSE00002510377	91271323	91273653
ENSE00003470172	91279238	91279306
ENSE00003491256	91342380	91342463
ENSE00003500558	91277922	91278211
ENSE00003544223	91343599	91343657
ENSE00003547578	91281457	91281525
ENSE00003585693	91408659	91408767
ENSE00003654415	91339884	91340024
ENSE00003659335	91416738	91416838
ENSE00003677529	91283329	91283517
ENSE00003685147	91359642	91359711

Expression profiles

Bgee: expression breadth ubiquitous, 220 present calls, max score 96.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.1438 / max 342.1206, expressed in 1222 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144514	9.1246	1177
144513	0.9118	367
144510	0.4912	207
144512	0.2927	128
144509	0.2014	90
144511	0.0919	40
144504	0.0205	3
144505	0.0097	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	96.93	gold quality
granulocyte	CL:0000094	96.50	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.74	gold quality
leukocyte	CL:0000738	92.31	gold quality
bronchial epithelial cell	CL:0002328	92.15	gold quality
monocyte	CL:0000576	92.12	gold quality
mononuclear cell	CL:0000842	92.04	gold quality
lymph node	UBERON:0000029	91.59	gold quality
blood	UBERON:0000178	91.20	gold quality
spleen	UBERON:0002106	90.84	gold quality
ganglionic eminence	UBERON:0004023	90.56	gold quality
bone marrow cell	CL:0002092	89.58	gold quality
caudate nucleus	UBERON:0001873	89.17	gold quality
nucleus accumbens	UBERON:0001882	88.66	gold quality
tonsil	UBERON:0002372	88.60	gold quality
mucosa of transverse colon	UBERON:0004991	88.44	gold quality
colonic epithelium	UBERON:0000397	87.92	gold quality
bone marrow	UBERON:0002371	87.91	gold quality
putamen	UBERON:0001874	87.76	gold quality
buccal mucosa cell	CL:0002336	87.33	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.90	gold quality
ventricular zone	UBERON:0003053	86.50	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.53	gold quality
vermiform appendix	UBERON:0001154	85.44	gold quality
esophagus mucosa	UBERON:0002469	85.20	gold quality
epithelium of bronchus	UBERON:0002031	84.97	gold quality
bronchus	UBERON:0002185	84.91	gold quality
upper lobe of left lung	UBERON:0008952	84.81	gold quality
lower esophagus mucosa	UBERON:0035834	84.81	gold quality
upper lobe of lung	UBERON:0008948	84.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.45
E-MTAB-6058	no	167.75

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

68 targeting CCDC88C, 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-574-5P	100.00	66.01	989
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909

Literature-anchored findings (GeneRIF, showing 20)

• Our data validate CCDC88C as causing autosomal recessive, primary non-syndromic congenital hydrocephalus, suggesting this gene may be an important cause of congenital hydrocephalus. (PMID:23042809)
• LDI-PCR revealed a fusion between CCDC88C exon 25 and PDGFRB exon 11. (PMID:24772479)
• A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia. (PMID:25062847)
• Spinocerebellar ataxia 40 (SCA40) displays typical cerebellar ataxia signs and pontocerebellar atrophy. Whole-exome sequencing led to the identification of a novel missense mutation in the gene CCDC88C in all SCA40-affected individuals. Cell-based assays showed that the SCA40 mutation causes an up-regulation of the JNK stress kinase signaling cascade that subsequently triggers programmed cell death. (PMID:25062847)
• Thus, Daple activates Galphai proteins and enhances non-canonical Wnt signaling by Frizzled receptors, and its dysregulation can impact both tumor initiation and progression to metastasis. (PMID:26126266)
• we demonstrated the relevance of Daple expression to gastric cancer progression. (PMID:26577606)
• This work not only identifies Daple as a platform for cross-talk between Akt and the noncanonical Wnt pathway but also reveals the impact of such cross-talk on tumor cell phenotypes that are critical for cancer initiation and progression. (PMID:29021338)
• Our report further establishes CCDC88C as one of the few known recessive causes of severe prenatal-onset hydrocephalus. Recognition of this syndrome has important diagnostic and genetic implications for families identified in the future. (PMID:29341397)
• Whole-exome sequencing (WES) of the proband revealed a heterozygous substitution, c.127G>A, in the CCDC88C gene (NM_001080414) that resulted in a missense mutation, p.(Asp43Asn) (PMID:30398676)
• Detection of Daple transcripts in the peripheral blood (i.e., liquid biopsies) of patients with melanoma may serve as a prognostic marker and an effective strategy for non-invasive long-term follow-up of patients with melanoma. (PMID:30575751)
• DAPLE and MPDZ function as cooperative partners at apical junctions. (PMID:31268831)
• Two Isoforms of the Guanine Nucleotide Exchange Factor, Daple/CCDC88C Cooperate as Tumor Suppressors. (PMID:31431650)
• Fusion driven JMML: a novel CCDC88C-FLT3 fusion responsive to sorafenib identified by RNA sequencing. (PMID:31511612)
• DAPLE protein inhibits nucleotide exchange on Galphas and Galphaq via the same motif that activates Galphai. (PMID:31949046)
• The Daple-CK1epsilon complex regulates Dvl2 phosphorylation and canonical Wnt signaling. (PMID:32888647)
• Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variants. (PMID:34092257)
• Spinocerebellar Ataxia in a Hungarian Female Patient with a Novel Variant of Unknown Significance in the CCDC88C Gene. (PMID:36768938)
• Confirmation of the Pathogenetic Role of the CCDC88C Gene in Early-Onset Pure Spastic Paraplegia. (PMID:37317935)
• A Novel c.3636-4 A>G Mutation in the CCDC88C Plays a Causative Role in Familial Spinocerebellar Ataxia. (PMID:37899026)
• CCDC88C variants are associated with focal epilepsy and genotype-phenotype correlation. (PMID:38173219)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ccdc88c	ENSDARG00000053713
mus_musculus	Ccdc88c	ENSMUSG00000021182
rattus_norvegicus	Ccdc88c	ENSRNOG00000004482
drosophila_melanogaster	Girdin	FBGN0283724
caenorhabditis_elegans		WBGENE00013082

Paralogs (5): HOOK2 (ENSG00000095066), CCDC88A (ENSG00000115355), HOOK1 (ENSG00000134709), CCDC88B (ENSG00000168071), HOOK3 (ENSG00000168172)

Protein

Protein identifiers

Protein Daple — Q9P219 (reviewed: Q9P219)

Alternative names: Coiled-coil domain-containing protein 88C, Dvl-associating protein with a high frequency of leucine residues, Hook-related protein 2

All UniProt accessions (4): Q9P219, G3V3S0, H0YJX5, Q0P665

UniProt curated annotations — full annotation on UniProt →

Function. Required for activation of guanine nucleotide-binding proteins (G-proteins) during non-canonical Wnt signaling. Binds to ligand-activated Wnt receptor FZD7, displacing DVL1 from the FZD7 receptor and leading to inhibition of canonical Wnt signaling. Acts as a non-receptor guanine nucleotide exchange factor by also binding to guanine nucleotide-binding protein G(i) alpha (Gi-alpha) subunits, leading to their activation. Binding to Gi-alpha subunits displaces the beta and gamma subunits from the heterotrimeric G-protein complex, triggering non-canonical Wnt responses such as activation of RAC1 and PI3K-AKT signaling. Promotes apical constriction of cells via ARHGEF18.

Subunit / interactions. Homooligomer. Interacts with DVL1 (via PDZ domain); dissociates following initiation of non-canonical Wnt signaling. Interacts (via C-terminus) with ligand-activated Wnt receptor FZD7; competes with DVL1 for binding to FZD7 and displaces DVL1 from ligand-activated FZD7. Interacts (via GBA motif) with guanine nucleotide-binding protein G(i) alpha subunits GNAI1, GNAI2 and GNAI3 (inactive GDP-bound form); interacts with higher affinity with GNAI1 and GNAI3 than with GNAI2 and interaction leads to G(i) alpha subunit activation. Does not interact with GNAO1.

Subcellular location. Cytoplasm. Cell junction.

Disease relevance. Hydrocephalus, congenital, 1 (HYC1) [MIM:236600] A form of congenital hydrocephalus, a disease characterized by onset in utero of enlarged ventricles due to accumulation of ventricular cerebrospinal fluid. Affected individuals may have neurologic impairment. HYC1 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Spinocerebellar ataxia 40 (SCA40) [MIM:616053] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA40 is an autosomal dominant, slowly progressive form. Brain MRI shows pontocerebellar atrophy along with a global reduction in brain volume. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The GBA (G-alpha binding and activating) motif mediates binding to the alpha subunits of guanine nucleotide-binding proteins (G proteins). The PDZ domain is required for localization to apical junctions.

Miscellaneous. Due to intron retention.

Similarity. Belongs to the CCDC88 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9P219-1	1	yes
Q9P219-2	2
Q9P219-3	3

RefSeq proteins (1): NP_001073883* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001715	CH_dom	Domain
IPR036872	CH_dom_sf	Homologous_superfamily
IPR043936	HOOK_N	Domain

Pfam: PF19047

UniProt features (46 total): compositionally biased region 12, modified residue 7, region of interest 6, sequence variant 5, coiled-coil region 4, splice variant 4, short sequence motif 2, mutagenesis site 2, sequence conflict 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P219-F1	65.69	0.14

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 (7): 227, 239, 486, 1444, 1601, 1806, 1954

Mutagenesis-validated functional residues (2):

Position	Phenotype
1675	abolishes interaction with and activation of gnai3 and abolishes release of the beta and gamma subunits from the heterot
2025–2028	failure to localize to apical cell junctions and to induce apical cell constriction.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5368598	Negative regulation of TCF-dependent signaling by DVL-interacting proteins

MSigDB gene sets: 314 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_RESPIRATORY_SYSTEM_PROCESS, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_PROTEIN_DESTABILIZATION, CADWELL_ATG16L1_TARGETS_DN, GOBP_MICROTUBULE_DEPOLYMERIZATION, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY

GO Biological Process (17): microtubule bundle formation (GO:0001578), apical constriction (GO:0003383), negative regulation of microtubule depolymerization (GO:0007026), small GTPase-mediated signal transduction (GO:0007264), cytoskeleton-dependent intracellular transport (GO:0030705), cytoplasmic microtubule organization (GO:0031122), protein destabilization (GO:0031648), non-canonical Wnt signaling pathway (GO:0035567), cilium organization (GO:0044782), positive regulation of JNK cascade (GO:0046330), Wnt signaling pathway, planar cell polarity pathway (GO:0060071), negative regulation of canonical Wnt signaling pathway (GO:0090090), mucociliary clearance (GO:0120197), respiratory basal cell differentiation (GO:1902691), cilium movement (GO:0003341), signal transduction (GO:0007165), Wnt signaling pathway (GO:0016055)

GO Molecular Function (9): G-protein alpha-subunit binding (GO:0001965), guanyl-nucleotide exchange factor activity (GO:0005085), frizzled binding (GO:0005109), microtubule binding (GO:0008017), PDZ domain binding (GO:0030165), identical protein binding (GO:0042802), protein dimerization activity (GO:0046983), dynein light intermediate chain binding (GO:0051959), protein binding (GO:0005515)

GO Cellular Component (6): extracellular region (GO:0005576), cytoplasm (GO:0005737), centrosome (GO:0005813), cell junction (GO:0030054), apical junction complex (GO:0043296), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	4
cellular anatomical structure	3
microtubule cytoskeleton organization	2
epithelial cell morphogenesis	1
actin-mediated cell contraction	1
microtubule depolymerization	1
negative regulation of microtubule polymerization or depolymerization	1
regulation of microtubule depolymerization	1
negative regulation of protein depolymerization	1
negative regulation of supramolecular fiber organization	1
intracellular signaling cassette	1
intracellular transport	1
supramolecular fiber organization	1
regulation of protein stability	1
Wnt signaling pathway	1
organelle organization	1
plasma membrane bounded cell projection organization	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
non-canonical Wnt signaling pathway	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
respiratory system process	1
epithelial cilium movement involved in extracellular fluid movement	1
stem cell differentiation	1
microtubule-based movement	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
G protein-coupled receptor binding	1
tubulin binding	1
protein domain specific binding	1

Protein interactions and networks

STRING

776 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCDC88C	DVL1	O14640	983
CCDC88C	DVL2	O14641	633
CCDC88C	GNAI3	P08754	622
CCDC88C	MPDZ	O75970	552
CCDC88C	PARD3	Q8TEW0	531
CCDC88C	AP1S2	P56377	522
CCDC88C	WNT3A	P56704	510
CCDC88C	COPB1	P53618	509
CCDC88C	LNX1	Q8TBB1	506
CCDC88C	L1CAM	P32004	479
CCDC88C	MYH1	P12882	470
CCDC88C	ETV6	P41212	462
CCDC88C	FER	P16591	453
CCDC88C	WNK1	P54963	436
CCDC88C	NUCB1	Q02818	415

IntAct

41 interactions, top by confidence:

A	B	Type	Score
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
MCM7	CEP290	psi-mi:“MI:0914”(association)	0.530
MCM7	VPS26A	psi-mi:“MI:0914”(association)	0.530
CCDC88C	PKM	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
CCDC88C		psi-mi:“MI:0915”(physical association)	0.370
MAPK8	CCDC88C	psi-mi:“MI:0915”(physical association)	0.370
	CCDC88C	psi-mi:“MI:0915”(physical association)	0.370
KATNA1	KATNBL1	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
APBB1	SSPOP	psi-mi:“MI:0914”(association)	0.350
RAB5A	PSMD14	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
ERBB2	TPR	psi-mi:“MI:0914”(association)	0.350
FGFR3	TPR	psi-mi:“MI:0914”(association)	0.350
FGFR3	U2SURP	psi-mi:“MI:0914”(association)	0.350
SCRIB	CHD2	psi-mi:“MI:0914”(association)	0.350
	GTPBP10	psi-mi:“MI:0914”(association)	0.350
SYCE1	RABGAP1L	psi-mi:“MI:0914”(association)	0.350
	POLRMT	psi-mi:“MI:0914”(association)	0.350
CCDC88C	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
SIKE1	ALDH7A1	psi-mi:“MI:0914”(association)	0.350
KRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
HOOK2	SEC16A	psi-mi:“MI:2364”(proximity)	0.270
SFN	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
YWHAB	E2F8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (89): CCDC88C (Two-hybrid), CCDC88C (Affinity Capture-MS), CCDC88C (Affinity Capture-MS), CCDC88C (Affinity Capture-MS), CCDC88C (Affinity Capture-MS), WDFY1 (Affinity Capture-MS), RNASE7 (Affinity Capture-MS), ALDH1L1 (Affinity Capture-MS), CCDC88C (Biochemical Activity), CCDC88C (Affinity Capture-RNA), DYNC1H1 (Affinity Capture-Western), DCTN1 (Affinity Capture-Western), CCDC88C (Proximity Label-MS), CCDC88C (Proximity Label-MS), CCDC88C (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8QCI3, A0JMK8, A3KGV1, A7YH32, A9X1A5, B0KWC9, B6MFW3, B8JK76, G5E861, G9G127, O35550, O35551, P59242, P85120, Q15276, Q3V6T2, Q502I3, Q5BJF6, Q5RG45, Q5SNZ0, Q5TZ80, Q5ZJ27, Q5ZKK5, Q66GS9, Q66KE8, Q6AYX5, Q6DIX6, Q6NRB0, Q6P402, Q6P5D4, Q6PGZ0, Q6VGS5, Q6ZU80, Q7TMK6, Q80UF4, Q80YF0, Q80YT7, Q86SQ7, Q8BIL5, Q8CJ99

Diamond homologs: A0A2R8QCI3, A6NC98, B4KE73, F3Y5P4, O61493, P85120, Q3V6T2, Q4QRL3, Q5SNZ0, Q6VGS5, Q7PWT9, Q86VS8, Q8BUK6, Q9P219, B0WPU9, B3MNR6, B3NL60, B4G831, B4I5P7, B4JAL5, B4N1C2, B4PAF2, B4Q9E6, Q17AF4, Q24185, Q29N92, Q5TZ80, Q5ZJ27, Q6GQ73, Q6NRB0, Q7TMK6, B6MFW3, Q8BIL5, Q9UJC3, Q96ED9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
DVL1P1	up-regulates	CCDC88C	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 42 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
Activation of BAD and translocation to mitochondria	7	177.6×	4e-13
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	156.8×	6e-13
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	156.8×	6e-13
Activation of BH3-only proteins	8	132.4×	1e-13
Intrinsic Pathway for Apoptosis	8	78.1×	3e-12
RHO GTPases activate PKNs	7	74.0×	2e-10
FOXO-mediated transcription	5	56.0×	5e-07
SARS-CoV-1-host interactions	8	46.9×	2e-10

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	50.9×	8e-06
regulation of protein localization	5	28.5×	1e-04
intracellular protein localization	7	20.4×	8e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

1881 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	64
Likely pathogenic	52
Uncertain significance	508
Likely benign	1037
Benign	104

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2053024	NM_001080414.4(CCDC88C):c.4132C>T (p.Arg1378Ter)	Pathogenic
2080624	NM_001080414.4(CCDC88C):c.3700C>T (p.Arg1234Ter)	Pathogenic
2115441	NM_001080414.4(CCDC88C):c.720del (p.Thr241fs)	Pathogenic
2697351	NM_001080414.4(CCDC88C):c.3050_3054dup (p.His1019fs)	Pathogenic
2698849	NM_001080414.4(CCDC88C):c.5613T>A (p.Cys1871Ter)	Pathogenic
2702446	NM_001080414.4(CCDC88C):c.5385del (p.Ser1796fs)	Pathogenic
2702855	NM_001080414.4(CCDC88C):c.6_12del (p.Asp2fs)	Pathogenic
2703417	NM_001080414.4(CCDC88C):c.2871C>A (p.Tyr957Ter)	Pathogenic
2704867	NM_001080414.4(CCDC88C):c.302T>A (p.Leu101Ter)	Pathogenic
2706303	NM_001080414.4(CCDC88C):c.5575G>T (p.Glu1859Ter)	Pathogenic
2709936	NM_001080414.4(CCDC88C):c.5295_5325del (p.Ser1765fs)	Pathogenic
2710115	NM_001080414.4(CCDC88C):c.5120dup (p.Ala1708fs)	Pathogenic
2731033	NM_001080414.4(CCDC88C):c.3043G>T (p.Gly1015Ter)	Pathogenic
2735465	NM_001080414.4(CCDC88C):c.3842dup (p.Leu1282fs)	Pathogenic
2736898	NM_001080414.4(CCDC88C):c.3555dup (p.Glu1186fs)	Pathogenic
2746211	NM_001080414.4(CCDC88C):c.5834del (p.Pro1945fs)	Pathogenic
2748573	NM_001080414.4(CCDC88C):c.1768A>T (p.Lys590Ter)	Pathogenic
2756944	NM_001080414.4(CCDC88C):c.5134C>T (p.Gln1712Ter)	Pathogenic
2762323	NM_001080414.4(CCDC88C):c.3247_3248del (p.Leu1083fs)	Pathogenic
2766575	NM_001080414.4(CCDC88C):c.5234_5235dup (p.Lys1746Ter)	Pathogenic
2768340	NM_001080414.4(CCDC88C):c.1535del (p.Lys512fs)	Pathogenic
2770263	NM_001080414.4(CCDC88C):c.3187G>T (p.Glu1063Ter)	Pathogenic
2790748	NM_001080414.4(CCDC88C):c.5562_5563del (p.His1854fs)	Pathogenic
2799834	NM_001080414.4(CCDC88C):c.1606A>T (p.Arg536Ter)	Pathogenic
2800823	NM_001080414.4(CCDC88C):c.5518_5521del (p.Thr1840fs)	Pathogenic
2805843	NM_001080414.4(CCDC88C):c.3555C>G (p.Tyr1185Ter)	Pathogenic
2818253	NM_001080414.4(CCDC88C):c.3492C>G (p.Tyr1164Ter)	Pathogenic
2821870	NM_001080414.4(CCDC88C):c.1624C>T (p.Gln542Ter)	Pathogenic
2821936	NM_001080414.4(CCDC88C):c.3380_3384del (p.Ser1126_Ser1127insTer)	Pathogenic
2829133	NM_001080414.4(CCDC88C):c.5308C>T (p.Gln1770Ter)	Pathogenic

SpliceAI

5298 predictions. Top by Δscore:

Variant	Effect	Δscore
14:91273649:GTGTC:G	acceptor_gain	1.0000
14:91273650:TGTC:T	acceptor_gain	1.0000
14:91273652:TC:T	acceptor_gain	1.0000
14:91273653:CC:C	acceptor_gain	1.0000
14:91277920:A:AC	donor_gain	1.0000
14:91277921:C:CC	donor_gain	1.0000
14:91278216:G:GC	acceptor_gain	1.0000
14:91279305:CA:C	acceptor_gain	1.0000
14:91279307:C:CC	acceptor_gain	1.0000
14:91281522:TAGC:T	acceptor_gain	1.0000
14:91281524:GCC:G	acceptor_loss	1.0000
14:91281525:CCTA:C	acceptor_loss	1.0000
14:91281526:C:CA	acceptor_loss	1.0000
14:91281526:C:CC	acceptor_gain	1.0000
14:91281527:T:G	acceptor_loss	1.0000
14:91290993:A:AC	donor_gain	1.0000
14:91290994:C:CT	donor_gain	1.0000
14:91290994:CTT:C	donor_gain	1.0000
14:91290996:T:TA	donor_gain	1.0000
14:91291080:TGTCT:T	acceptor_gain	1.0000
14:91291083:CT:C	acceptor_gain	1.0000
14:91291085:C:CC	acceptor_gain	1.0000
14:91294163:C:CA	donor_gain	1.0000
14:91294167:GCTTA:G	donor_loss	1.0000
14:91294168:CTTAC:C	donor_loss	1.0000
14:91294171:A:AC	donor_gain	1.0000
14:91294171:ACAT:A	donor_loss	1.0000
14:91294172:C:CA	donor_gain	1.0000
14:91294172:CA:C	donor_gain	1.0000
14:91294172:CATGT:C	donor_gain	1.0000

AlphaMissense

13289 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:91324889:A:G	L411P	1.000
14:91291034:A:G	I1388T	0.999
14:91291046:A:G	L1384P	0.999
14:91294272:A:G	L1338P	0.999
14:91321244:A:G	L468P	0.999
14:91321250:A:G	L466P	0.999
14:91324814:A:G	L436P	0.999
14:91324826:A:G	L432P	0.999
14:91324868:A:G	L418P	0.999
14:91324919:C:G	R401P	0.999
14:91325938:A:G	L390P	0.999
14:91325998:A:G	L370P	0.999
14:91326052:A:G	L352P	0.999
14:91342387:A:C	I159S	0.999
14:91342387:A:G	I159T	0.999
14:91342387:A:T	I159N	0.999
14:91343603:A:T	V132D	0.999
14:91291034:A:C	I1388S	0.998
14:91294305:A:G	L1327P	0.998
14:91321223:A:G	L475P	0.998
14:91321277:A:G	L457P	0.998
14:91324860:C:G	A421P	0.998
14:91325944:A:G	L388P	0.998
14:91326010:A:G	L366P	0.998
14:91338012:C:G	R348P	0.998
14:91342453:T:A	K137I	0.998
14:91343606:G:T	A131D	0.998
14:91343607:C:G	A131P	0.998
14:91343608:A:C	C130W	0.998
14:91343610:A:G	C130R	0.998

dbSNP variants (sampled 300 via entrez): RS1000021878 (14:91387579 G>A,T), RS1000025642 (14:91274178 G>A,C), RS1000027049 (14:91414085 T>C), RS1000054996 (14:91274383 C>T), RS1000056873 (14:91406525 A>C), RS1000058157 (14:91373366 C>CTGGGGCCAAGCAGAACT), RS1000072993 (14:91315999 C>T), RS1000079188 (14:91273925 G>A), RS1000085284 (14:91383405 G>A), RS1000107377 (14:91277115 A>C), RS1000135346 (14:91302102 G>A), RS1000160275 (14:91368233 T>C), RS1000162889 (14:91331517 T>A,C), RS1000238754 (14:91346195 C>A), RS1000243195 (14:91404577 G>C)

Disease associations

OMIM: gene MIM:611204 | disease phenotypes: MIM:108600, MIM:236600, MIM:616053

GenCC curated gene-disease

Disease	Classification	Inheritance
hydrocephalus, nonsyndromic, autosomal recessive 1	Strong	Autosomal recessive
spinocerebellar ataxia type 40	Moderate	Autosomal dominant

Mondo (7): spastic ataxia (MONDO:0017845), hydrocephalus, nonsyndromic, autosomal recessive 1 (MONDO:0009360), spinocerebellar ataxia type 40 (MONDO:0014475), intellectual disability (MONDO:0001071), epilepsy (MONDO:0005027), congenital hydrocephalus (MONDO:0016349), hydrocephalus (MONDO:0001150)

Orphanet (4): Spastic ataxia (Orphanet:316226), Congenital hydrocephalus (Orphanet:2185), Spinocerebellar ataxia type 40 (Orphanet:423275), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000238	Hydrocephalus
HP:0000511	Vertical supranuclear gaze palsy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001310	Dysmetria
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0002066	Gait ataxia
HP:0002075	Dysdiadochokinesis
HP:0002080	Intention tremor
HP:0002119	Ventriculomegaly
HP:0002136	Broad-based gait
HP:0002167	Abnormal speech pattern
HP:0002168	Scanning speech
HP:0002313	Spastic paraparesis
HP:0002317	Unsteady gait
HP:0003596	Middle age onset
HP:0003677	Slowly progressive
HP:0004302	Functional motor deficit
HP:0006879	Pontocerebellar atrophy
HP:0011448	Ankle clonus
HP:0034198	Second trimester onset

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001937_29	Breast cancer	4.000000e-10
GCST003518_92	Daytime sleep phenotypes	8.000000e-06
GCST004988_213	Breast cancer	8.000000e-13
GCST005956_47	Waist-to-hip ratio adjusted for BMI	7.000000e-07
GCST005962_28	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	7.000000e-07
GCST010703_103	Brain morphology (MOSTest)	8.000000e-21
GCST010797_16	Breast cancer, ovarian cancer or prostate cancer (pleiotropy)	9.000000e-12
GCST010916_24	Proportion of activated microglia (inferior temporal cortex)	3.000000e-06
GCST011946_39	White matter hyperintensity volume	7.000000e-10
GCST011947_7	White matter hyperintensity volume	1.000000e-10
GCST011949_9	White matter hyperintensity volume (adjusted for hypertension)	5.000000e-11
GCST011952_10	White matter hyperintensity volume x hypertension interaction (2df)	5.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004346	neuroimaging measurement
EFO:0005665	white matter hyperintensity measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D006849	Hydrocephalus	C10.228.140.602
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

52 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation, affects cotreatment, increases expression	7
sodium arsenite	affects methylation, decreases expression, increases abundance, increases expression	4
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
Tobacco Smoke Pollution	decreases expression, decreases methylation	3
Nickel	increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tretinoin	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
sodium arsenate	decreases expression, increases abundance	1
arsenite	decreases expression, increases abundance	1
afimoxifene	decreases reaction, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
monomethylarsonic acid	decreases expression	1
arsenic acid	increases abundance, decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
hydroquinone	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
dimethylmonothioarsinic acid	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

199 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
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
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)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04297891	Not specified	UNKNOWN	Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1