CCDC88C

Chr 14ADAR

coiled-coil and HOOK domain protein 88C

Also known as: DAPLE, HKRP2, HYC1, KIAA1509, SCA40

NCBI Gene: 440193 ENSG00000015133 UniProt: Q9P219 OMIM: 611204

This gene encodes a coiled-coil domain-containing protein that acts as a non-receptor guanine nucleotide exchange factor and negative regulator of canonical Wnt signaling by binding to Wnt receptor FZD7 and displacing dishevelled protein. Mutations cause autosomal recessive congenital hydrocephalus and possibly autosomal dominant spinocerebellar ataxia 40, affecting the central nervous system. The gene is highly constrained against loss-of-function variants (LOEUF 0.454), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Jan 2013]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.452 OMIM phenotypes

Clinical Summary— CCDC88C

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

122 unique Pathogenic / Likely Pathogenic· 506 VUS of 1884 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.45LOEUF

pLI 0.000

Z-score 5.90

OE 0.34 (0.25–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.71Z-score

OE missense 0.94 (0.90–0.99)

1104 obs / 1172.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.25–0.45)

0≤0.351.4

Missense OE?0.94 (0.90–0.99)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 31 / 92.2Missense obs/exp: 1104 / 1172.2Syn Z: -0.72

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCCDC88C-related hydrocephalus, nonsyndromicLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7327th %ile

GOF

0.6442th %ile

LOF

0.3647th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

GOFThe mutation was found by a combination of linkage analysis and whole-exome sequencing. Functional studies showed that mutant CCDC88C activated JNK (601158) and triggered apoptosis, consistent with a gain of function.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 25062847 ↗

ClinVar Variant Classifications

1884 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic65

Likely Pathogenic57

VUS506

Likely Benign1063

Benign104

Conflicting54

Pathogenic

Likely Pathogenic

506

VUS

1063

Likely Benign

104

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	63	0	2	0	65
Likely Pathogenic	50	3	4	0	57
VUS	4	495	6	1	506
Likely Benign	0	47	359	657	1,063
Benign	0	16	59	29	104
Conflicting	—				54
Total	117	561	430	687	1,849

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

19 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap CCDC88C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →