CCDC88C

Chr 14ADAR

coiled-coil domain containing 88C

NCBI Gene: 440193ENSG00000015133UniProt: Q9P219

Required for activation of guanine nucleotide-binding proteins (G-proteins) during non-canonical Wnt signaling (PubMed:26126266). Binds to ligand-activated Wnt receptor FZD7, displacing DVL1 from the FZD7 receptor and leading to inhibition of canonical Wnt signaling (PubMed:26126266). 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 (PubMed:26126266). 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 (PubMed:26126266). Promotes apical constriction of cells via ARHGEF18 (PubMed:30948426)

Primary Disease Associations & Inheritance

?Spinocerebellar ataxia 40MIM #616053
AD
Hydrocephalus, congenital, 1MIM #236600
AR
1902
ClinVar variants
43
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— CCDC88C
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
43 Pathogenic / Likely Pathogenic· 223 VUS of 1902 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.71Z-score
OE missense 0.94 (0.90–0.99)
1104 obs / 1172.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.34 (0.25–0.45)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.90–0.99)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.04
0≤1.21.6
LoF obs/exp: 31 / 92.2Missense obs/exp: 1104 / 1172.2Syn Z: -0.72

ClinVar Variant Classifications

1902 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic32
VUS223
Likely Benign193
Benign1
Conflicting5
11
Pathogenic
32
Likely Pathogenic
223
VUS
193
Likely Benign
1
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
0
8
0
11
Likely Pathogenic
23
0
9
0
32
VUS
0
218
5
0
223
Likely Benign
0
15
64
114
193
Benign
0
0
1
0
1
Conflicting
—5
Total2623387114465

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

View in ClinVar →

Protein Context — Lollipop Plot

CCDC88C · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CCDC88C-related hydrocephalus, nonsyndromic

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Spinocerebellar ataxia 40

MIM #616053

Molecular basis of disorder known

Autosomal dominant

Hydrocephalus, congenital, 1

MIM #236600

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Congenital hydrocephalus: a review of recent advances in genetic etiology and molecular mechanisms.
Liu XY et al.·Mil Med Res
2024Review
CCDC88C variants are associated with focal epilepsy and genotype-phenotype correlation.
Chen YJ et al.·Clin Genet
2024
Blood transcriptome sequencing identifies biomarkers able to track disease stages in spinocerebellar ataxia type 3.
Raposo M et al.·Brain
2023
A Novel c.3636-4 A>G Mutation in the CCDC88C Plays a Causative Role in Familial Spinocerebellar Ataxia.
Chai S et al.·Hum Hered
2023
Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variants.
Marguet F et al.·Acta Neuropathol Commun
2021Case report
Spinocerebellar Ataxia in a Hungarian Female Patient with a Novel Variant of Unknown Significance in the CCDC88C Gene.
Boros FA et al.·Int J Mol Sci
2023
Prognostic Relevance of CCDC88C (Daple) Transcripts in the Peripheral Blood of Patients with Cutaneous Melanoma.
Dunkel Y et al.·Sci Rep
2018Cohort
A heterozygous mutation in the CCDC88C gene likely causes early-onset pure hereditary spastic paraplegia: a case report.
Yahia A et al.·BMC Neurol
2021Case report
A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia.
Tsoi H et al.·J Med Genet
2014Case report
Bi-allelic variations in CRB2, encoding the crumbs cell polarity complex component 2, lead to non-communicating hydrocephalus due to atresia of the aqueduct of sylvius and central canal of the medulla.
Tessier A et al.·Acta Neuropathol Commun
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools