CCDC166

Chr 8

coiled-coil domain containing 166

NCBI Gene: 100130274 ENSG00000255181 UniProt: P0CW27 OMIM: 621599

This gene encodes a coiled-coil domain containing protein of unknown function. Mutations cause autosomal recessive intellectual disability with microcephaly and growth retardation. The gene shows low constraint against loss-of-function variants (pLI 0.003), suggesting complete loss of function may be tolerated in heterozygous carriers.

OMIM Research

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.66

Clinical Summary— CCDC166

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

81 VUS of 85 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.66LOEUF

pLI 0.003

Z-score 0.47

OE 0.77 (0.38–1.66)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.03Z-score

OE missense 0.81 (0.72–0.92)

193 obs / 237.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.77 (0.38–1.66)

0≤0.351.4

Missense OE?0.81 (0.72–0.92)

0≤0.61.4

Synonymous OE?0.73

0≤1.21.6

LoF obs/exp: 4 / 5.2Missense obs/exp: 193 / 237.5Syn Z: 2.38

This gene — mechanism propensity

0.75top 25%

GOF

0.79top 10%

LOF

0.2581th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

85 submitted variants in ClinVar

ClinVar

Classification Summary

VUS81

Likely Benign4

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	81	81
Likely Benign	4	4
Benign	0	0
Total	85	85

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

View in ClinVar →

61 pathogenic / likely-pathogenic (of 68) ClinVar copy-number / structural variants overlap CCDC166 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →