WWC3

Chr X

WWC family member 3

Also known as: BM042

NCBI Gene: 55841 ENSG00000047644 UniProt: Q9ULE0

The protein regulates the Hippo signaling pathway by enhancing phosphorylation of LATS1 and YAP1, thereby suppressing YAP1 transcriptional activity and negatively regulating cell proliferation and organ growth. Mutations cause autosomal dominant developmental delay with hypotonia and dysmorphic facies. This gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be pathogenic.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the WWC family of proteins, which also includes the WWC1 (KIBRA) gene product and the WWC2 gene product. The protein encoded by this gene includes a C2 domain, which is known to mediate homodimerization in the related WWC1 gene product. [provided by RefSeq, Sep 2011]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.18

Clinical Summary— WWC3

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

140 VUS of 331 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.18LOEUF

pLI 1.000

Z-score 5.58

OE 0.07 (0.03–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.51Z-score

OE missense 0.81 (0.75–0.88)

424 obs / 521.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.18)

0≤0.351.4

Missense OE?0.81 (0.75–0.88)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 3 / 42.0Missense obs/exp: 424 / 521.2Syn Z: -0.38

This gene — mechanism propensity

0.4388th %ile

GOF

0.4481th %ile

LOF

0.72top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.18

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

ClinVar Variant Classifications

331 submitted variants in ClinVar

ClinVar

Classification Summary

VUS140

Likely Benign22

Benign8

Conflicting1

140

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	139	1	0	140
Likely Benign	0	11	0	11	22
Benign	0	4	0	4	8
Conflicting	—				1
Total	0	154	1	15	171

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

View in ClinVar →

81 pathogenic / likely-pathogenic (of 91) ClinVar copy-number / structural variants overlap WWC3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →