WWC3

Chr X

WWC family member 3

Also known as: BM042

NCBI Gene: 55841 ENSG00000047644 UniProt: Q9ULE0 OMIM: 301089

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.18

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

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

Background carrier burden — how many people carry a rare variant somewhere in WWC3?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 49

940 rare PASS variants

Rare truncating (LoF)

1 in 6,600

26 rare PASS variants

Rare synonymous (reference)

1 in 52

501 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for WWC3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 80	1 in 13,000
South Asian	~36k	1 in 40	1 in 1,500
Remaining (unassigned)	~31k	1 in 38	none seen
European (Finnish)	~27k	1 in 170	1 in 1,600
Admixed American	~23k	1 in 33	≈ 1 in 5,400
African / African American	~21k	1 in 36	≈ 1 in 4,600
East Asian	~20k	1 in 54	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 130	none seen
Middle Eastern	~2,758	1 in 59	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 21 of 24 coding exons well covered in gnomAD exomes; exons 1, 2 poorly covered; exon 3 marginal. Genomes: 23 of 24 (exon 1 below).? see exons ↓