WWOX

Chr 16AR

WW domain containing oxidoreductase

Also known as: D16S432E, DEE28, EIEE28, FOR, FRA16D, HHCMA56, PRO0128, SCAR12

NCBI Gene: 51741 ENSG00000186153 UniProt: Q9NZC7 OMIM: 605131

The WWOX protein is an oxidoreductase that functions as a tumor suppressor by inducing apoptosis and inhibiting Wnt signaling. Biallelic mutations cause autosomal recessive developmental and epileptic encephalopathy 28 and spinocerebellar ataxia 12. The gene shows very low constraint against loss-of-function variants, consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) protein family. This gene spans the FRA16D common chromosomal fragile site and appears to function as a tumor suppressor gene. Expression of the encoded protein is able to induce apoptosis, while defects in this gene are associated with multiple types of cancer. Disruption of this gene is also associated with autosomal recessive spinocerebellar ataxia 12. Disruption of a similar gene in mouse results in impaired steroidogenesis, additionally suggesting a metabolic function for the protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.533 OMIM phenotypes

Clinical Summary— WWOX

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

137 unique Pathogenic / Likely Pathogenic· 458 VUS of 1169 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — WWOX

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.53LOEUF

pLI 0.000

Z-score -0.31

OE 1.07 (0.77–1.53)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-4.44Z-score

OE missense 1.81 (1.67–1.94)

435 obs / 241.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.07 (0.77–1.53)

0≤0.351.4

Missense OE?1.81 (1.67–1.94)

0≤0.61.4

Synonymous OE?1.82

0≤1.21.6

LoF obs/exp: 22 / 20.5Missense obs/exp: 435 / 241.0Syn Z: -6.24

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongWWOX-related epileptic encephalopathy, early infantileLOFAR

strongWWOX-related spinocerebellar ataxiaOTHERAR

Mechanism Note (expert annotation)

LOF

Biallelic LOF causes WOREE syndrome (DEE28) or SCAR12 (spinocerebellar ataxia). This is an autosomal recessive LOF gene; the GOF prediction does not apply.1

This gene — mechanism propensity

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

0.6647th %ile

GOF

0.6639th %ile

LOF

0.3260th %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.

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

References

1.PMID 25644381 ↗

ClinVar Variant Classifications

1169 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic84

Likely Pathogenic53

VUS458

Likely Benign438

Benign85

Conflicting40

Pathogenic

Likely Pathogenic

458

VUS

438

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	42	6	36	0	84
Likely Pathogenic	32	8	13	0	53
VUS	12	403	38	5	458
Likely Benign	1	9	205	223	438
Benign	0	10	72	3	85
Conflicting	—				40
Total	87	436	364	231	1,158

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

View in ClinVar →

63 pathogenic / likely-pathogenic (of 149) ClinVar copy-number / structural variants overlap WWOX — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →