WWOX

Chr 16AR

WW domain containing oxidoreductase

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

NCBI Gene: 51741ENSG00000186153UniProt: Q9NZC7

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]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 28MIM #616211
AR
Esophageal squamous cell carcinoma, somaticMIM #133239
Spinocerebellar ataxia, autosomal recessive 12MIM #614322
AR
UniProtEsophageal cancer
689
ClinVar variants
97
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— WWOX
🧬
Gene-Disease Validity (ClinGen)
developmental and epileptic encephalopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
97 Pathogenic / Likely Pathogenic· 279 VUS of 689 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
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?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.
-4.44Z-score
OE missense 1.81 (1.67–1.94)
435 obs / 241.0 exp
Tolerant

Tolerant to missense variation

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.1.07 (0.77–1.53)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.81 (1.67–1.94)
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.1.82
0≤1.21.6
LoF obs/exp: 22 / 20.5Missense obs/exp: 435 / 241.0Syn Z: -6.24

ClinVar Variant Classifications

689 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic72
Likely Pathogenic25
VUS279
Likely Benign253
Benign48
Conflicting12
72
Pathogenic
25
Likely Pathogenic
279
VUS
253
Likely Benign
48
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
19
3
50
0
72
Likely Pathogenic
10
4
11
0
25
VUS
4
217
54
4
279
Likely Benign
1
1
127
124
253
Benign
0
1
46
1
48
Conflicting
—12
Total34226288129689

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

View in ClinVar →

Protein Context — Lollipop Plot

WWOX · protein map & ClinVar variants

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

Gene2Phenotype Curations

WWOX-related epileptic encephalopathy, early infantile

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

WWOX-related spinocerebellar ataxia

strong
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 28

MIM #616211

Molecular basis of disorder known

Autosomal recessive

Esophageal squamous cell carcinoma, somatic

MIM #133239

Molecular basis of disorder known

Spinocerebellar ataxia, autosomal recessive 12

MIM #614322

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — WWOX
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer's disease.
Stevenson-Hoare J et al.·Brain
2023
The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.
Burgess R et al.·Ann Neurol
2019
Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer.
Lee NY et al.·Hum Genomics
2023Cohort
WWOX tuning of oleic acid signaling orchestrates immunosuppressive macrophage polarization and sensitizes hepatocellular carcinoma to immunotherapy.
Liu S et al.·J Immunother Cancer
2024
WWOX-Related Developmental and Epileptic Encephalopathy: Expanding the Clinical Spectrum and Deciphering the Genotype-Phenotype.
Gao K et al.·Neurology
2025
WWOX, the FRA16D gene: A target of and a contributor to genomic instability.
Hussain T et al.·Genes Chromosomes Cancer
2019Review
Shared genetic risk loci between Alzheimer's disease and related dementias, Parkinson's disease, and amyotrophic lateral sclerosis.
Wainberg M et al.·Alzheimers Res Ther
2023
WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk.
Oliver KL et al.·Epilepsia
2023
Expansion of the clinical and molecular spectrum of WWOX-related epileptic encephalopathy.
Chong SC et al.·Am J Med Genet A
2023
WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders.
Aldaz CM et al.·Int J Mol Sci
2020Review
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
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07
Helicobacter Pylori Infection

Tailored Vs. Empirical Helicobacter Pylori Infection Treatment

NOT YET RECRUITING
NCT06200779Phase PHASE4Manuel Coelho da RochaStarted 2025-09
Clarithromycin (mutations in the 23S rRNA gene, A2134G, A2142G and A2142C mutations) and levofloxacin resistance (mutations in the gyrA gene) PCR testEmpirically H. pylori eradication treatment with bismuth quadruple therapy (Pylera®)PPI, amoxicillin 1 g and clarithromycin 500 mg, twice daily, for 10 days

External Resources

Links to major genomics databases and tools