Is WWOX p.Ser296= (c.888C>G) pathogenic?

WWOX p.Ser296= (c.888C>G) is classified Benign/Likely benign in WWOX (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-29). Low-frequency (popmax 1.47%, eas); Associated with autosomal recessive spinocerebellar ataxia 12.

What condition is associated with WWOX p.Ser296= (c.888C>G)?

WWOX p.Ser296= (c.888C>G) is associated with autosomal recessive spinocerebellar ataxia 12, developmental and epileptic encephalopathy, 1, developmental and epileptic encephalopathy, 28 (ClinVar).

How common is WWOX p.Ser296= (c.888C>G) in the general population?

WWOX p.Ser296= (c.888C>G) is low-frequency (popmax 1.47%, eas) (gnomAD).

WWOX p.Ser296=

Q: How is Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.888C>G · rs3764341 · VCV384940

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.47%, eas)

Conditions

autosomal recessive spinocerebellar ataxia 12

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.07	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.85	GERP 1.4, phastCons 1
Overall
CADD	7.13	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.47% East Asian · 660/44,880 alleles

Filtering AF 1.38% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.34%

Overall 0.0482% 778/1,614,200 alleles · low-frequency exomes 681/1,461,892 · genomes 97/152,308 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.47%	68
Remaining individualsnot grpmax-eligible	0.0832%	1,202
African / African-American	0.0413%	2,421
Middle Eastern	0.033%	3,031
South Asian	0.0329%	3,036
Admixed American	0.005%	20,007

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: WWOX
Protein: p.Ser296=
Coding: c.888C>G
MANE Select: NM_016373
dbSNP: rs3764341
Type: single nucleotide variant
Location: chr16:78432584 (GRCh38)
Gene constraint: LOEUF 1.82 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.43 · 1 PDB
Residue 296: the 'interaction with mapt' region

Full WWOX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive spinocerebellar ataxia 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 1 developmental and epileptic encephalopathy, 28

For Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

WWOX p.Ser296Cys Uncertain significance ★★ ⚠ same residue
WWOX c.107+1G>A Pathogenic/Likely pathogenic ★★ same condition
WWOX c.173-1G>C Pathogenic ★★ same condition
WWOX c.173-1G>T Pathogenic ★★ same condition
WWOX c.409+1G>C Pathogenic/Likely pathogenic ★★ same condition
WWOX c.410-1G>A Pathogenic/Likely pathogenic ★★ same condition
WWOX c.605+2T>C Pathogenic/Likely pathogenic ★★ same condition
WWOX c.606-1G>A Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/wwox-p-ser296 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown