Is WWOX p.Ser166= (c.498A>G) pathogenic?

WWOX p.Ser166= (c.498A>G) is classified Likely benign in WWOX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-27). Very rare (popmax 8.47e-05%, nfe); Associated with autosomal recessive spinocerebellar ataxia 12.

What condition is associated with WWOX p.Ser166= (c.498A>G)?

WWOX p.Ser166= (c.498A>G) is associated with autosomal recessive spinocerebellar ataxia 12, developmental and epileptic encephalopathy, 1 (ClinVar).

How common is WWOX p.Ser166= (c.498A>G) in the general population?

WWOX p.Ser166= (c.498A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

WWOX p.Ser166=

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.498A>G · rs2507402553 · VCV2922639

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

autosomal recessive spinocerebellar ataxia 12

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3.9
Overall
CADD	2.999	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,980 alleles

Overall 6.2e-05% 1/1,614,034 alleles · very rare exomes 1/1,461,762 · genomes 0/152,272 · joint denominator

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.Ser166=
Coding: c.498A>G
MANE Select: NM_016373
dbSNP: rs2507402553
Type: single nucleotide variant
Location: chr16:78164271 (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 166: 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

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 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
WWOX c.791+1G>T Likely 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-ser166 (accessed [today's date]).

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