Is WWOX p.Ser271Phe (c.812C>T) pathogenic?

WWOX p.Ser271Phe (c.812C>T) is classified Uncertain significance in WWOX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-26). AlphaMissense: likely benign (0.1647); Very rare (popmax 0.00267%, afr); Associated with autosomal recessive spinocerebellar ataxia 12.

What condition is associated with WWOX p.Ser271Phe (c.812C>T)?

WWOX p.Ser271Phe (c.812C>T) is associated with autosomal recessive spinocerebellar ataxia 12, developmental and epileptic encephalopathy, 1 (ClinVar).

How common is WWOX p.Ser271Phe (c.812C>T) in the general population?

WWOX p.Ser271Phe (c.812C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about WWOX p.Ser271Phe (c.812C>T)?

AlphaMissense predicts likely benign (score 0.1647) — an in-silico prediction, not a clinical call.

WWOX p.Ser271Phe

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.812C>T · rs758222414 · VCV944720

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive spinocerebellar ataxia 12

Computational evidence

Protein change
AlphaMissense	0.1647	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.45, phastCons 0.27
Regional constraint	o/e 1.69	unconstrained · MANE · 1,112 kb · p 9.9e-59 · regional, not allelic
Overall
CADD	19.62	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,910 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00173% 28/1,614,002 alleles · very rare exomes 25/1,461,880 · genomes 3/152,122 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-Americangrpmax	0.00267%	37,455
European (non-Finnish)	0.00203%	49,168

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser271Phe
Coding: c.812C>T
MANE Select: NM_016373
dbSNP: rs758222414
Type: single nucleotide variant
Location: chr16:78432508 (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 271: the 'interaction with mapt' region; the 'mediates targeting to the mitochondria' 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 p.Ser271= Likely benign ★ same residue
WWOX p.Ser271Ter Pathogenic ★ 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

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-ser271phe (accessed [today's date]).

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