Is WWOX p.Pro20= (c.60G>C) pathogenic?

WWOX p.Pro20= (c.60G>C) is classified Likely benign in WWOX (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Rare (popmax 0.145%, afr); Associated with autosomal recessive spinocerebellar ataxia 12.

What condition is associated with WWOX p.Pro20= (c.60G>C)?

WWOX p.Pro20= (c.60G>C) is associated with autosomal recessive spinocerebellar ataxia 12, developmental and epileptic encephalopathy, 1 (ClinVar).

How common is WWOX p.Pro20= (c.60G>C) in the general population?

WWOX p.Pro20= (c.60G>C) is rare (popmax 0.145%, afr) (gnomAD).

WWOX p.Pro20=

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.60G>C · rs376165565 · VCV696684

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.145%, afr)

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 0.56	GERP -4.2, phastCons 1
Overall
CADD	10.84	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.145% African / African-American · 107/74,046 alleles

Filtering AF 0.122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.114%

Overall 0.00739% 117/1,582,228 alleles · rare exomes 48/1,429,900 · genomes 69/152,328 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.145%	692
Remaining individualsnot grpmax-eligible	0.00653%	15,322
Admixed American	0.00361%	27,672
European (non-Finnish)	0.000343%	291,284

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.Pro20=
Coding: c.60G>C
MANE Select: NM_016373
dbSNP: rs376165565
Type: single nucleotide variant
Location: chr16:78099838 (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 20: the ww 1 domain; the 'disordered' 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.Pro20Leu Uncertain significance ★★ ⚠ same residue
WWOX p.Pro20Arg Uncertain significance ★ ⚠ same residue
WWOX p.Pro20Ser 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

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-pro20 (accessed [today's date]).

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