Is WWOX p.Pro20Ser (c.58C>T) pathogenic?

WWOX p.Pro20Ser (c.58C>T) is classified Uncertain significance in WWOX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-27). AlphaMissense: likely benign (0.169); Very rare (popmax 0.00135%, afr); Associated with Inborn genetic diseases.

What condition is associated with WWOX p.Pro20Ser (c.58C>T)?

WWOX p.Pro20Ser (c.58C>T) is associated with Inborn genetic diseases (ClinVar).

How common is WWOX p.Pro20Ser (c.58C>T) in the general population?

WWOX p.Pro20Ser (c.58C>T) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about WWOX p.Pro20Ser (c.58C>T)?

AlphaMissense predicts likely benign (score 0.169) — an in-silico prediction, not a clinical call.

WWOX p.Pro20Ser

c.58C>T · rs768240338 · VCV2313577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.169 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.169	likely benign
REVEL	0.551	indeterminate
SaProt	LLR -8.97	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.69	unconstrained · MANE · 1,112 kb · p 9.9e-59 · regional, not allelic
Overall
CADD	28.2	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 0.00135% African / African-American · 1/73,926 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000316% 5/1,581,998 alleles · very rare exomes 4/1,429,778 · genomes 1/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	73,926
South Asian	0.00116%	86,074
European (non-Finnish)	0.000257%	388,372

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.Pro20Ser
Coding: c.58C>T
MANE Select: NM_016373
dbSNP: rs768240338
Type: single nucleotide variant
Location: chr16:78099836 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

WWOX p.Pro20Leu Uncertain significance ★★ ⚠ same residue
WWOX p.Pro20= Likely benign ★★ same residue
WWOX p.Pro20Arg Uncertain significance ★ ⚠ same residue
WWOX p.Ala149Thr Uncertain significance ★★ ⚠ same condition
WWOX p.Ala7Thr Uncertain significance ★★ ⚠ same condition
WWOX p.Ala91Val Uncertain significance ★★ ⚠ same condition
WWOX p.Arg309Cys Uncertain significance ★★ ⚠ same condition
WWOX p.Arg333Cys Uncertain significance ★★ ⚠ 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-pro20ser (accessed [today's date]).

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