Is WWOX p.Phe74= (c.222T>C) pathogenic?

WWOX p.Phe74= (c.222T>C) is classified Likely benign in WWOX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-12). Ultra-rare (popmax 0.0329%, mid); Associated with developmental and epileptic encephalopathy, 1.

What condition is associated with WWOX p.Phe74= (c.222T>C)?

WWOX p.Phe74= (c.222T>C) is associated with developmental and epileptic encephalopathy, 1, autosomal recessive spinocerebellar ataxia 12 (ClinVar).

How common is WWOX p.Phe74= (c.222T>C) in the general population?

WWOX p.Phe74= (c.222T>C) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

How is Infantile epileptic spasms syndrome inherited?

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

WWOX p.Phe74=

c.222T>C · rs748079925 · VCV511916

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

developmental and epileptic encephalopathy, 1

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 1.9	GERP 0.93, phastCons 1
Overall
CADD	9.759	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00155% 25/1,614,072 alleles · ultra-rare exomes 23/1,461,894 · genomes 2/152,178 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00169%	59,003

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.Phe74=
Coding: c.222T>C
MANE Select: NM_016373
dbSNP: rs748079925
Type: single nucleotide variant
Location: chr16:78109827 (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 74: the ww 2 domain; a β-strand

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

Disease context

developmental and epileptic encephalopathy, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive spinocerebellar ataxia 12

For Infantile epileptic spasms syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked dominant

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-phe74 (accessed [today's date]).

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