Is WEE2 p.Glu75fs (c.224_227del) pathogenic?

WEE2 p.Glu75fs (c.224227del) is classified Pathogenic/Likely pathogenic in WEE2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-04-01). Ultra-rare (popmax 0.0493%, mid); Associated with WEE2-related disorder.

What condition is associated with WEE2 p.Glu75fs (c.224_227del)?

WEE2 p.Glu75fs (c.224_227del) is associated with WEE2-related disorder, oocyte maturation defect 5 (ClinVar).

How common is WEE2 p.Glu75fs (c.224_227del) in the general population?

WEE2 p.Glu75fs (c.224_227del) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

WEE2 p.Glu75fs

c.224_227del · rs768323979 · VCV545471

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Conditions

WEE2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1	GERP -0.88
Overall
CADD	19.08	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00888%

Overall 0.00582% 94/1,614,010 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
South Asian	0.0176%	5,693
East Asian	0.0134%	7,480
Admixed American	0.0117%	8,573
African / African-American	0.00934%	10,701
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)	0.00441%	22,693

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: WEE2
Protein: p.Glu75fs
Coding: c.224_227del
MANE Select: NM_001105558
dbSNP: rs768323979
Type: Microsatellite
Location: chr7:141708978 (GRCh38)
Gene constraint: LOEUF 1.031 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.50 · 1 PDB
Residue 75: the 'disordered' region

Full WEE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

WEE2-related disorder

Also linked: oocyte maturation defect 5

Similar variants

WEE2 p.His337fs Pathogenic ★ same condition
WEE2 p.Tyr163His Uncertain significance ★ ⚠ same condition
WEE2 p.Arg200Ter Pathogenic same condition
WEE2 p.Arg410Trp Pathogenic ⚠ same condition
WEE2 p.Asp234His Pathogenic same condition
WEE2 p.Glu407= Pathogenic same condition
WEE2 p.Thr493fs Pathogenic same condition
WEE2 c.1536-9G>A Likely benign 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/wee2-p-glu75fs (accessed [today's date]).

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