Is WEE1 p.Ser421Phe (c.1262C>T) pathogenic?

WEE1 p.Ser421Phe (c.1262C>T) is classified Uncertain significance in WEE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: ambiguous (0.4157); Very rare (popmax 0.00133%, afr).

How common is WEE1 p.Ser421Phe (c.1262C>T) in the general population?

WEE1 p.Ser421Phe (c.1262C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about WEE1 p.Ser421Phe (c.1262C>T)?

AlphaMissense predicts ambiguous (score 0.4157) — an in-silico prediction, not a clinical call.

WEE1 p.Ser421Phe

c.1262C>T · VCV4605031

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4157 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
AlphaMissense	0.4157	ambiguous
REVEL	0.336	indeterminate
SaProt	LLR -10.43	damaging
Splicing
SpliceAI	Δ0.22	donor loss · deltas
Constraint at this position
Conservation	phyloP 3.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 3,962 bp · p 0.0002 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,976 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00116% 17/1,460,616 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,444
African / African-Americangrpmax	0.00133%	74,976
European (non-Finnish)	0.00127%	78,648

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: WEE1
Protein: p.Ser421Phe
Coding: c.1262C>T
MANE Select: NM_003390
Type: single nucleotide variant
Location: chr11:9581652 (GRCh38)
Gene constraint: LOEUF 0.405 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.90 · 29 PDB
Residue 421: the protein kinase domain

Full WEE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

WEE1 p.Gly210Cys Benign ★★ same type
WEE1 p.Ala130Val Uncertain significance ★ ⚠ same type
WEE1 p.Ala156Thr Uncertain significance ★ ⚠ same type
WEE1 p.Ala15Ser Uncertain significance ★ ⚠ same type
WEE1 p.Ala387Ser Uncertain significance ★ ⚠ same type
WEE1 p.Ala510Thr Uncertain significance ★ ⚠ same type
WEE1 p.Arg13Cys Uncertain significance ★ ⚠ same type
WEE1 p.Arg223Gly Uncertain significance ★ ⚠ same type

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/wee1-p-ser421phe (accessed [today's date]).

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