Is WEE1 p.Pro517Ala (c.1549C>G) pathogenic?

WEE1 p.Pro517Ala (c.1549C>G) is classified Uncertain significance in WEE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-07). AlphaMissense: likely pathogenic (0.7706); Very rare (popmax 0.00333%, amr).

How common is WEE1 p.Pro517Ala (c.1549C>G) in the general population?

WEE1 p.Pro517Ala (c.1549C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about WEE1 p.Pro517Ala (c.1549C>G)?

AlphaMissense predicts likely pathogenic (score 0.7706) — an in-silico prediction, not a clinical call.

WEE1 p.Pro517Ala

c.1549C>G · rs1326890678 · VCV2323457

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7706 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7706	likely pathogenic
REVEL	0.413	indeterminate
SaProt	LLR -9.11	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 1,055 bp · p 8.5e-07 · regional, not allelic
Overall
CADD	26.9	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 0.00333% Admixed American · 2/59,988 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,613,952 alleles · very rare exomes 1/1,461,828 · genomes 1/152,124 · joint denominator

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.Pro517Ala
Coding: c.1549C>G
MANE Select: NM_003390
dbSNP: rs1326890678
Type: single nucleotide variant
Location: chr11:9586527 (GRCh38)
Gene constraint: LOEUF 0.405 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.90 · 29 PDB
Residue 517: the protein kinase domain; an α-helix

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-pro517ala (accessed [today's date]).

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