Is CHEK2 p.Glu239Val (c.716A>T) pathogenic?

CHEK2 p.Glu239Val (c.716A>T) is classified Uncertain significance in CHEK2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-03-06). AlphaMissense: likely pathogenic (0.6891); Very rare (popmax 0.0022%, sas); Associated with CHEK2-related cancer predisposition.

What condition is associated with CHEK2 p.Glu239Val (c.716A>T)?

CHEK2 p.Glu239Val (c.716A>T) is associated with CHEK2-related cancer predisposition, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Glu239Val (c.716A>T) in the general population?

CHEK2 p.Glu239Val (c.716A>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CHEK2 p.Glu239Val (c.716A>T)?

AlphaMissense predicts likely pathogenic (score 0.6891) — an in-silico prediction, not a clinical call.

CHEK2 p.Glu239Val

c.716A>T · rs763892124 · VCV1332136

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CHEK2-related cancer predisposition

Computational evidence

Protein change
AlphaMissense	0.6891	likely pathogenic
REVEL	0.692	pathogenic-leaning
SaProt	LLR -9.71	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	28.2	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 0.0022% South Asian · 2/91,072 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000137% 2/1,461,714 alleles · very rare

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: CHEK2
Protein: p.Glu239Val
Coding: c.716A>T
MANE Select: NM_007194
dbSNP: rs763892124
Type: single nucleotide variant
Location: chr22:28711985 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 239: a β-strand; the protein kinase domain; a UniProt-annotated variant site (in prostate cancer; germline mutation)

Full CHEK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

CHEK2 p.Glu239Ter Pathogenic ★★ same residue
CHEK2 p.Glu239Asp Uncertain significance ★★ ⚠ same residue
CHEK2 p.Glu239Gln Uncertain significance ★★ ⚠ same residue
CHEK2 p.Glu239Gly Uncertain significance ★★ ⚠ same residue
CHEK2 p.Glu239= Benign/Likely benign ★★ same residue
CHEK2 p.Glu239Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same condition
CHEK2 c.1008+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/chek2-p-glu239val (accessed [today's date]).

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