Is CHEK2 p.Gln336= (c.1008G>A) pathogenic?

CHEK2 p.Gln336= (c.1008G>A) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.0333%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Gln336= (c.1008G>A)?

CHEK2 p.Gln336= (c.1008G>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Gln336= (c.1008G>A) in the general population?

CHEK2 p.Gln336= (c.1008G>A) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

CHEK2 p.Gln336=

c.1008G>A · rs201544715 · VCV279766

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.085	moderately benign-leaning
Splicing
SpliceAI	Δ0.37	donor loss · deltas
Pangolin	Δ0.72	loss · gain 0.07 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.7	GERP 0.59, phastCons 1
Overall
CADD	18.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% Admixed American · 20/60,002 alleles

Filtering AF 0.0221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.00124% 20/1,609,806 alleles · ultra-rare exomes 14/1,457,576 · genomes 6/152,230 · 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: CHEK2
Protein: p.Gln336=
Coding: c.1008G>A
MANE Select: NM_007194
dbSNP: rs201544715
Type: single nucleotide variant
Location: chr22:28699838 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 336: an α-helix; the protein kinase domain

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome hereditary breast carcinoma CHEK2-related cancer predisposition

Similar variants

CHEK2 p.Gln336Ter Pathogenic/Likely pathogenic ★★ same residue
CHEK2 p.Gln336Arg Uncertain significance ★★ ⚠ same residue
CHEK2 p.Gln336His Uncertain significance ★★ ⚠ same residue
CHEK2 p.Gln336Pro Uncertain significance ★★ ⚠ same residue
CHEK2 p.Gln336fs Likely pathogenic ★ same residue
CDS1 p.Pro336Ala Uncertain significance ★ ⚠ 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-gln336 (accessed [today's date]).

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