Is CHEK2 p.Ser356Ter (c.1067C>A) pathogenic?

CHEK2 p.Ser356Ter (c.1067C>A) is classified Pathogenic in CHEK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-07-01). Very rare (popmax 0.00223%, eas); Associated with gastric cancer.

What condition is associated with CHEK2 p.Ser356Ter (c.1067C>A)?

CHEK2 p.Ser356Ter (c.1067C>A) is associated with gastric cancer (ClinVar).

How common is CHEK2 p.Ser356Ter (c.1067C>A) in the general population?

CHEK2 p.Ser356Ter (c.1067C>A) is very rare (popmax 0.00223%, eas) (gnomAD).

CHEK2 p.Ser356Ter

c.1067C>A · rs121908703 · VCV1801560

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

gastric cancer

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 10 of 15
REVEL	0.727	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.46	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Overall
CADD	40.0	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 0.00223% East Asian · 1/44,870 alleles

Overall 6.2e-05% 1/1,612,914 alleles · very rare exomes 1/1,460,648 · genomes 0/152,266 · 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.Ser356Ter
Coding: c.1067C>A
MANE Select: NM_007194
dbSNP: rs121908703
Type: single nucleotide variant
Location: chr22:28696929 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 356: a β-strand; the protein kinase domain

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

Disease context

gastric cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHEK2 p.Ser356Leu Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser356Pro Uncertain significance ★★ ⚠ same residue
CDS1 p.Ser356Gly Uncertain significance ★ ⚠ same residue
CHEK2 p.Ser356= Likely benign ★ same residue
CHEK2 c.1096-1G>T Likely pathogenic ★★ same condition
CHEK2 c.684-1G>A Likely pathogenic ★★ same condition
CHEK2 c.792+1G>A Likely pathogenic ★★ same condition
CHEK2 c.847-1G>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-ser356ter (accessed [today's date]).

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