Is CHEK2 p.His371= (c.1113C>T) pathogenic?

CHEK2 p.His371= (c.1113C>T) is classified Benign/Likely benign in CHEK2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-11). Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.His371= (c.1113C>T)?

CHEK2 p.His371= (c.1113C>T) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.His371= (c.1113C>T) in the general population?

CHEK2 p.His371= (c.1113C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

CHEK2 p.His371=

c.1113C>T · rs876659094 · VCV231327

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.014	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.86	GERP -0.11, phastCons 1
Overall
CADD	10.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,878 alleles

Overall 0.000342% 5/1,460,876 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,819
East Asiangrpmax	0.00223%	44,878
European (non-Finnish)	8.48e-05%	1,179,138

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: CHEK2
Protein: p.His371=
Coding: c.1113C>T
MANE Select: NM_007194
dbSNP: rs876659094
Type: single nucleotide variant
Location: chr22:28695856 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 371: an α-helix; the protein kinase domain; the 't-loop/activation segment' region; a UniProt-annotated variant site (confers a moderate risk of breast cancer; partially reduces kinase activity)

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 carcinoma

Similar variants

CHEK2 p.His371Arg Uncertain significance ★★ same residue
CHEK2 p.His371Pro Uncertain significance ★★ ⚠ same residue
CHEK2 p.His371Gln Uncertain significance ★ ⚠ same residue
CHEK2 p.His371Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.His371fs Pathogenic ★★ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same condition
CHEK2 c.1008+1G>T Likely pathogenic ★★ same condition
CHEK2 c.1008+2T>A 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-his371 (accessed [today's date]).

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