Is CHEK2 p.Met1Val (c.1A>G) pathogenic?

CHEK2 p.Met1Val (c.1A>G) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-28). Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Met1Val (c.1A>G)?

CHEK2 p.Met1Val (c.1A>G) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Met1Val (c.1A>G) in the general population?

CHEK2 p.Met1Val (c.1A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

CHEK2 p.Met1Val

c.1A>G · rs863224748 · VCV216643

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.391	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.5, phastCons 1
Overall
CADD	21.2	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 8.48e-05% European (non-Finnish) · 1/1,179,682 alleles

Overall 0.000137% 2/1,461,310 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00158%	63,202
European (non-Finnish)grpmax	8.48e-05%	1,179,682

Finnish 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.Met1Val
Coding: c.1A>G
MANE Select: NM_007194
dbSNP: rs863224748
Type: single nucleotide variant
Location: chr22:28734721 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 1: the 'disordered' region

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.Met1Thr Uncertain significance ★★ same residue
CHEK2 p.Met1Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Met1Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Met1Lys Uncertain significance ★ same residue
CHEK2 p.Met1fs Likely pathogenic ★ same residue
CHEK2 p.Met1Phe 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-met1val (accessed [today's date]).

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