Is CHEK2 p.Ile251= (c.753C>T) pathogenic?

CHEK2 p.Ile251= (c.753C>T) is classified Benign/Likely benign in CHEK2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-08). Very rare (popmax 0.000339%, nfe); Associated with Li-Fraumeni syndrome.

What condition is associated with CHEK2 p.Ile251= (c.753C>T)?

CHEK2 p.Ile251= (c.753C>T) is associated with Li-Fraumeni syndrome, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Ile251= (c.753C>T) in the general population?

CHEK2 p.Ile251= (c.753C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Li-Fraumeni syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

CHEK2 p.Ile251=

c.753C>T · rs1422471902 · VCV754842

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

Li-Fraumeni syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.031	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1.7, phastCons 1
Overall
CADD	10.64	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,948 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,796 alleles · very rare exomes 4/1,461,654 · genomes 1/152,142 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)grpmax	0.000339%	294,987

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.Ile251=
Coding: c.753C>T
MANE Select: NM_007194
dbSNP: rs1422471902
Type: single nucleotide variant
Location: chr22:28711948 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 251: a β-strand; the protein kinase domain; a UniProt-annotated variant site (in prostate cancer; uncertain significance)

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

Disease context

Li-Fraumeni syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome hereditary breast carcinoma

For Li-Fraumeni syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

CHEK2 p.Ile251Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ile251Asn Uncertain significance ★ ⚠ same residue
CHEK2 p.Ile251Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Ile251fs Pathogenic ★★ same residue
CHEK2 p.Ile251del Uncertain significance ★★ 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-ile251 (accessed [today's date]).

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