Is CHEK2 p.Ile221= (c.663C>A) pathogenic?

CHEK2 p.Ile221= (c.663C>A) is classified Likely benign in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-08). No allele count reported in gnomAD v4.1 (AN 1,589,630); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Ile221= (c.663C>A)?

CHEK2 p.Ile221= (c.663C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CHEK2 p.Ile221= (c.663C>A) in the general population?

CHEK2 p.Ile221= (c.663C>A) is no allele count reported in gnomAD v4.1 (AN 1,589,630) (gnomAD).

CHEK2 p.Ile221=

c.663C>A · rs200451612 · VCV1754612

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,589,630)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.23	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 6.7	GERP 0.61, phastCons 1
Overall
CADD	9.212	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,589,630). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CHEK2
Protein: p.Ile221=
Coding: c.663C>A
MANE Select: NM_007194
dbSNP: rs200451612
Type: single nucleotide variant
Location: chr22:28719415 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 221: the protein kinase domain; a β-strand

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

Similar variants

CHEK2 p.Ile221Met Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Ile221Val Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Ile221Leu 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
CHEK2 c.1008+2T>G Likely pathogenic ★★ same condition
CHEK2 c.1009-1G>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-ile221 (accessed [today's date]).

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