Is CHEK2 p.Ser500Phe (c.1499C>T) pathogenic?

CHEK2 p.Ser500Phe (c.1499C>T) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-13). AlphaMissense: likely benign (0.0904); Very rare (popmax 0.00669%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Ser500Phe (c.1499C>T)?

CHEK2 p.Ser500Phe (c.1499C>T) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Ser500Phe (c.1499C>T) in the general population?

CHEK2 p.Ser500Phe (c.1499C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about CHEK2 p.Ser500Phe (c.1499C>T)?

AlphaMissense predicts likely benign (score 0.0904) — an in-silico prediction, not a clinical call.

CHEK2 p.Ser500Phe

c.1499C>T · rs28909981 · VCV183902

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0904 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0904	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -8.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.6, phastCons 0.097
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	5.107	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% East Asian · 3/44,866 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000251% 4/1,594,826 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,955
European (non-Finnish)	8.49e-05%	1,178,538

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.Ser500Phe
Coding: c.1499C>T
MANE Select: NM_007194
dbSNP: rs28909981
Type: single nucleotide variant
Location: chr22:28689178 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 500: an α-helix; a UniProt-annotated variant site (in)

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.Ser500Pro Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser500Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser500= Benign/Likely benign ★★ same residue
CHEK2 p.Ser500Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Ser500fs Likely 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-ser500phe (accessed [today's date]).

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