Is CHEK2 p.Pro484= (c.1452G>A) pathogenic?

CHEK2 p.Pro484= (c.1452G>A) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2025-12-21). Very rare (popmax 0.0011%, sas); Associated with CHEK2-related cancer predisposition.

What condition is associated with CHEK2 p.Pro484= (c.1452G>A)?

CHEK2 p.Pro484= (c.1452G>A) is associated with CHEK2-related cancer predisposition, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Pro484= (c.1452G>A) in the general population?

CHEK2 p.Pro484= (c.1452G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

CHEK2 p.Pro484=

c.1452G>A · rs749156425 · VCV230446

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

CHEK2-related cancer predisposition

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.24	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.3
Overall
CADD	0.541	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,946 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00119% 19/1,594,088 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0473%	2,112
South Asiangrpmax	0.0011%	90,946
European (non-Finnish)	0.00034%	294,452

Ashkenazi Jewish 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.Pro484=
Coding: c.1452G>A
MANE Select: NM_007194
dbSNP: rs749156425
Type: single nucleotide variant
Location: chr22:28694041 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 484: an α-helix; the protein kinase domain

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

Disease context

Also linked: hereditary neoplastic syndrome hereditary breast carcinoma hereditary nonpolyposis colon cancer

Similar variants

CHEK2 p.Pro484Arg Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro484Ser Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro484Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro484Ala Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro484Gln Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro484Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Pro484fs Pathogenic ★★ same residue
CHEK2 p.Pro484_Trp485insGlnArgHisValLeuArgGlnLysLysProTer Uncertain significance ★ same residue

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-pro484 (accessed [today's date]).

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