Is MSH2 p.Arg524= (c.1572T>A) pathogenic?

MSH2 p.Arg524= (c.1572T>A) is classified Likely benign in MSH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-18). Very rare (popmax 0.0011%, sas); Associated with Lynch syndrome.

What condition is associated with MSH2 p.Arg524= (c.1572T>A)?

MSH2 p.Arg524= (c.1572T>A) is associated with Lynch syndrome (ClinVar).

How common is MSH2 p.Arg524= (c.1572T>A) in the general population?

MSH2 p.Arg524= (c.1572T>A) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Lynch syndrome inherited?

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

MSH2 p.Arg524=

c.1572T>A · rs2104177298 · VCV1153022

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Lynch syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5	GERP -4.1
Overall
CADD	0.956	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,080 alleles

Overall 6.2e-05% 1/1,614,082 alleles · very rare exomes 1/1,461,724 · genomes 0/152,358 · joint denominator

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: MSH2
Protein: p.Arg524=
Coding: c.1572T>A
MANE Select: NM_000251
dbSNP: rs2104177298
Type: single nucleotide variant
Location: chr2:47466719 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 524: a β-strand; a UniProt-annotated variant site (in lynch1; decreased mismatch repair activity)

Full MSH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH2 p.Arg524Pro Likely pathogenic ★★★ same residue
MSH2 p.Arg524Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Arg524His Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Arg524Leu Uncertain significance ★★ ⚠ same residue
MSH2 p.Arg524Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>C 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/msh2-p-arg524 (accessed [today's date]).

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