Is MSH3 p.Arg727= (c.2181A>G) pathogenic?

MSH3 p.Arg727= (c.2181A>G) is classified Likely benign in MSH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-17). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Arg727= (c.2181A>G)?

MSH3 p.Arg727= (c.2181A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Arg727= (c.2181A>G) in the general population?

MSH3 p.Arg727= (c.2181A>G) is absent from gnomAD v4.1 (gnomAD).

MSH3 p.Arg727=

c.2181A>G · rs2546774277 · VCV2586052

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.5, phastCons 0.98
Overall
CADD	12.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MSH3
Protein: p.Arg727=
Coding: c.2181A>G
MANE Select: NM_002439
dbSNP: rs2546774277
Type: single nucleotide variant
Location: chr5:80768931 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 727: an α-helix

Full MSH3 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

MSH3 p.Arg727Ter Pathogenic/Likely pathogenic ★★ same residue
MSH3 p.Arg727Leu Uncertain significance ★★ ⚠ same residue
MSH3 p.Arg727Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH3 p.Arg727Gly Uncertain significance ★ ⚠ same residue
MSH3 c.1341-2A>C Likely pathogenic ★★ same condition
MSH3 c.1341-2A>G Likely pathogenic ★★ same condition
MSH3 c.1568+1G>C Likely pathogenic ★★ same condition
MSH3 c.1653+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/msh3-p-arg727 (accessed [today's date]).

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