Is MSH3 p.Ala22= (c.66G>C) pathogenic?

MSH3 p.Ala22= (c.66G>C) is classified Likely benign in MSH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-11). Very rare (popmax 8.49e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Ala22= (c.66G>C)?

MSH3 p.Ala22= (c.66G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Ala22= (c.66G>C) in the general population?

MSH3 p.Ala22= (c.66G>C) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

MSH3 p.Ala22=

c.66G>C · rs1580537815 · VCV1607168

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.35	GERP -3.7, phastCons 0.029
Overall
CADD	5.009	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,362 alleles

Overall 6.87e-05% 1/1,455,092 alleles · very rare

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: MSH3
Protein: p.Ala22=
Coding: c.66G>C
MANE Select: NM_000791 · reported on NM_002439
dbSNP: rs1580537815
Type: single nucleotide variant
Location: chr5:80654793 (GRCh38)

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

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-ala22 (accessed [today's date]).

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