Is MSH3 p.Ile348= (c.1044C>A) pathogenic?

MSH3 p.Ile348= (c.1044C>A) is classified Likely benign in MSH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-24). Very rare (popmax 0.00894%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Ile348= (c.1044C>A)?

MSH3 p.Ile348= (c.1044C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Ile348= (c.1044C>A) in the general population?

MSH3 p.Ile348= (c.1044C>A) is very rare (popmax 0.00894%, eas) (gnomAD).

MSH3 p.Ile348=

c.1044C>A · rs766534747 · VCV754144

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00894%, eas)

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 0.16	GERP 1.5, phastCons 0.77
Overall
CADD	8.562	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00894% East Asian · 4/44,742 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000275% 4/1,455,630 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.Ile348=
Coding: c.1044C>A
MANE Select: NM_002439
dbSNP: rs766534747
Type: single nucleotide variant
Location: chr5:80674999 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 348: a β-strand

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.Ile348Leu Uncertain significance ★★ ⚠ same residue
MSH3 p.Ile348Met Uncertain significance ★★ ⚠ same residue
MSH3 p.Ile348Val Conflicting classifications of pathogenicity ★ ⚠ 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
MSH3 c.1764-1G>A Pathogenic/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-ile348 (accessed [today's date]).

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