Is MSH3 p.Arg417Pro (c.1250G>C) pathogenic?

MSH3 p.Arg417Pro (c.1250G>C) is classified Uncertain significance in MSH3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-31). AlphaMissense: likely pathogenic (0.9532); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Arg417Pro (c.1250G>C)?

MSH3 p.Arg417Pro (c.1250G>C) is associated with hereditary neoplastic syndrome, endometrial carcinoma (ClinVar).

How common is MSH3 p.Arg417Pro (c.1250G>C) in the general population?

MSH3 p.Arg417Pro (c.1250G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH3 p.Arg417Pro (c.1250G>C)?

AlphaMissense predicts likely pathogenic (score 0.9532) — an in-silico prediction, not a clinical call.

MSH3 p.Arg417Pro

c.1250G>C · rs778162840 · VCV1043823

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9532 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9532	likely pathogenic · top 7% in MSH3
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -17.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Arg417Pro
Coding: c.1250G>C
MANE Select: NM_002439
dbSNP: rs778162840
Type: single nucleotide variant
Location: chr5:80679003 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 417: 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

Also linked: endometrial carcinoma

Similar variants

MSH3 p.Arg417Gln Uncertain significance ★★ ⚠ same residue
MSH3 p.Arg417Leu Uncertain significance ★★ ⚠ same residue
MSH3 p.Arg417Trp Uncertain significance ★★ ⚠ same residue
MSH3 p.Arg417= Likely benign ★★ same residue
MSH3 p.Arg417Gly 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

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-arg417pro (accessed [today's date]).

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