Is MSH3 p.Asp352Val (c.1055A>T) pathogenic?

MSH3 p.Asp352Val (c.1055A>T) is classified Uncertain significance in MSH3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.1623); Very rare (popmax 8.5e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Asp352Val (c.1055A>T)?

MSH3 p.Asp352Val (c.1055A>T) is associated with hereditary neoplastic syndrome, endometrial carcinoma (ClinVar).

How common is MSH3 p.Asp352Val (c.1055A>T) in the general population?

MSH3 p.Asp352Val (c.1055A>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about MSH3 p.Asp352Val (c.1055A>T)?

AlphaMissense predicts likely benign (score 0.1623) — an in-silico prediction, not a clinical call.

MSH3 p.Asp352Val

c.1055A>T · rs2112815953 · VCV2586069

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1623 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1623	likely benign
REVEL	0.598	indeterminate
SaProt	LLR -10.52	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.5e-05% European (non-Finnish) · 1/1,177,122 alleles

Overall 6.86e-05% 1/1,458,384 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.Asp352Val
Coding: c.1055A>T
MANE Select: NM_002439
dbSNP: rs2112815953
Type: single nucleotide variant
Location: chr5:80675010 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB

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.Asp352Gly Uncertain significance ★★ ⚠ same residue
MSH3 p.Asp352His 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
MSH3 c.1653+2T>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-asp352val (accessed [today's date]).

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