Is MSH3 p.Ser445Pro (c.1333T>C) pathogenic?

MSH3 p.Ser445Pro (c.1333T>C) is classified Uncertain significance in MSH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-21). AlphaMissense: ambiguous (0.3459); Absent from gnomAD v4.1.

How common is MSH3 p.Ser445Pro (c.1333T>C) in the general population?

MSH3 p.Ser445Pro (c.1333T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH3 p.Ser445Pro (c.1333T>C)?

AlphaMissense predicts ambiguous (score 0.3459) — an in-silico prediction, not a clinical call.

MSH3 p.Ser445Pro

c.1333T>C · rs2112819228 · VCV1361822

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3459 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3459	ambiguous
REVEL	0.284	benign-leaning
SaProt	LLR -13.20	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.4	GERP -0.14, phastCons 0.99
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	21.0	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

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.Ser445Pro
Coding: c.1333T>C
MANE Select: NM_002439
dbSNP: rs2112819228
Type: single nucleotide variant
Location: chr5:80679086 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 445: an α-helix

Full MSH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MSH3 p.Ser445Phe Uncertain significance ★★ ⚠ same residue
MSH3 p.Ser445= Likely benign ★ same residue
MSH3 c.1341-2A>C Likely pathogenic ★★ same type
MSH3 c.1341-2A>G Likely pathogenic ★★ same type
MSH3 c.1568+1G>A Likely pathogenic ★★ same type
MSH3 c.1568+1G>C Likely pathogenic ★★ same type
MSH3 c.1653+1G>A Likely pathogenic ★★ same type
MSH3 c.1653+2T>A Likely pathogenic ★★ same type

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-ser445pro (accessed [today's date]).

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