Is MSH3 p.Pro49Ala (c.145C>G) pathogenic?

MSH3 p.Pro49Ala (c.145C>G) is classified Uncertain significance in MSH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0533); Very rare (popmax 0.00346%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Pro49Ala (c.145C>G)?

MSH3 p.Pro49Ala (c.145C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Pro49Ala (c.145C>G) in the general population?

MSH3 p.Pro49Ala (c.145C>G) is very rare (popmax 0.00346%, amr) (gnomAD).

What do computational predictors say about MSH3 p.Pro49Ala (c.145C>G)?

AlphaMissense predicts likely benign (score 0.0533) — an in-silico prediction, not a clinical call.

MSH3 p.Pro49Ala

c.145C>G · rs775307118 · VCV1422678

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0533 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00346%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0533	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -5.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.34	GERP -0.026
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	3.899	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00346% Admixed American · 2/57,790 alleles

Filtering AF 0.00071% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000555%

Overall 0.00109% 17/1,561,424 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00346%	28,895
Remaining individualsnot grpmax-eligible	0.00165%	60,430
European (non-Finnish)	0.00122%	81,759

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.Pro49Ala
Coding: c.145C>G
MANE Select: NM_002439
dbSNP: rs775307118
Type: single nucleotide variant
Location: chr5:80654872 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 49: the 'disordered' region

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.Pro49Thr Uncertain significance ★★ ⚠ same residue
MSH3 p.Pro49fs Pathogenic/Likely pathogenic ★★ 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
MSH3 c.1764-2A>C 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-pro49ala (accessed [today's date]).

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