Is MSH3 p.Pro77Arg (c.230C>G) pathogenic?

MSH3 p.Pro77Arg (c.230C>G) is classified Uncertain significance in MSH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-22). AlphaMissense: likely benign (0.0756); Very rare (popmax 0.00148%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Pro77Arg (c.230C>G)?

MSH3 p.Pro77Arg (c.230C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Pro77Arg (c.230C>G) in the general population?

MSH3 p.Pro77Arg (c.230C>G) is very rare (popmax 0.00148%, afr) (gnomAD).

What do computational predictors say about MSH3 p.Pro77Arg (c.230C>G)?

AlphaMissense predicts likely benign (score 0.0756) — an in-silico prediction, not a clinical call.

MSH3 p.Pro77Arg

c.230C>G · rs1258205404 · VCV1789407

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00148%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0756	likely benign
REVEL	0.226	benign-leaning
SaProt	LLR -7.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.19	GERP -2.5
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	8.819	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 0.00148% African / African-American · 1/67,522 alleles

Overall 0.000136% 2/1,475,694 alleles · very rare exomes 1/1,324,584 · genomes 1/151,110 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00148%	67,522
European (non-Finnish)	8.98e-05%	1,113,826

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.Pro77Arg
Coding: c.230C>G
MANE Select: NM_002439
dbSNP: rs1258205404
Type: single nucleotide variant
Location: chr5:80654957 (GRCh38)

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

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-pro77arg (accessed [today's date]).

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