Is MSH3 p.Pro72Arg (c.215C>G) pathogenic?

MSH3 p.Pro72Arg (c.215C>G) is classified Uncertain significance in MSH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-12). AlphaMissense: likely benign (0.1044); Very rare (popmax 8.9e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Pro72Arg (c.215C>G)?

MSH3 p.Pro72Arg (c.215C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Pro72Arg (c.215C>G) in the general population?

MSH3 p.Pro72Arg (c.215C>G) is very rare (popmax 8.9e-05%, nfe) (gnomAD).

What do computational predictors say about MSH3 p.Pro72Arg (c.215C>G)?

AlphaMissense predicts likely benign (score 0.1044) — an in-silico prediction, not a clinical call.

MSH3 p.Pro72Arg

c.215C>G · rs1404800640 · VCV1786864

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1044 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.9e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.1044	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -7.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.96	GERP -1.9
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	18.36	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 8.9e-05% European (non-Finnish) · 1/1,123,178 alleles

Overall 6.7e-05% 1/1,493,186 alleles · very rare exomes 1/1,341,262 · genomes 0/151,924 · joint denominator

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.Pro72Arg
Coding: c.215C>G
MANE Select: NM_002439
dbSNP: rs1404800640
Type: single nucleotide variant
Location: chr5:80654942 (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-pro72arg (accessed [today's date]).

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