Is MSH3 p.Pro73Arg (c.218C>G) pathogenic?

MSH3 p.Pro73Arg (c.218C>G) is classified Uncertain significance in MSH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-02-13). AlphaMissense: likely benign (0.0938); No allele count reported in gnomAD v4.1 (AN 1,487,360); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Pro73Arg (c.218C>G)?

MSH3 p.Pro73Arg (c.218C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Pro73Arg (c.218C>G) in the general population?

MSH3 p.Pro73Arg (c.218C>G) is no allele count reported in gnomAD v4.1 (AN 1,487,360) (gnomAD).

What do computational predictors say about MSH3 p.Pro73Arg (c.218C>G)?

AlphaMissense predicts likely benign (score 0.0938) — an in-silico prediction, not a clinical call.

MSH3 p.Pro73Arg

c.218C>G · rs1580538949 · VCV820849

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0938 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,487,360)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0938	likely benign
REVEL	0.239	benign-leaning
SaProt	LLR -7.66	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 -0.013	GERP -0.72
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	19.22	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

No allele count reported in gnomAD v4.1 (AN 1,487,360). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MSH3
Protein: p.Pro73Arg
Coding: c.218C>G
MANE Select: NM_002439
dbSNP: rs1580538949
Type: single nucleotide variant
Location: chr5:80654945 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 73: 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 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
MSH3 c.1764-2A>G Pathogenic/Likely pathogenic ★★ same condition
MSH3 c.1896+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-pro73arg (accessed [today's date]).

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