Is MSH2 p.Pro439Ala (c.1315C>G) pathogenic?

MSH2 p.Pro439Ala (c.1315C>G) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-05-05). AlphaMissense: likely benign (0.172); Very rare (popmax 0.00333%, amr); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with MSH2 p.Pro439Ala (c.1315C>G)?

MSH2 p.Pro439Ala (c.1315C>G) is associated with hereditary breast ovarian cancer syndrome, Lynch syndrome, Lynch syndrome 1 (ClinVar).

How common is MSH2 p.Pro439Ala (c.1315C>G) in the general population?

MSH2 p.Pro439Ala (c.1315C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MSH2 p.Pro439Ala (c.1315C>G)?

AlphaMissense predicts likely benign (score 0.172) — an in-silico prediction, not a clinical call.

MSH2 p.Pro439Ala

c.1315C>G · rs786203116 · VCV422351

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.172 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
AlphaMissense	0.172	likely benign
REVEL	0.791	moderately pathogenic-leaning
SaProt	LLR -10.03	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	23.7	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

Grpmax group 0.00333% Admixed American · 2/60,004 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,613,378 alleles · very rare exomes 2/1,461,136 · genomes 0/152,242 · 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: MSH2
Protein: p.Pro439Ala
Coding: c.1315C>G
MANE Select: NM_000251
dbSNP: rs786203116
Type: single nucleotide variant
Location: chr2:47445586 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 439: an α-helix

Full MSH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary breast ovarian cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome Lynch syndrome 1 Muir-Torre syndrome hereditary neoplastic syndrome mismatch repair cancer syndrome 2

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

MSH2 p.Pro439Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro439Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro439= Benign ★ same residue
MSH2 p.Pro439del Conflicting classifications of pathogenicity ★ same residue
MSH2 p.Pro439Arg Uncertain significance ★ ⚠ same residue
MSH2 p.Pro439Thr Uncertain significance ★ ⚠ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T 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/msh2-p-pro439ala (accessed [today's date]).

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