Is MSH2 p.Gln170Pro (c.509A>C) pathogenic?

MSH2 p.Gln170Pro (c.509A>C) is classified Uncertain significance in MSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-09). AlphaMissense: ambiguous (0.4515); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MSH2 p.Gln170Pro (c.509A>C)?

MSH2 p.Gln170Pro (c.509A>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Gln170Pro (c.509A>C) in the general population?

MSH2 p.Gln170Pro (c.509A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH2 p.Gln170Pro (c.509A>C)?

AlphaMissense predicts ambiguous (score 0.4515) — an in-silico prediction, not a clinical call.

MSH2 p.Gln170Pro

c.509A>C · VCV3398648

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4515 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4515	ambiguous
REVEL	0.684	pathogenic-leaning
SaProt	LLR -7.59	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9	GERP 2.6, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	23.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MSH2
Protein: p.Gln170Pro
Coding: c.509A>C
MANE Select: NM_000251
Type: single nucleotide variant
Location: chr2:47410236 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 170: a turn

Full MSH2 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

MSH2 p.Gln170Ter Pathogenic ★★★ same residue
MSH2 p.Gln170Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Gln170Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Gln170His Uncertain significance ★ ⚠ same residue
MSH2 p.Gln170Lys Uncertain significance ★ ⚠ same residue
MSH2 p.Gln170= Likely benign ★ 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-gln170pro (accessed [today's date]).

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