Is MSH2 p.Pro618Ala (c.1852C>G) pathogenic?

MSH2 p.Pro618Ala (c.1852C>G) is classified Uncertain significance in MSH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-03). AlphaMissense: likely benign (0.0809); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MSH2 p.Pro618Ala (c.1852C>G)?

MSH2 p.Pro618Ala (c.1852C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Pro618Ala (c.1852C>G) in the general population?

MSH2 p.Pro618Ala (c.1852C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH2 p.Pro618Ala (c.1852C>G)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

MSH2 p.Pro618Ala

c.1852C>G · rs1573566801 · VCV820184

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.497	indeterminate
SaProt	LLR -7.85	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.8, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	18.06	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

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.Pro618Ala
Coding: c.1852C>G
MANE Select: NM_000251
dbSNP: rs1573566801
Type: single nucleotide variant
Location: chr2:47475117 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 618: the 'interaction with exo1' region

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.Pro618Leu Uncertain significance ★★ ⚠ same residue
MSH2 p.Pro618Ser Uncertain significance ★★ ⚠ same residue
MSH2 p.Pro618= Conflicting classifications of pathogenicity ★ same residue
MSH2 p.Pro618fs Pathogenic/Likely pathogenic ★★ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>C Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>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-pro618ala (accessed [today's date]).

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