Is MSH2 p.Pro652His (c.1955C>A) pathogenic?

MSH2 p.Pro652His (c.1955C>A) is classified Likely pathogenic in MSH2 (ClinVar, Expert panel, 1 submitter; last evaluated 2019-06-21). AlphaMissense: likely pathogenic (0.7818); Absent from gnomAD v4.1; Associated with Lynch syndrome.

What condition is associated with MSH2 p.Pro652His (c.1955C>A)?

MSH2 p.Pro652His (c.1955C>A) is associated with Lynch syndrome (ClinVar).

How common is MSH2 p.Pro652His (c.1955C>A) in the general population?

MSH2 p.Pro652His (c.1955C>A) is absent from gnomAD v4.1 (gnomAD).

How is Lynch syndrome inherited?

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

What do computational predictors say about MSH2 p.Pro652His (c.1955C>A)?

AlphaMissense predicts likely pathogenic (score 0.7818) — an in-silico prediction, not a clinical call.

MSH2 p.Pro652His

c.1955C>A · rs267607983 · VCV90823

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7818 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Lynch syndrome

Computational evidence

Protein change
AlphaMissense	0.7818	likely pathogenic ✓ concordant with ClinVar
REVEL	0.879	moderately pathogenic-leaning
SaProt	LLR -14.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	27.9	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.Pro652His
Coding: c.1955C>A
MANE Select: NM_000251
dbSNP: rs267607983
Type: single nucleotide variant
Location: chr2:47475220 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 652: the 'interaction with exo1' region; an α-helix

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

Disease context

Lynch syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH2 p.Pro652Leu Uncertain significance ★★ ⚠ same residue
MSH2 p.Pro652Ser Uncertain significance ★★ ⚠ same residue
MSH2 p.Pro652Thr Uncertain significance ★★ ⚠ same residue
MSH2 p.Pro652= Benign/Likely benign ★★ same residue
MSH2 p.Pro652Ala Uncertain significance ★ ⚠ same residue
MSH2 p.Pro652Arg 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-pro652his (accessed [today's date]).

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