Is MSH2 p.Pro652Ser (c.1954C>T) pathogenic?

MSH2 p.Pro652Ser (c.1954C>T) is classified Uncertain significance in MSH2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-25). AlphaMissense: likely benign (0.3031); Very rare (popmax 8.48e-05%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Pro652Ser (c.1954C>T)?

MSH2 p.Pro652Ser (c.1954C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Pro652Ser (c.1954C>T) in the general population?

MSH2 p.Pro652Ser (c.1954C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about MSH2 p.Pro652Ser (c.1954C>T)?

AlphaMissense predicts likely benign (score 0.3031) — an in-silico prediction, not a clinical call.

MSH2 p.Pro652Ser

c.1954C>T · rs876660900 · VCV1171494

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.3031	likely benign
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -12.76	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
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	25.9	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,924 alleles

Overall 6.2e-05% 1/1,613,578 alleles · very rare exomes 1/1,461,788 · genomes 0/151,790 · 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.Pro652Ser
Coding: c.1954C>T
MANE Select: NM_000251
dbSNP: rs876660900
Type: single nucleotide variant
Location: chr2:47475219 (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

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

Similar variants

MSH2 p.Pro652Leu 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 p.Pro652fs Pathogenic ★ same residue
MSH2 p.Pro652His Likely pathogenic ★★★ same residue
MSH2 c.1076+1G>A 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-pro652ser (accessed [today's date]).

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