Is MSH2 p.Pro69Ser (c.205C>T) pathogenic?

MSH2 p.Pro69Ser (c.205C>T) is classified Uncertain significance in MSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-22). AlphaMissense: likely benign (0.0793); No allele count reported in gnomAD v4.1 (AN 1,599,294); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Pro69Ser (c.205C>T)?

MSH2 p.Pro69Ser (c.205C>T) is associated with Hereditary nonpolyposis colorectal neoplasms (ClinVar).

How common is MSH2 p.Pro69Ser (c.205C>T) in the general population?

MSH2 p.Pro69Ser (c.205C>T) is no allele count reported in gnomAD v4.1 (AN 1,599,294) (gnomAD).

What do computational predictors say about MSH2 p.Pro69Ser (c.205C>T)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

MSH2 p.Pro69Ser

c.205C>T · VCV3625050

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,599,294)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
REVEL	0.464	indeterminate
SaProt	LLR -6.44	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 4.1	GERP 1.6, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	21.3	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

No allele count reported in gnomAD v4.1 (AN 1,599,294). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MSH2
Protein: p.Pro69Ser
Coding: c.205C>T
MANE Select: NM_000251
Type: single nucleotide variant
Location: chr2:47403396 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 69: a β-strand

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

Similar variants

MSH2 p.Pro69Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro69fs Pathogenic ★ same residue
MSH2 p.Pro69Leu Uncertain significance ★★ ⚠ same residue
MSH2 p.Pro69= Benign/Likely benign ★★ same residue
MSH2 c.1276+2T>C Pathogenic/Likely pathogenic ★★ same condition
MSH2 c.1277-1G>T Pathogenic/Likely pathogenic ★★ same condition
MSH2 c.1510+1G>T Pathogenic/Likely pathogenic ★★ same condition
MSH2 c.1510+2T>C Pathogenic/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-pro69ser (accessed [today's date]).

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