Is MSH2 p.Pro895Ser (c.2683C>T) pathogenic?

MSH2 p.Pro895Ser (c.2683C>T) is classified Likely benign in MSH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-18). AlphaMissense: likely benign (0.1264); Very rare (popmax 0.00134%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Pro895Ser (c.2683C>T)?

MSH2 p.Pro895Ser (c.2683C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Pro895Ser (c.2683C>T) in the general population?

MSH2 p.Pro895Ser (c.2683C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about MSH2 p.Pro895Ser (c.2683C>T)?

AlphaMissense predicts likely benign (score 0.1264) — an in-silico prediction, not a clinical call.

MSH2 p.Pro895Ser

c.2683C>T · rs1186801216 · VCV655967

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1264 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.1264	likely benign
REVEL	0.538	indeterminate
SaProt	LLR -8.94	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 2.7	GERP 0.016, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	20.8	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 0.00134% African / African-American · 1/74,894 alleles

Overall 0.000186% 3/1,613,574 alleles · very rare exomes 2/1,461,452 · genomes 1/152,122 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,894
South Asian	0.0011%	91,048
European (non-Finnish)	8.48e-05%	1,179,837

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.Pro895Ser
Coding: c.2683C>T
MANE Select: NM_000251
dbSNP: rs1186801216
Type: single nucleotide variant
Location: chr2:47482827 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB

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.Pro895= Benign/Likely benign ★★ same residue
MSH2 p.Pro895Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro895Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro895His Uncertain significance ★ ⚠ same residue
MSH2 p.Pro895Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro895Thr 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-pro895ser (accessed [today's date]).

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