Is MSH2 p.Ser281Pro (c.841T>C) pathogenic?

MSH2 p.Ser281Pro (c.841T>C) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-02-19). AlphaMissense: likely pathogenic (0.7548); Very rare (popmax 0.00331%, sas); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MSH2 p.Ser281Pro (c.841T>C) in the general population?

MSH2 p.Ser281Pro (c.841T>C) is very rare (popmax 0.00331%, sas) (gnomAD).

What do computational predictors say about MSH2 p.Ser281Pro (c.841T>C)?

AlphaMissense predicts likely pathogenic (score 0.7548) — an in-silico prediction, not a clinical call.

MSH2 p.Ser281Pro

Q: What condition is associated with MSH2 p.Ser281Pro (c.841T>C)?

MSH2 p.Ser281Pro (c.841T>C) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

c.841T>C · rs587779977 · VCV127653

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7548 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.7548	likely pathogenic
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -10.93	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 5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	24.2	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 0.00331% South Asian · 3/90,536 alleles

Filtering AF 0.00088% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000444%

Overall 0.00031% 5/1,611,082 alleles · very rare exomes 3/1,460,538 · genomes 2/150,544 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00331%	30,179
African / African-American	0.00269%	37,193

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.Ser281Pro
Coding: c.841T>C
MANE Select: NM_000251
dbSNP: rs587779977
Type: single nucleotide variant
Location: chr2:47414317 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 281: an α-helix; a UniProt-annotated variant site (in lynch1)

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.Ser281Ter Pathogenic ★★ same residue
MSH2 p.Ser281Thr Uncertain significance ★★ ⚠ same residue
MSH2 p.Ser281Leu Likely benign ★★ ⚠ same residue
MSH2 p.Ser281= Conflicting classifications of pathogenicity ★ same residue
MSH2 p.Ser281fs 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

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-ser281pro (accessed [today's date]).

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