Is MSH2 p.Ser271Phe (c.812C>T) pathogenic?

MSH2 p.Ser271Phe (c.812C>T) is classified Likely benign in MSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-28). AlphaMissense: ambiguous (0.4614); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MSH2 p.Ser271Phe (c.812C>T)?

MSH2 p.Ser271Phe (c.812C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Ser271Phe (c.812C>T) in the general population?

MSH2 p.Ser271Phe (c.812C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH2 p.Ser271Phe (c.812C>T)?

AlphaMissense predicts ambiguous (score 0.4614) — an in-silico prediction, not a clinical call.

MSH2 p.Ser271Phe

c.812C>T · rs139891783 · VCV2453500

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4614 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4614	ambiguous
REVEL	0.743	pathogenic-leaning
SaProt	LLR -14.84	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.4, 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

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.Ser271Phe
Coding: c.812C>T
MANE Select: NM_000251
dbSNP: rs139891783
Type: single nucleotide variant
Location: chr2:47414288 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 271: 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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MSH2 p.Ser271Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ser271Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ser271fs Pathogenic ★★ same residue
MSH2 p.Ser271_Ala272insSerSerLeuSer Uncertain significance ★ same residue
MSH2 p.Ser271= Benign/Likely benign ★★ 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-ser271phe (accessed [today's date]).

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