Is MSH2 p.Ser129Phe (c.386C>T) pathogenic?

MSH2 p.Ser129Phe (c.386C>T) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.2962); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH2 p.Ser129Phe (c.386C>T)?

MSH2 p.Ser129Phe (c.386C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 1, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Ser129Phe (c.386C>T) in the general population?

MSH2 p.Ser129Phe (c.386C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH2 p.Ser129Phe (c.386C>T)?

AlphaMissense predicts likely benign (score 0.2962) — an in-silico prediction, not a clinical call.

MSH2 p.Ser129Phe

c.386C>T · rs587779972 · VCV127645

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2962 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.2962	likely benign
REVEL	0.645	pathogenic-leaning
SaProt	LLR -10.98	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	Δ0.70	acceptor gain · deltas
Pangolin	Δ0.37	gain · loss 0.15 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 2.7, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	34.0	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.Ser129Phe
Coding: c.386C>T
MANE Select: NM_000251
dbSNP: rs587779972
Type: single nucleotide variant
Location: chr2:47410113 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 129: 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: Lynch syndrome 1 hereditary neoplastic syndrome

Similar variants

MSH2 p.Ser129Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Ser129Pro 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
MSH2 c.1077-1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-2A>C Pathogenic ★★★ same condition
MSH2 c.1077-2A>G 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-ser129phe (accessed [today's date]).

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