Is MSH2 p.Phe136Cys (c.407T>G) pathogenic?

MSH2 p.Phe136Cys (c.407T>G) is classified Uncertain significance in MSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-22). AlphaMissense: likely pathogenic (0.8973); Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH2 p.Phe136Cys (c.407T>G)?

MSH2 p.Phe136Cys (c.407T>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Phe136Cys (c.407T>G) in the general population?

MSH2 p.Phe136Cys (c.407T>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MSH2 p.Phe136Cys (c.407T>G)?

AlphaMissense predicts likely pathogenic (score 0.8973) — an in-silico prediction, not a clinical call.

MSH2 p.Phe136Cys

c.407T>G · VCV4860308

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8973 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8973	likely pathogenic
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -12.38	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 6	GERP 2.7, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.0011% South Asian · 1/91,088 alleles

Overall 6.2e-05% 1/1,614,142 alleles · very rare exomes 1/1,461,810 · genomes 0/152,332 · joint denominator

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.Phe136Cys
Coding: c.407T>G
MANE Select: NM_000251
Type: single nucleotide variant
Location: chr2:47410134 (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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MSH2 p.Phe136Leu Uncertain significance ★★ ⚠ same residue
MSH2 p.Phe136= Benign/Likely benign ★★ same residue
MSH2 p.Phe136fs Pathogenic ★★★ same residue
MSH2 p.Phe136Ser Uncertain significance ★ ⚠ 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

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-phe136cys (accessed [today's date]).

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