Is MSH6 p.Phe596Ser (c.1787T>C) pathogenic?

MSH6 p.Phe596Ser (c.1787T>C) is classified Uncertain significance in MSH6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-24). AlphaMissense: ambiguous (0.4329); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with MSH6 p.Phe596Ser (c.1787T>C)?

MSH6 p.Phe596Ser (c.1787T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH6 p.Phe596Ser (c.1787T>C) in the general population?

MSH6 p.Phe596Ser (c.1787T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH6 p.Phe596Ser (c.1787T>C)?

AlphaMissense predicts ambiguous (score 0.4329) — an in-silico prediction, not a clinical call.

MSH6 p.Phe596Ser

c.1787T>C · rs1064793774 · VCV419291

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4329 · 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	0.4329	ambiguous
REVEL	0.752	pathogenic-leaning
SaProt	LLR -11.09	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 1.1, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 24 kb · p 9.6e-36 · regional, not allelic
Overall
CADD	23.5	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: MSH6
Protein: p.Phe596Ser
Coding: c.1787T>C
MANE Select: NM_000179
dbSNP: rs1064793774
Type: single nucleotide variant
Location: chr2:47799770 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 596: a β-strand

Full MSH6 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

MSH6 p.Phe596Cys Uncertain significance ★★ ⚠ same residue
MSH6 p.Phe596Leu Uncertain significance ★★ ⚠ same residue
MSH6 p.Phe596Tyr Uncertain significance ★★ ⚠ same residue
MSH6 p.Phe596Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Phe596= Likely benign ★ same residue
MSH6 c.3172+1G>T Likely pathogenic ★★★ same condition
MSH6 c.3438+1G>A Likely pathogenic ★★★ same condition
MSH6 c.3439-1G>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/msh6-p-phe596ser (accessed [today's date]).

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