Is MSH6 p.Ser549Phe (c.1646C>T) pathogenic?

MSH6 p.Ser549Phe (c.1646C>T) is classified Uncertain significance in MSH6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-05-08). AlphaMissense: likely benign (0.0926); Absent from gnomAD v4.1; Associated with Lynch syndrome 5.

What condition is associated with MSH6 p.Ser549Phe (c.1646C>T)?

MSH6 p.Ser549Phe (c.1646C>T) is associated with Lynch syndrome 5, hereditary neoplastic syndrome (ClinVar).

How common is MSH6 p.Ser549Phe (c.1646C>T) in the general population?

MSH6 p.Ser549Phe (c.1646C>T) is absent from gnomAD v4.1 (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MSH6 p.Ser549Phe (c.1646C>T)?

AlphaMissense predicts likely benign (score 0.0926) — an in-silico prediction, not a clinical call.

MSH6 p.Ser549Phe

c.1646C>T · rs200447622 · VCV926628

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0926 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Lynch syndrome 5

Computational evidence

Protein change
AlphaMissense	0.0926	likely benign
REVEL	0.435	indeterminate
SaProt	LLR -7.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.17	GERP 0.36
Regional constraint	o/e 1.31	unconstrained · MANE · 24 kb · p 9.6e-36 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

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

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.Ser549Phe
Coding: c.1646C>T
MANE Select: NM_000179
dbSNP: rs200447622
Type: single nucleotide variant
Location: chr2:47799629 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB

Full MSH6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Lynch syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH6 p.Ser549= Benign/Likely benign ★★ same residue
MSH6 p.Ser549Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Ser549Thr Uncertain significance ★ ⚠ same residue
MSH6 p.Ser549Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Ser549fs Pathogenic ★★ same residue
MSH6 p.Ser549Pro Uncertain significance ★ ⚠ same residue
MSH6 c.3172+1G>T Likely pathogenic ★★★ same condition
MSH6 c.3438+1G>A 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-ser549phe (accessed [today's date]).

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