Is MSH6 p.Pro57Ser (c.169C>T) pathogenic?

MSH6 p.Pro57Ser (c.169C>T) is classified Uncertain significance in MSH6 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-03-06). AlphaMissense: likely benign (0.0719); Absent from gnomAD v4.1; Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH6 p.Pro57Ser (c.169C>T)?

MSH6 p.Pro57Ser (c.169C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, hereditary neoplastic syndrome (ClinVar).

How common is MSH6 p.Pro57Ser (c.169C>T) in the general population?

MSH6 p.Pro57Ser (c.169C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MSH6 p.Pro57Ser (c.169C>T)?

AlphaMissense predicts likely benign (score 0.0719) — an in-silico prediction, not a clinical call.

MSH6 p.Pro57Ser

c.169C>T · rs773367009 · VCV938631

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0719 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.0719	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -6.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.17	GERP -1.1, phastCons 0.029
Regional constraint	o/e 1.31	unconstrained · MANE · 24 kb · p 9.6e-36 · regional, not allelic
Overall
CADD	15.64	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.Pro57Ser
Coding: c.169C>T
MANE Select: NM_000179
dbSNP: rs773367009
Type: single nucleotide variant
Location: chr2:47783402 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 57: the 'disordered' region

Full MSH6 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 hereditary neoplastic syndrome

Similar variants

MSH6 p.Pro57Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Pro57Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Pro57Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Pro57Thr Uncertain significance ★ ⚠ same residue
MSH6 p.Pro57= Likely benign ★ same residue
MSH6 p.Pro57His Likely benign ★ same residue
MSH6 p.Pro57_Ala61del Uncertain significance ★★ same residue
MSH6 p.Pro57fs Pathogenic ★ same residue

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-pro57ser (accessed [today's date]).

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