Is MSH6 p.Ser63Pro (c.187T>C) pathogenic?

MSH6 p.Ser63Pro (c.187T>C) is classified Conflicting classifications of pathogenicity in MSH6 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0617); Ultra-rare (popmax 0.0717%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH6 p.Ser63Pro (c.187T>C)?

MSH6 p.Ser63Pro (c.187T>C) is associated with Hereditary nonpolyposis colorectal neoplasms, endometrial carcinoma, mismatch repair cancer syndrome 1 (ClinVar).

How common is MSH6 p.Ser63Pro (c.187T>C) in the general population?

MSH6 p.Ser63Pro (c.187T>C) is ultra-rare (popmax 0.0717%, afr) (gnomAD).

What do computational predictors say about MSH6 p.Ser63Pro (c.187T>C)?

AlphaMissense predicts likely benign (score 0.0617) — an in-silico prediction, not a clinical call.

MSH6 p.Ser63Pro

c.187T>C · rs763702846 · VCV220796

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0617 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0717%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.0617	likely benign
REVEL	0.276	benign-leaning
SaProt	LLR -5.22	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 0.45	GERP -3.4, phastCons 0.002
Regional constraint	o/e 1.31	unconstrained · MANE · 24 kb · p 9.6e-36 · regional, not allelic
Overall
CADD	15.02	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

Grpmax group 0.0717% African / African-American · 50/69,702 alleles

Filtering AF 0.0559% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0502%

Overall 0.00344% 52/1,510,744 alleles · ultra-rare exomes 20/1,358,776 · genomes 32/151,968 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0717%	1,394
Remaining individualsnot grpmax-eligible	0.00173%	57,946
European (non-Finnish)	8.84e-05%	1,131,456

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: MSH6
Protein: p.Ser63Pro
Coding: c.187T>C
MANE Select: NM_000179
dbSNP: rs763702846
Type: single nucleotide variant
Location: chr2:47783420 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 63: 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: endometrial carcinoma mismatch repair cancer syndrome 1 Lynch syndrome 5 hereditary neoplastic syndrome

Similar variants

MSH6 p.Ser63Ala Uncertain significance ★★ ⚠ same residue
MSH6 p.Ser63Phe Uncertain significance ★★ ⚠ same residue
MSH6 p.Ser63Thr Uncertain significance ★★ ⚠ same residue
MSH6 p.Ser63= Benign/Likely benign ★★ same residue
MSH6 p.Ser63Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Ser63Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Ser63fs Pathogenic ★ same residue
MSH6 c.3172+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-ser63pro (accessed [today's date]).

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