Is MSH6 p.Ser65Pro (c.193T>C) pathogenic?

MSH6 p.Ser65Pro (c.193T>C) is classified Uncertain significance in MSH6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-25). AlphaMissense: likely benign (0.0719); No allele count reported in gnomAD v4.1 (AN 1,506,980); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MSH6 p.Ser65Pro (c.193T>C) in the general population?

MSH6 p.Ser65Pro (c.193T>C) is no allele count reported in gnomAD v4.1 (AN 1,506,980) (gnomAD).

What do computational predictors say about MSH6 p.Ser65Pro (c.193T>C)?

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

MSH6 p.Ser65Pro

Q: What condition is associated with MSH6 p.Ser65Pro (c.193T>C)?

MSH6 p.Ser65Pro (c.193T>C) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

c.193T>C · rs1553408350 · VCV1364992

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0719 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,506,980)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.0719	likely benign
REVEL	0.212	benign-leaning
SaProt	LLR -5.62	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 -0.14	GERP 0.072, phastCons 0.001
Regional constraint	o/e 1.31	unconstrained · MANE · 24 kb · p 9.6e-36 · regional, not allelic
Overall
CADD	13.49	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

No allele count reported in gnomAD v4.1 (AN 1,506,980). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MSH6
Protein: p.Ser65Pro
Coding: c.193T>C
MANE Select: NM_000179
dbSNP: rs1553408350
Type: single nucleotide variant
Location: chr2:47783426 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 65: the 'disordered' region; a UniProt-annotated variant site (in)

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: hereditary neoplastic syndrome

Similar variants

MSH6 p.Ser65Leu Likely benign ★★★ same residue
MSH6 p.Ser65Ter Pathogenic ★★ same residue
MSH6 p.Ser65Ala Uncertain significance ★★ ⚠ same residue
MSH6 p.Ser65Thr Uncertain significance ★ ⚠ same residue
MSH6 p.Ser65= 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-ser65pro (accessed [today's date]).

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