Is MSH6 p.Pro399= (c.1197T>C) pathogenic?

MSH6 p.Pro399= (c.1197T>C) is classified Benign/Likely benign in MSH6 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-14). Very rare (popmax 6.2e-05%); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with MSH6 p.Pro399= (c.1197T>C)?

MSH6 p.Pro399= (c.1197T>C) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 5, hereditary neoplastic syndrome (ClinVar).

How common is MSH6 p.Pro399= (c.1197T>C) in the general population?

MSH6 p.Pro399= (c.1197T>C) is very rare (popmax 6.2e-05%) (gnomAD).

MSH6 p.Pro399=

c.1197T>C · rs1572722145 · VCV698954

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.13	GERP -1.7, phastCons 0.76
Overall
CADD	5.859	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,614,206 alleles · very rare exomes 1/1,461,878 · genomes 0/152,328 · joint denominator

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.Pro399=
Coding: c.1197T>C
MANE Select: NM_000179
dbSNP: rs1572722145
Type: single nucleotide variant
Location: chr2:47799180 (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

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome 5 hereditary neoplastic syndrome

Similar variants

MSH6 p.Pro399His Uncertain significance ★★ ⚠ same residue
MSH6 p.Pro399Leu Uncertain significance ★★ ⚠ 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
MSH6 c.3439-2A>G Likely pathogenic ★★★ same condition
MSH6 c.3647-1G>A Pathogenic ★★★ same condition
MSH6 c.3647-2A>C 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-pro399 (accessed [today's date]).

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