Is MSH6 p.Pro320= (c.960C>T) pathogenic?

MSH6 p.Pro320= (c.960C>T) is classified Benign/Likely benign in MSH6 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0351%, sas); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MSH6 p.Pro320= (c.960C>T) in the general population?

MSH6 p.Pro320= (c.960C>T) is ultra-rare (popmax 0.0351%, sas) (gnomAD).

MSH6 p.Pro320=

Q: What condition is associated with MSH6 p.Pro320= (c.960C>T)?

MSH6 p.Pro320= (c.960C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 5 (ClinVar).

c.960C>T · rs575325950 · VCV186984

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0351%, sas)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -3.8
Overall
CADD	1.431	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0351% South Asian · 32/91,074 alleles

Filtering AF 0.0256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00229% 37/1,614,162 alleles · ultra-rare exomes 33/1,461,868 · genomes 4/152,294 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0351%	2,846
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0064%	15,627

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.Pro320=
Coding: c.960C>T
MANE Select: NM_000179
dbSNP: rs575325950
Type: single nucleotide variant
Location: chr2:47798943 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 320: 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 Lynch syndrome 5 hereditary neoplastic syndrome

Similar variants

MSH6 p.Pro320Ser Uncertain significance ★★ ⚠ same residue
MSH6 p.Pro320Ala Uncertain significance ★ ⚠ same residue
MSH6 p.Pro320His Uncertain significance ★ ⚠ same residue
MSH6 p.Pro320Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Pro320Thr Conflicting classifications of pathogenicity ★ ⚠ 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-pro320 (accessed [today's date]).

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