Is MSH6 p.Pro623= (c.1869C>T) pathogenic?

MSH6 p.Pro623= (c.1869C>T) is classified Benign/Likely benign in MSH6 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-02). Rare (popmax 0.219%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is MSH6 p.Pro623= (c.1869C>T) in the general population?

MSH6 p.Pro623= (c.1869C>T) is rare (popmax 0.219%, afr) (gnomAD).

MSH6 p.Pro623=

Q: What condition is associated with MSH6 p.Pro623= (c.1869C>T)?

MSH6 p.Pro623= (c.1869C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, breast cancer, Lynch syndrome 5 (ClinVar).

c.1869C>T · rs141242295 · VCV182663

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

rare (popmax 0.219%, afr)

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 0.65	GERP -3.7, phastCons 0.92
Overall
CADD	4.459	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.219% African / African-American · 164/75,046 alleles

Filtering AF 0.191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.181%

Overall 0.0149% 241/1,614,156 alleles · rare exomes 149/1,461,852 · genomes 92/152,304 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.219%	458
Remaining individualsnot grpmax-eligible	0.0544%	1,839
Middle Eastern	0.0495%	2,020
East Asian	0.0223%	4,489
Admixed American	0.02%	5,002
South Asian	0.0154%	6,506
European (non-Finnish)	0.000339%	295,005

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.Pro623=
Coding: c.1869C>T
MANE Select: NM_000179
dbSNP: rs141242295
Type: single nucleotide variant
Location: chr2:47799852 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 623: a UniProt-annotated variant site (in); a UniProt-annotated variant site (in lynch5; uncertain significance; no impairment of heterodimerization with msh2; normal mismatch repair activity)

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: breast cancer Lynch syndrome 5 hereditary neoplastic syndrome

Similar variants

MSH6 p.Pro623Arg Uncertain significance ★★ ⚠ same residue
MSH6 p.Pro623Leu Uncertain significance ★★ ⚠ same residue
MSH6 p.Pro623Ser Uncertain significance ★★ ⚠ same residue
MSH6 p.Pro623Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Pro623His Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Pro623Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Pro623fs Pathogenic/Likely 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-pro623 (accessed [today's date]).

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