Is MSH6 p.Arg385= (c.1153A>C) pathogenic?

MSH6 p.Arg385= (c.1153A>C) is classified Benign/Likely benign in MSH6 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0268%, eas); Associated with mismatch repair cancer syndrome 3.

What condition is associated with MSH6 p.Arg385= (c.1153A>C)?

MSH6 p.Arg385= (c.1153A>C) is associated with mismatch repair cancer syndrome 3, endometrial carcinoma, Lynch syndrome 5 (ClinVar).

How common is MSH6 p.Arg385= (c.1153A>C) in the general population?

MSH6 p.Arg385= (c.1153A>C) is ultra-rare (popmax 0.0268%, eas) (gnomAD).

MSH6 p.Arg385=

Q: How is Constitutional mismatch repair deficiency syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1153A>C · rs781652274 · VCV184833

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, eas)

Conditions

mismatch repair cancer syndrome 3

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 0.38	GERP 0.18, phastCons 0.99
Overall
CADD	10.69	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0268% East Asian · 12/44,848 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00273% 44/1,613,194 alleles · ultra-rare exomes 42/1,461,886 · genomes 2/151,308 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0268%	3,737
Remaining individualsnot grpmax-eligible	0.0032%	31,230
European (non-Finnish)	0.00237%	42,135
Finnishnot grpmax-eligible	0.00156%	64,006
South Asian	0.0011%	91,024

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.Arg385=
Coding: c.1153A>C
MANE Select: NM_000179
dbSNP: rs781652274
Type: single nucleotide variant
Location: chr2:47799136 (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

mismatch repair cancer syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: endometrial carcinoma Lynch syndrome 5 hereditary neoplastic syndrome

For Constitutional mismatch repair deficiency syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

MSH6 p.Arg385Lys Uncertain significance ★★ ⚠ same residue
MSH6 p.Arg385Ser Uncertain significance ★ same residue
MSH6 p.Arg385Thr Uncertain significance ★ ⚠ same residue
MSH6 p.Arg385fs Pathogenic ★★ same residue
MSH6 p.Arg385del Conflicting classifications of pathogenicity ★ same residue
MSH6 p.Arg385Pro Uncertain significance ★ same residue
MSH6 p.Arg385Trp Uncertain significance ★ ⚠ 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-arg385 (accessed [today's date]).

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