Is MSH2 p.Arg389Ter (c.1165C>T) pathogenic?

MSH2 p.Arg389Ter (c.1165C>T) is classified Pathogenic in MSH2 (ClinVar, Expert panel, 28 submitters; last evaluated 2013-09-05). Very rare (popmax 0.000424%, nfe); Associated with Lynch syndrome.

What condition is associated with MSH2 p.Arg389Ter (c.1165C>T)?

MSH2 p.Arg389Ter (c.1165C>T) is associated with Lynch syndrome, gastric cancer, colon carcinoma (ClinVar).

How common is MSH2 p.Arg389Ter (c.1165C>T) in the general population?

MSH2 p.Arg389Ter (c.1165C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

How is Lynch syndrome inherited?

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

MSH2 p.Arg389Ter

c.1165C>T · rs587779075 · VCV90557

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 28 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

Lynch syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 7 of 16
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.3	GERP -0.33, phastCons 0.99
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,002 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,614,058 alleles · very rare exomes 6/1,461,840 · genomes 0/152,218 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)grpmax	0.000424%	236,000

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MSH2
Protein: p.Arg389Ter
Coding: c.1165C>T
MANE Select: NM_000251
dbSNP: rs587779075
Type: single nucleotide variant
Location: chr2:47429830 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 389: an α-helix

Full MSH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Lynch syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: gastric cancer colon carcinoma Lynch syndrome 1 mismatch repair cancer syndrome 1 hereditary neoplastic syndrome mismatch repair cancer syndrome 2

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH2 p.Arg389Leu Uncertain significance ★★ ⚠ same residue
MSH2 p.Arg389= Benign/Likely benign ★★ same residue
MSH2 p.Arg389Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Arg389Pro Uncertain significance ★ ⚠ same residue
MSH2 p.Arg389fs Pathogenic ★★ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>C 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/msh2-p-arg389ter (accessed [today's date]).

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