Is PMS2 p.Arg665= (c.1995A>G) pathogenic?

PMS2 p.Arg665= (c.1995A>G) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-11). Ultra-rare (popmax 0.0386%, mid); Associated with Lynch syndrome.

What condition is associated with PMS2 p.Arg665= (c.1995A>G)?

PMS2 p.Arg665= (c.1995A>G) is associated with Lynch syndrome, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Arg665= (c.1995A>G) in the general population?

PMS2 p.Arg665= (c.1995A>G) is ultra-rare (popmax 0.0386%, mid) (gnomAD).

How is Lynch syndrome inherited?

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

PMS2 p.Arg665=

c.1995A>G · rs781780543 · VCV186882

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0386%, mid)

Conditions

Lynch syndrome

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 -1.4
Overall
CADD	3.507	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0386% Middle Eastern · 2/5,184 alleles

Filtering AF 0.00683% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.000939% 15/1,597,936 alleles · ultra-rare exomes 14/1,445,768 · genomes 1/152,168 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0386%	2,592
European (non-Finnish)	0.00111%	90,429

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: PMS2
Protein: p.Arg665=
Coding: c.1995A>G
MANE Select: NM_000535
dbSNP: rs781780543
Type: single nucleotide variant
Location: chr7:5986770 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB

Full PMS2 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: Lynch syndrome 4 hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Arg665Thr Uncertain significance ★ ⚠ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.163+2T>C Likely pathogenic ★★★ same condition
PMS2 c.164-2A>G Likely pathogenic ★★★ same condition
PMS2 c.2007-1G>A Likely pathogenic ★★★ same condition
PMS2 c.2174+1G>A Pathogenic ★★★ same condition
PMS2 c.251-2A>G Likely pathogenic ★★★ same condition
PMS2 c.705+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/pms2-p-arg665 (accessed [today's date]).

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