Is PMS2 p.Arg747Ter (c.2239A>T) pathogenic?

PMS2 p.Arg747Ter (c.2239A>T) is classified Pathogenic in PMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-01). Absent from gnomAD v4.1; Associated with Lynch syndrome.

What condition is associated with PMS2 p.Arg747Ter (c.2239A>T)?

PMS2 p.Arg747Ter (c.2239A>T) is associated with Lynch syndrome, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Arg747Ter (c.2239A>T) in the general population?

PMS2 p.Arg747Ter (c.2239A>T) is absent from gnomAD v4.1 (gnomAD).

How is Lynch syndrome inherited?

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

PMS2 p.Arg747Ter

c.2239A>T · rs1554294448 · VCV504753

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 13 of 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	phastCons 1
Overall
CADD	35.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PMS2
Protein: p.Arg747Ter
Coding: c.2239A>T
MANE Select: NM_000535
dbSNP: rs1554294448
Type: single nucleotide variant
Location: chr7:5978632 (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.Arg747Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Arg747Ile Uncertain significance ★★ same residue
PMS2 p.Arg747Thr Uncertain significance ★★ ⚠ same residue
PMS2 p.Arg747= Benign/Likely benign ★★ 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

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-arg747ter (accessed [today's date]).

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