Is PMS2 p.Arg451= (c.1353G>A) pathogenic?

PMS2 p.Arg451= (c.1353G>A) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-18). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Arg451= (c.1353G>A)?

PMS2 p.Arg451= (c.1353G>A) is associated with hereditary neoplastic syndrome, Lynch syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Arg451= (c.1353G>A) in the general population?

PMS2 p.Arg451= (c.1353G>A) is absent from gnomAD v4.1 (gnomAD).

PMS2 p.Arg451=

c.1353G>A · VCV3387512

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.23	donor gain · deltas
Pangolin	Δ0.39	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.84
Overall
CADD	5.591	PHRED · no single calibrated threshold — expert panels disagree

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.Arg451=
Coding: c.1353G>A
MANE Select: NM_000535
Type: single nucleotide variant
Location: chr7:5987412 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 451: the 'disordered' region

Full PMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: Lynch syndrome Lynch syndrome 4

Similar variants

PMS2 p.Arg451Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Arg451Thr Uncertain significance ★★ ⚠ same residue
PMS2 p.Arg451Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Arg451fs Likely pathogenic ★ same residue
PMS2 p.Arg451Ser 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

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-arg451 (accessed [today's date]).

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