Is PMS2 p.Arg151Pro (c.452G>C) pathogenic?

PMS2 p.Arg151Pro (c.452G>C) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-04-29). AlphaMissense: likely pathogenic (0.979); Absent from gnomAD v4.1; Associated with Lynch syndrome 4.

What condition is associated with PMS2 p.Arg151Pro (c.452G>C)?

PMS2 p.Arg151Pro (c.452G>C) is associated with Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Arg151Pro (c.452G>C) in the general population?

PMS2 p.Arg151Pro (c.452G>C) 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.

What do computational predictors say about PMS2 p.Arg151Pro (c.452G>C)?

AlphaMissense predicts likely pathogenic (score 0.979) — an in-silico prediction, not a clinical call.

PMS2 p.Arg151Pro

c.452G>C · rs35629870 · VCV979105

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.979 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Lynch syndrome 4

Computational evidence

Protein change
AlphaMissense	0.979	likely pathogenic · top 8% in PMS2
REVEL	0.575	indeterminate
SaProt	LLR -14.46	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Arg151Pro
Coding: c.452G>C
MANE Select: NM_000535
dbSNP: rs35629870
Type: single nucleotide variant
Location: chr7:6002538 (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 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Arg151Cys Uncertain significance ★★ ⚠ same residue
PMS2 p.Arg151Ser Uncertain significance ★★ ⚠ same residue
PMS2 p.Arg151Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Arg151His Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Arg151Leu Uncertain significance ★ ⚠ same residue
PMS2 p.Arg151= Likely benign ★ same residue
PMS2 p.Arg151fs Pathogenic ★★ same residue
PMS2 c.1144+2T>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-arg151pro (accessed [today's date]).

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