Is PMS2 p.Pro152Arg (c.455C>G) pathogenic?

PMS2 p.Pro152Arg (c.455C>G) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.2278); Ultra-rare (popmax 0.0167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Pro152Arg (c.455C>G)?

PMS2 p.Pro152Arg (c.455C>G) is associated with hereditary neoplastic syndrome, Lynch syndrome 4, mismatch repair cancer syndrome 4 (ClinVar).

How common is PMS2 p.Pro152Arg (c.455C>G) in the general population?

PMS2 p.Pro152Arg (c.455C>G) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about PMS2 p.Pro152Arg (c.455C>G)?

AlphaMissense predicts likely benign (score 0.2278) — an in-silico prediction, not a clinical call.

PMS2 p.Pro152Arg

c.455C>G · rs876660161 · VCV233056

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2278 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2278	likely benign
REVEL	0.345	indeterminate
SaProt	LLR -10.88	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Admixed American · 10/59,982 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.000745% 12/1,611,650 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,998
South Asian	0.0011%	90,980
European (non-Finnish)	8.48e-05%	1,179,690

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.Pro152Arg
Coding: c.455C>G
MANE Select: NM_000535
dbSNP: rs876660161
Type: single nucleotide variant
Location: chr7:6002535 (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

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

Also linked: Lynch syndrome 4 mismatch repair cancer syndrome 4

Similar variants

PMS2 p.Pro152= Likely benign ★★ same residue
PMS2 p.Pro152Thr 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.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-pro152arg (accessed [today's date]).

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