Is PMS2 p.Pro484Arg (c.1451C>G) pathogenic?

PMS2 p.Pro484Arg (c.1451C>G) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-01). AlphaMissense: likely benign (0.0639); Very rare (popmax 8.47e-05%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Pro484Arg (c.1451C>G)?

PMS2 p.Pro484Arg (c.1451C>G) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome, mismatch repair cancer syndrome 4 (ClinVar).

How common is PMS2 p.Pro484Arg (c.1451C>G) in the general population?

PMS2 p.Pro484Arg (c.1451C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PMS2 p.Pro484Arg (c.1451C>G)?

AlphaMissense predicts likely benign (score 0.0639) — an in-silico prediction, not a clinical call.

PMS2 p.Pro484Arg

c.1451C>G · rs1583319873 · VCV654473

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0639 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.0639	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -5.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	0.005	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,994 alleles

Overall 6.2e-05% 1/1,614,090 alleles · very rare exomes 1/1,461,840 · genomes 0/152,250 · joint denominator

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.Pro484Arg
Coding: c.1451C>G
MANE Select: NM_000535
dbSNP: rs1583319873
Type: single nucleotide variant
Location: chr7:5987314 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 484: the 'disordered' region

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

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome mismatch repair cancer syndrome 4

Similar variants

PMS2 p.Pro484Ser Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro484Thr Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro484Ala Uncertain significance ★ ⚠ same residue
PMS2 p.Pro484His Uncertain significance ★ ⚠ same residue
PMS2 p.Pro484= Likely benign ★ same residue
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-pro484arg (accessed [today's date]).

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