Is POLE p.Arg1631Pro (c.4892G>C) pathogenic?

POLE p.Arg1631Pro (c.4892G>C) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-26). AlphaMissense: likely pathogenic (0.7286); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Arg1631Pro (c.4892G>C)?

POLE p.Arg1631Pro (c.4892G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Arg1631Pro (c.4892G>C) in the general population?

POLE p.Arg1631Pro (c.4892G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POLE p.Arg1631Pro (c.4892G>C)?

AlphaMissense predicts likely pathogenic (score 0.7286) — an in-silico prediction, not a clinical call.

POLE p.Arg1631Pro

c.4892G>C · rs775590365 · VCV1743868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7286 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7286	likely pathogenic
REVEL	0.225	benign-leaning
SaProt	LLR -12.11	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.84	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	18.67	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

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: POLE
Protein: p.Arg1631Pro
Coding: c.4892G>C
MANE Select: NM_006231
dbSNP: rs775590365
Type: single nucleotide variant
Location: chr12:132642566 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1631: an α-helix; a UniProt-annotated variant site (in imagei)

Full POLE 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

Similar variants

POLE p.Arg1631Cys Uncertain significance ★★ ⚠ same residue
POLE p.Arg1631Gly Uncertain significance ★★ ⚠ same residue
POLE p.Arg1631Leu Uncertain significance ★★ ⚠ same residue
POLE p.Arg1631Ser Uncertain significance ★★ ⚠ same residue
POLE p.Arg1631His Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Arg1631= Likely benign ★ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE p.Leu424Val 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/pole-p-arg1631pro (accessed [today's date]).

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