Is POLE p.Arg1879Pro (c.5636G>C) pathogenic?

POLE p.Arg1879Pro (c.5636G>C) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-25). AlphaMissense: likely pathogenic (0.6368); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Arg1879Pro (c.5636G>C)?

POLE p.Arg1879Pro (c.5636G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Arg1879Pro (c.5636G>C) in the general population?

POLE p.Arg1879Pro (c.5636G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about POLE p.Arg1879Pro (c.5636G>C)?

AlphaMissense predicts likely pathogenic (score 0.6368) — an in-silico prediction, not a clinical call.

POLE p.Arg1879Pro

c.5636G>C · rs145621558 · VCV644756

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6368 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.6368	likely pathogenic
REVEL	0.224	benign-leaning
SaProt	LLR -9.88	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.41	phastCons 0.028
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	19.11	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 8.47e-05% European (non-Finnish) · 1/1,179,974 alleles

Overall 6.2e-05% 1/1,614,062 alleles · very rare exomes 1/1,461,816 · genomes 0/152,246 · 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: POLE
Protein: p.Arg1879Pro
Coding: c.5636G>C
MANE Select: NM_006231
dbSNP: rs145621558
Type: single nucleotide variant
Location: chr12:132638056 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1879: 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.Arg1879Cys Uncertain significance ★★ ⚠ same residue
POLE p.Arg1879Leu Uncertain significance ★★ ⚠ same residue
POLE p.Arg1879His Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Arg1879= Likely benign ★ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ same condition
POLE c.1020+5G>A Uncertain significance ★★ same condition
POLE c.1106+3G>C Uncertain significance ★★ 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-arg1879pro (accessed [today's date]).

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