Is POLE p.Arg266Pro (c.797G>C) pathogenic?

POLE p.Arg266Pro (c.797G>C) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-19). AlphaMissense: likely pathogenic (0.7503); No allele count reported in gnomAD v4.1 (AN 1,613,104).

How common is POLE p.Arg266Pro (c.797G>C) in the general population?

POLE p.Arg266Pro (c.797G>C) is no allele count reported in gnomAD v4.1 (AN 1,613,104) (gnomAD).

What do computational predictors say about POLE p.Arg266Pro (c.797G>C)?

AlphaMissense predicts likely pathogenic (score 0.7503) — an in-silico prediction, not a clinical call.

POLE p.Arg266Pro

c.797G>C · VCV3613410

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7503 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,104)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7503	likely pathogenic
REVEL	0.42	indeterminate
SaProt	LLR -5.07	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	23.7	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

No allele count reported in gnomAD v4.1 (AN 1,613,104). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: POLE
Protein: p.Arg266Pro
Coding: c.797G>C
MANE Select: NM_006231
Type: single nucleotide variant
Location: chr12:132677367 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB

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

Similar variants

POLE p.Arg266Gln Uncertain significance ★★ same residue
POLE p.Arg266Leu Uncertain significance ★★ ⚠ same residue
POLE p.Arg266Ter Conflicting classifications of pathogenicity ★ same residue
POLE p.Arg266= Likely benign ★ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same type
POLE c.3276-1G>C Likely pathogenic ★★ same type
POLE c.5678+1G>T Pathogenic ★★ same type
POLE p.Gln1763Ter Pathogenic/Likely pathogenic ★★ same type

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-arg266pro (accessed [today's date]).

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