Is POLE p.Ala566Pro (c.1696G>C) pathogenic?

POLE p.Ala566Pro (c.1696G>C) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-18). AlphaMissense: likely pathogenic (0.9486); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ala566Pro (c.1696G>C)?

POLE p.Ala566Pro (c.1696G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ala566Pro (c.1696G>C) in the general population?

POLE p.Ala566Pro (c.1696G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POLE p.Ala566Pro (c.1696G>C)?

AlphaMissense predicts likely pathogenic (score 0.9486) — an in-silico prediction, not a clinical call.

POLE p.Ala566Pro

c.1696G>C · rs773813430 · VCV3225399

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9486 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9486	likely pathogenic
REVEL	0.504	indeterminate
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.37	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 0.61, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	32.0	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.Ala566Pro
Coding: c.1696G>C
MANE Select: NM_006231
dbSNP: rs773813430
Type: single nucleotide variant
Location: chr12:132672313 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 566: an α-helix

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.Ala566Asp Uncertain significance ★★ ⚠ same residue
POLE p.Ala566Thr Uncertain significance ★★ same residue
POLE p.Ala566Val Uncertain significance ★★ same residue
POLE p.Ala566= 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-ala566pro (accessed [today's date]).

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