Is POLE p.Ile1585Phe (c.4753A>T) pathogenic?

POLE p.Ile1585Phe (c.4753A>T) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-28). AlphaMissense: ambiguous (0.3997); Absent from gnomAD v4.1.

How common is POLE p.Ile1585Phe (c.4753A>T) in the general population?

POLE p.Ile1585Phe (c.4753A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POLE p.Ile1585Phe (c.4753A>T)?

AlphaMissense predicts ambiguous (score 0.3997) — an in-silico prediction, not a clinical call.

POLE p.Ile1585Phe

c.4753A>T · VCV4740935

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3997 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3997	ambiguous
REVEL	0.163	moderately benign-leaning
SaProt	LLR -8.74	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.008	phastCons 0.14
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic
Overall
CADD	12.32	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.Ile1585Phe
Coding: c.4753A>T
MANE Select: NM_006231
Type: single nucleotide variant
Location: chr12:132642705 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1585: a β-strand; a UniProt-annotated variant site (in imagei)

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

Similar variants

POLE p.Ile1585Asn Uncertain significance ★★ ⚠ same residue
POLE p.Ile1585Thr Uncertain significance ★★ ⚠ same residue
POLE p.Ile1585Val Uncertain significance ★★ ⚠ same residue
POLE p.Ile1585= Benign/Likely benign ★★ same residue
POLE p.Ile1585Met Uncertain significance ★ ⚠ same residue
POLE p.Ile1585fs Pathogenic ★ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same type
POLE c.3276-1G>C 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-ile1585phe (accessed [today's date]).

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