Is POLE p.Asp490Glu (c.1470C>A) pathogenic?

POLE p.Asp490Glu (c.1470C>A) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-15). AlphaMissense: likely pathogenic (0.9246); Very rare (popmax 6.93e-05%).

How common is POLE p.Asp490Glu (c.1470C>A) in the general population?

POLE p.Asp490Glu (c.1470C>A) is very rare (popmax 6.93e-05%) (gnomAD).

What do computational predictors say about POLE p.Asp490Glu (c.1470C>A)?

AlphaMissense predicts likely pathogenic (score 0.9246) — an in-silico prediction, not a clinical call.

POLE p.Asp490Glu

c.1470C>A · rs5744777 · VCV1056930

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9246 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.93e-05%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9246	likely pathogenic
REVEL	0.289	benign-leaning
SaProt	LLR -9.07	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 -0.82	GERP -1.7
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	7.424	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 6.93e-05%

Overall 6.93e-05% 1/1,443,544 alleles · very rare

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.Asp490Glu
Coding: c.1470C>A
MANE Select: NM_006231
dbSNP: rs5744777
Type: single nucleotide variant
Location: chr12:132673167 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 490: an α-helix

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

Similar variants

POLE p.Asp490His Uncertain significance ★★ ⚠ same residue
POLE p.Asp490= Benign/Likely benign ★★ same residue
POLE p.Asp490Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Asp490Gly Uncertain significance ★ ⚠ same residue
POLE p.Asp490Tyr Uncertain significance ★ ⚠ same residue
POLE p.Asp490fs 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-asp490glu (accessed [today's date]).

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