Is POLE p.Asp490= (c.1470C>T) pathogenic?

POLE p.Asp490= (c.1470C>T) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-02-03). Low-frequency (popmax 2.09%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Asp490= (c.1470C>T)?

POLE p.Asp490= (c.1470C>T) is associated with hereditary neoplastic syndrome, colon carcinoma, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Asp490= (c.1470C>T) in the general population?

POLE p.Asp490= (c.1470C>T) is low-frequency (popmax 2.09%, afr) (gnomAD).

POLE p.Asp490=

c.1470C>T · rs5744777 · VCV220802

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.09%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.82	GERP -1.7
Overall
CADD	1.822	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.09% African / African-American · 1,562/74,682 alleles

Filtering AF 2.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.97%

Overall 0.125% 2,001/1,595,862 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.09%	48
Middle Eastern	0.166%	601
Remaining individualsnot grpmax-eligible	0.158%	632
Admixed American	0.14%	714
European (non-Finnish)	0.02%	4,993
South Asian	0.0143%	6,977
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,500

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.Asp490=
Coding: c.1470C>T
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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colon carcinoma colorectal cancer, susceptibility to, 12

Similar variants

POLE p.Asp490His Uncertain significance ★★ ⚠ same residue
POLE p.Asp490Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Asp490Gly Uncertain significance ★ ⚠ same residue
POLE p.Asp490Glu Uncertain significance ★ ⚠ same residue
POLE p.Asp490Tyr Uncertain significance ★ ⚠ same residue
POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same condition
POLE c.5678+1G>T Pathogenic ★★ same condition
POLE p.Leu424Val Pathogenic ★★ 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-asp490 (accessed [today's date]).

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