Is POLE p.Asp490His (c.1468G>C) pathogenic?

POLE p.Asp490His (c.1468G>C) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-03). AlphaMissense: likely pathogenic (0.9944); Very rare (popmax 0.00446%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Asp490His (c.1468G>C)?

POLE p.Asp490His (c.1468G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Asp490His (c.1468G>C) in the general population?

POLE p.Asp490His (c.1468G>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about POLE p.Asp490His (c.1468G>C)?

AlphaMissense predicts likely pathogenic (score 0.9944) — an in-silico prediction, not a clinical call.

POLE p.Asp490His

c.1468G>C · rs755463796 · VCV1472997

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9944	likely pathogenic · top 6% in POLE
REVEL	0.488	indeterminate
SaProt	LLR -8.90	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 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	24.4	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 0.00446% East Asian · 2/44,812 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000125% 2/1,598,778 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.Asp490His
Coding: c.1468G>C
MANE Select: NM_006231
dbSNP: rs755463796
Type: single nucleotide variant
Location: chr12:132673169 (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

Similar variants

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.Asp490Glu Uncertain significance ★ ⚠ same residue
POLE p.Asp490Tyr Uncertain significance ★ ⚠ 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

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-asp490his (accessed [today's date]).

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