Is POLE p.Ala1510Val (c.4529_4530inv) pathogenic?

POLE p.Ala1510Val (c.45294530inv) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-21). Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ala1510Val (c.4529_4530inv)?

POLE p.Ala1510Val (c.4529_4530inv) is associated with hereditary neoplastic syndrome (ClinVar).

POLE p.Ala1510Val

c.4529_4530inv · VCV576750

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

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 · substitutions only
Constraint at this position
Conservation	phyloP -12	GERP -3.5
Regional constraint	o/e 0.92	unconstrained · MANE · 36 kb · p 0.001 · regional, not allelic

Variant & gene context

Gene: POLE
Protein: p.Ala1510Val
Coding: c.4529_4530inv
MANE Select: NM_006231
Type: Inversion
Location: chr12:132643245 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1510: a β-strand; a UniProt-annotated variant site (in imagei)

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.Ala1510= Benign ★★ same residue
POLE p.Gln394Pro Uncertain significance ★★ same condition
POLE p.Glu1241Ser Uncertain significance ★★ same condition
POLE p.Ser2084Leu Uncertain significance ★★ same condition
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-ala1510val (accessed [today's date]).

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