Is POLE p.Gln520= (c.1560A>G) pathogenic?

POLE p.Gln520= (c.1560A>G) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Rare (popmax 0.112%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Gln520= (c.1560A>G)?

POLE p.Gln520= (c.1560A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Gln520= (c.1560A>G) in the general population?

POLE p.Gln520= (c.1560A>G) is rare (popmax 0.112%, amr) (gnomAD).

POLE p.Gln520=

c.1560A>G · rs201841065 · VCV413505

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.112%, amr)

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 0.42	GERP -3.7, phastCons 1
Overall
CADD	9.489	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.112% Admixed American · 67/60,026 alleles

Filtering AF 0.0901% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0823%

Overall 0.00427% 69/1,614,160 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.112%	896
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)	8.47e-05%	1,180,027

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.Gln520=
Coding: c.1560A>G
MANE Select: NM_006231
dbSNP: rs201841065
Type: single nucleotide variant
Location: chr12:132672753 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB

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.Gln520Arg Uncertain significance ★★ ⚠ same residue
POLE p.Gln520Pro Uncertain significance ★★ ⚠ same residue
POLE p.Gln520Leu 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
POLE c.1106+3G>C Uncertain significance ★★ same condition
POLE c.1106+4A>G 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-gln520 (accessed [today's date]).

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