Is POLE c.285+13C>A pathogenic?

POLE c.285+13C>A is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). Rare (popmax 0.395%, eas); Associated with POLE-related polyposis and colorectal cancer syndrome.

How common is POLE c.285+13C>A in the general population?

POLE c.285+13C>A is rare (popmax 0.395%, eas) (gnomAD).

How is Polymerase proofreading-related polyposis inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

POLE c.285+13C>A

Q: What condition is associated with POLE c.285+13C>A?

POLE c.285+13C>A is associated with POLE-related polyposis and colorectal cancer syndrome, hereditary neoplastic syndrome (ClinVar).

rs76960367 · VCV386826

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.395%, eas)

Conditions

POLE-related polyposis and colorectal cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +13	near-intronic (+13 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.94	GERP -3, phastCons 0.001
Non-coding constraint	Z 3.05	1 kb window · o/e 0.80 · regional · uncalibrated
Overall
CADD	4.103	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.395% East Asian · 177/44,856 alleles

Filtering AF 0.347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.329%

Overall 0.0125% 201/1,608,536 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.395%	253
Middle Eastern	0.0165%	6,050
Remaining individualsnot grpmax-eligible	0.0128%	7,785
South Asian	0.0099%	10,106
Admixed American	0.005%	20,005
European (non-Finnish)	0.000255%	391,641

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
Coding: c.285+13C>A
MANE Select: NM_006231
dbSNP: rs76960367
Type: single nucleotide variant
Location: chr12:132680594 (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

Also linked: hereditary neoplastic syndrome

For Polymerase proofreading-related polyposis (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

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
POLE c.1226+3A>G Uncertain significance ★★ same condition
POLE c.1359+4C>A Uncertain significance ★★ same condition
POLE c.1474-3C>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-c-285-plus-13c-a (accessed [today's date]).

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