Is POLE p.Asp339= (c.1017T>C) pathogenic?

POLE p.Asp339= (c.1017T>C) is classified Benign/Likely benign in POLE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-07). Very rare (popmax 0.00223%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Asp339= (c.1017T>C)?

POLE p.Asp339= (c.1017T>C) is associated with hereditary neoplastic syndrome, colorectal cancer, susceptibility to, 12 (ClinVar).

How common is POLE p.Asp339= (c.1017T>C) in the general population?

POLE p.Asp339= (c.1017T>C) is very rare (popmax 0.00223%, sas) (gnomAD).

POLE p.Asp339=

c.1017T>C · rs756833644 · VCV818269

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, sas)

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 0.18	GERP -0.47, phastCons 0.2
Overall
CADD	2.114	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% South Asian · 2/89,786 alleles

Filtering AF 0.00037% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000138%

Overall 0.000208% 3/1,445,022 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00223%	44,893
European (non-Finnish)	8.56e-05%	1,168,273

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.Asp339=
Coding: c.1017T>C
MANE Select: NM_006231
dbSNP: rs756833644
Type: single nucleotide variant
Location: chr12:132676097 (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

Also linked: colorectal cancer, susceptibility to, 12

Similar variants

POLE p.Asp339Tyr Uncertain significance ★★ ⚠ same residue
POLE p.Asp339Val Uncertain significance ★★ ⚠ same residue
POLE p.Asp339Ala Uncertain significance ★ same residue
POLE p.Asp339Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Asp339Gly 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-asp339 (accessed [today's date]).

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