Is POLE p.Asp1709= (c.5127T>C) pathogenic?

POLE p.Asp1709= (c.5127T>C) is classified Likely benign in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-24). Very rare (popmax 0.00111%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Asp1709= (c.5127T>C)?

POLE p.Asp1709= (c.5127T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Asp1709= (c.5127T>C) in the general population?

POLE p.Asp1709= (c.5127T>C) is very rare (popmax 0.00111%, sas) (gnomAD).

POLE p.Asp1709=

c.5127T>C · rs2541883448 · VCV2956926

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.21	phastCons 0.003
Overall
CADD	0.179	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% South Asian · 1/90,036 alleles

Overall 0.000124% 2/1,608,448 alleles · very rare exomes 2/1,456,114 · genomes 0/152,334 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	90,036
European (non-Finnish)	8.49e-05%	1,177,232

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.Asp1709=
Coding: c.5127T>C
MANE Select: NM_006231
dbSNP: rs2541883448
Type: single nucleotide variant
Location: chr12:132642223 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1709: 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.Asp1709Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Asp1709Tyr 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
POLE c.1226+3A>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-asp1709 (accessed [today's date]).

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