Is POLE p.Ala1751= (c.5253C>T) pathogenic?

POLE p.Ala1751= (c.5253C>T) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-23). Very rare (popmax 0.00668%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ala1751= (c.5253C>T)?

POLE p.Ala1751= (c.5253C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ala1751= (c.5253C>T) in the general population?

POLE p.Ala1751= (c.5253C>T) is very rare (popmax 0.00668%, afr) (gnomAD).

POLE p.Ala1751=

c.5253C>T · rs765888059 · VCV413515

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

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 -5.7
Overall
CADD	1.195	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% African / African-American · 5/74,890 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00137% 22/1,609,674 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,978
Finnishnot grpmax-eligible	0.00334%	29,901
East Asian	0.00223%	44,884
European (non-Finnish)	0.0011%	90,767
South Asian	0.0011%	91,076

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.Ala1751=
Coding: c.5253C>T
MANE Select: NM_006231
dbSNP: rs765888059
Type: single nucleotide variant
Location: chr12:132641772 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1751: 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.Ala1751Val Uncertain significance ★★ ⚠ same residue
POLE p.Ala1751Ser Uncertain significance ★ ⚠ same residue
POLE p.Ala1751Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Ala1751Asp 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

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-ala1751 (accessed [today's date]).

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