Is POLE p.Thr1689= (c.5067A>G) pathogenic?

POLE p.Thr1689= (c.5067A>G) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-04). Very rare (popmax 0.00134%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Thr1689= (c.5067A>G)?

POLE p.Thr1689= (c.5067A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Thr1689= (c.5067A>G) in the general population?

POLE p.Thr1689= (c.5067A>G) is very rare (popmax 0.00134%, afr) (gnomAD).

POLE p.Thr1689=

c.5067A>G · rs1256621322 · VCV484564

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.81	acceptor loss · deltas
Constraint at this position
Conservation	phyloP -14
Overall
CADD	0.572	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,590 alleles

Overall 6.22e-05% 1/1,608,680 alleles · very rare exomes 0/1,456,598 · genomes 1/152,082 · joint denominator

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.Thr1689=
Coding: c.5067A>G
MANE Select: NM_006231
dbSNP: rs1256621322
Type: single nucleotide variant
Location: chr12:132642283 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1689: a β-strand; 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.Thr1689fs Conflicting classifications of pathogenicity ★ same residue
POLE p.Thr1689Ile 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-thr1689 (accessed [today's date]).

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