POLE p.Thr69=
c.207C>A · rs146986360 · VCV1971827
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.0011%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.28 | acceptor gain · deltas |
|---|---|---|
| Pangolin | Δ0.33 | gain · loss 0.05 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP -0.84 | GERP -3.1 |
| Overall | ||
| CADD | 5.045 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0011%
South Asian · 1/91,034 alleles
Overall
0.000124%
2/1,611,612 alleles · very rare
exomes 2/1,459,422 · genomes 0/152,190 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0011% | 91,034 |
| European (non-Finnish) | 8.49e-05% | 1,177,799 |
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.Thr69=
- Coding
- c.207C>A
- MANE Select
- NM_006231
- dbSNP
- rs146986360
- Type
- single nucleotide variant
- Location
- chr12:132680685 (GRCh38)
- Gene constraint
- LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
- Structure
- AlphaFold pLDDT 80.32 · 18 PDB
- Residue 69
- a β-strand
Similar variants
- POLE p.Thr69Asn Uncertain significance ★★ ⚠ same residue
- POLE p.Thr69Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
- POLE c.1686+32C>G Pathogenic/Likely pathogenic ★★ same type
- POLE c.3276-1G>C Likely pathogenic ★★ same type
- POLE c.5678+1G>T Pathogenic ★★ same type
- POLE p.Gln1763Ter Pathogenic/Likely pathogenic ★★ same type
- POLE p.Leu424Val Pathogenic ★★ same type
- POLE p.Pro436Ser Likely pathogenic ★★ ⚠ same type
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-thr69 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown