Is POLE p.Phe1673del (c.5013CTT[1]) pathogenic?

POLE p.Phe1673del (c.5013CTT[1]) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-16). Very rare (popmax 0.00113%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Phe1673del (c.5013CTT[1])?

POLE p.Phe1673del (c.5013CTT[1]) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Phe1673del (c.5013CTT[1]) in the general population?

POLE p.Phe1673del (c.5013CTT[1]) is very rare (popmax 0.00113%, sas) (gnomAD).

POLE p.Phe1673del

c.5013CTT[1] · rs1555222501 · VCV486093

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00113%, 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 · substitutions only
Constraint at this position
Conservation	phyloP 1.3	phastCons 1

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00113% South Asian · 1/88,436 alleles

Overall 6.26e-05% 1/1,596,800 alleles · very rare exomes 1/1,444,508 · genomes 0/152,292 · 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.Phe1673del
Coding: c.5013CTT[1]
MANE Select: NM_006231
dbSNP: rs1555222501
Type: Microsatellite
Location: chr12:132642332 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1673: an α-helix; 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.Phe1673Val Uncertain significance ★ ⚠ same residue
POLE p.Ala1225dup Uncertain significance ★★ same condition
POLE p.Ala782del Uncertain significance ★★ same condition
POLE p.Asn1843del Uncertain significance ★★ same condition
POLE p.Glu1698del Uncertain significance ★★ same condition
POLE p.Glu1966_Ala1967insGlu Uncertain significance ★★ same condition
POLE p.Glu1969dup Uncertain significance ★★ same condition
POLE p.Ile1145del 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-phe1673del (accessed [today's date]).

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