Is POLE p.Phe366fs (c.1097_1098insAA) pathogenic?

POLE p.Phe366fs (c.10971098insAA) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Phe366fs (c.1097_1098insAA)?

POLE p.Phe366fs (c.1097_1098insAA) is associated with hereditary neoplastic syndrome (ClinVar).

POLE p.Phe366fs

c.1097_1098insAA · VCV3781555

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 49
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP -1.2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: POLE
Protein: p.Phe366fs
Coding: c.1097_1098insAA
MANE Select: NM_006231
Type: Insertion
Location: chr12:132675743 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 366: an α-helix

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.Phe366= Benign/Likely benign ★★ same residue
POLE p.Phe366Cys Uncertain significance ★ same residue
POLE p.Phe366_Phe367insTer Pathogenic ★ same residue
POLE p.Glu714fs Uncertain significance ★ same condition
POLE p.Gly14fs Conflicting classifications of pathogenicity ★ same condition
POLE p.Gly1620fs Conflicting classifications of pathogenicity ★ same condition
POLE p.Ser117fs Uncertain significance ★ same condition
POLE p.Trp1013Ter 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-phe366fs (accessed [today's date]).

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