Is POLE p.Gln394Pro (c.1181_1182inv) pathogenic?

POLE p.Gln394Pro (c.11811182inv) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-04-02). Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Gln394Pro (c.1181_1182inv)?

POLE p.Gln394Pro (c.1181_1182inv) is associated with hereditary neoplastic syndrome (ClinVar).

POLE p.Gln394Pro

c.1181_1182inv · VCV1522332

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

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.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.25	GERP 0.76, phastCons 0.98
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic

Variant & gene context

Gene: POLE
Protein: p.Gln394Pro
Coding: c.1181_1182inv
MANE Select: NM_006231
Type: Inversion
Location: chr12:132675442 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 394: a turn

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.Gln394Arg Uncertain significance ★★ same residue
POLE p.Gln394His Uncertain significance ★★ ⚠ same residue
POLE p.Gln394fs Uncertain significance ★ same residue
POLE p.Gln394Ter Conflicting classifications of pathogenicity ★ same residue
POLE p.Glu1241Ser Uncertain significance ★★ same condition
POLE p.Ser2084Leu Uncertain significance ★★ same condition
POLE p.Ala1510Val Conflicting classifications of pathogenicity ★ same condition
POLE p.Gln394Lys Uncertain significance ★ ⚠ same residue

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-gln394pro (accessed [today's date]).

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