Is POLE p.Pro2282fs (c.6845del) pathogenic?

POLE p.Pro2282fs (c.6845del) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-28). Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Pro2282fs (c.6845del)?

POLE p.Pro2282fs (c.6845del) is associated with hereditary neoplastic syndrome (ClinVar).

POLE p.Pro2282fs

c.6845del · VCV4671898

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	escapes	premature termination codon in the last exon (49 of 49) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.086	phastCons 0.01

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

Variant & gene context

Gene: POLE
Protein: p.Pro2282fs
Coding: c.6845del
MANE Select: NM_006231
Type: Deletion
Location: chr12:132624713 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 2282: 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.Pro2282Arg Uncertain significance ★★ ⚠ same residue
POLE p.Pro2282Leu Uncertain significance ★★ ⚠ same residue
POLE p.Pro2282Thr Uncertain significance ★★ ⚠ same residue
POLE c.1359+4_1359+74del Uncertain significance ★★ same condition
POLE c.206_211delCCGAGA Uncertain significance ★★ same condition
POLE c.3459+4del Uncertain significance ★★ same condition
POLE p.Ala1288_Leu1295del Uncertain significance ★★ same condition
POLE p.Gln1950_Glu1956del 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-pro2282fs (accessed [today's date]).

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