Is POLE p.Lys391del (c.1171_1173del) pathogenic?

POLE p.Lys391del (c.11711173del) is classified Uncertain significance in POLE (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-19). Very rare (popmax 0.00873%, nfe); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Lys391del (c.1171_1173del)?

POLE p.Lys391del (c.1171_1173del) is associated with colorectal cancer, susceptibility to, 12, POLD1-related polyposis and colorectal cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Lys391del (c.1171_1173del) in the general population?

POLE p.Lys391del (c.1171_1173del) is very rare (popmax 0.00873%, nfe) (gnomAD).

POLE p.Lys391del

c.1171_1173del · rs753999122 · VCV240380

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00873%, nfe)

Conditions

colorectal cancer, susceptibility to, 12

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 7.7	GERP 1.9, phastCons 1
Overall
CADD	18.55	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00873% European (non-Finnish) · 103/1,180,036 alleles

Filtering AF 0.00733% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00684%

Overall 0.00651% 105/1,614,084 alleles · very rare exomes 101/1,461,876 · genomes 4/152,208 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00873%	11,457
African / African-American	0.00267%	37,467

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.Lys391del
Coding: c.1171_1173del
MANE Select: NM_006231
dbSNP: rs753999122
Type: Deletion
Location: chr12:132675451 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB

Full POLE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

colorectal cancer, susceptibility to, 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: POLD1-related polyposis and colorectal cancer syndrome hereditary neoplastic syndrome

Similar variants

POLE p.Lys391Glu Uncertain significance ★★ ⚠ same residue
POLE p.Lys391= Benign/Likely benign ★★ same residue
POLE p.Phe48fs Pathogenic/Likely pathogenic ★★ same condition
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-lys391del (accessed [today's date]).

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