Is POLE p.Phe699fs (c.2091dup) pathogenic?

POLE p.Phe699fs (c.2091dup) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-24). Very rare (popmax 0.00679%, nfe); Associated with colorectal cancer, susceptibility to, 12.

What condition is associated with POLE p.Phe699fs (c.2091dup)?

POLE p.Phe699fs (c.2091dup) is associated with colorectal cancer, susceptibility to, 12, POLD1-related polyposis and colorectal cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Phe699fs (c.2091dup) in the general population?

POLE p.Phe699fs (c.2091dup) is very rare (popmax 0.00679%, nfe) (gnomAD).

POLE p.Phe699fs

c.2091dup · rs752846614 · VCV473509

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00679%, nfe)

Conditions

colorectal cancer, susceptibility to, 12

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 19 of 49
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1	GERP -3.7, phastCons 0.03
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00679% European (non-Finnish) · 80/1,179,000 alleles

Filtering AF 0.00555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00509% 82/1,612,076 alleles · very rare exomes 80/1,459,988 · genomes 2/152,088 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00679%	14,738
Finnishnot grpmax-eligible	0.00156%	63,962
African / African-American	0.00134%	74,824

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.Phe699fs
Coding: c.2091dup
MANE Select: NM_006231
dbSNP: rs752846614
Type: Duplication
Location: chr12:132668437 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 699: a UniProt-annotated variant site (in imagei)

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.Phe699Tyr Uncertain significance ★★ ⚠ same residue
POLE c.802-2dup Uncertain significance ★★ same condition
POLE c.802-7_818dup Uncertain significance ★★ same condition
POLE p.Asp1026_Leu1032dup Uncertain significance ★★ same condition
POLE p.Gln1950_Glu1956dup Uncertain significance ★★ same condition
POLE p.Glu1963_Asn1971dup Uncertain significance ★★ same condition
POLE p.Ile1864dup Uncertain significance ★★ same condition
POLE p.Leu1975_Leu1976insAspLeu 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-phe699fs (accessed [today's date]).

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