Is POLE p.Pro1205fs (c.3612dup) pathogenic?

POLE p.Pro1205fs (c.3612dup) is classified Uncertain significance in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-05). No gnomAD frequency available for this variant; Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Pro1205fs (c.3612dup)?

POLE p.Pro1205fs (c.3612dup) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Pro1205fs (c.3612dup) in the general population?

POLE p.Pro1205fs (c.3612dup) is no gnomAD frequency available for this variant (gnomAD).

POLE p.Pro1205fs

c.3612dup · rs1555224123 · VCV486970

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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 30 of 49
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.1	GERP 0.81, phastCons 0.98

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: POLE
Protein: p.Pro1205fs
Coding: c.3612dup
MANE Select: NM_006231
dbSNP: rs1555224123
Type: Duplication
Location: chr12:132649859 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1205: 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.Pro1205= Benign/Likely benign ★★ same residue
POLE p.Pro1205Ala Uncertain significance ★ ⚠ same residue
POLE p.Pro1205Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Pro1205Leu Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro1205fs (accessed [today's date]).

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