Is POLE p.Ala428fs (c.1281dup) pathogenic?

POLE p.Ala428fs (c.1281dup) is classified Pathogenic in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-11). No gnomAD frequency available for this variant.

How common is POLE p.Ala428fs (c.1281dup) in the general population?

POLE p.Ala428fs (c.1281dup) is no gnomAD frequency available for this variant (gnomAD).

POLE p.Ala428fs

c.1281dup · rs2542146457 · VCV2711238

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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 13 of 49
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1

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.Ala428fs
Coding: c.1281dup
MANE Select: NM_006231
dbSNP: rs2542146457
Type: Duplication
Location: chr12:132673652 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 428: an α-helix

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

Similar variants

POLE p.Ala428= Benign/Likely benign ★★ same residue
POLE p.Ala428Pro Uncertain significance ★ ⚠ same residue
POLE p.Ala428Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE c.802-2dup Uncertain significance ★★ same type
POLE c.802-7_818dup Uncertain significance ★★ same type
POLE p.Asp1026_Leu1032dup Uncertain significance ★★ same type
POLE p.Gln1950_Glu1956dup Uncertain significance ★★ same type
POLE p.Glu1963_Asn1971dup Uncertain significance ★★ same type

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-ala428fs (accessed [today's date]).

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