Is POLE p.Ala730fs (c.2187_2199delinsGT) pathogenic?

POLE p.Ala730fs (c.21872199delinsGT) is classified Conflicting classifications of pathogenicity in POLE (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-09). Absent from gnomAD; Associated with hereditary neoplastic syndrome.

What condition is associated with POLE p.Ala730fs (c.2187_2199delinsGT)?

POLE p.Ala730fs (c.2187_2199delinsGT) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POLE p.Ala730fs (c.2187_2199delinsGT) in the general population?

POLE p.Ala730fs (c.2187_2199delinsGT) is absent from gnomAD (gnomAD).

POLE p.Ala730fs

c.2187_2199delinsGT · rs1555227130 · VCV484580

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

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 20 of 49
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.1	GERP -0.39, 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.Ala730fs
Coding: c.2187_2199delinsGT
MANE Select: NM_006231
dbSNP: rs1555227130
Type: Indel
Location: chr12:132667623 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 730: an α-helix; 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 c.6531+4_6531+10delinsAGAAGG Uncertain significance ★★ same condition
POLE p.Ala1224Leu Uncertain significance ★★ same condition
POLE p.Asp1954Phe Uncertain significance ★★ same condition
POLE p.Glu926Gln Uncertain significance ★★ same condition
POLE p.Gly1191Ser Uncertain significance ★★ same condition
POLE p.Leu2033His Uncertain significance ★★ same condition
POLE p.Met1197delinsArgSerGlu Uncertain significance ★★ same condition
POLE p.Pro1601Ser 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-ala730fs (accessed [today's date]).

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