Is POLE p.Ala1778fs (c.5332del) pathogenic?

POLE p.Ala1778fs (c.5332del) is classified Pathogenic in POLE (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). Associated with facial dysmorphism-immunodeficiency-livedo-short stature syndrome.

What condition is associated with POLE p.Ala1778fs (c.5332del)?

POLE p.Ala1778fs (c.5332del) is associated with facial dysmorphism-immunodeficiency-livedo-short stature syndrome (ClinVar).

POLE p.Ala1778fs

Q: How is Facial dysmorphism-immunodeficiency-livedo-short stature syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.5332del · VCV3765549

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

facial dysmorphism-immunodeficiency-livedo-short stature 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 39 of 49
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.8	phastCons 0.16

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

Variant & gene context

Gene: POLE
Protein: p.Ala1778fs
Coding: c.5332del
MANE Select: NM_006231
Type: Deletion
Location: chr12:132641693 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.32 · 18 PDB
Residue 1778: a UniProt-annotated variant site (in imagei)

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

Disease context

facial dysmorphism-immunodeficiency-livedo-short stature syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

POLE p.Phe48fs Pathogenic/Likely pathogenic ★★ same condition
POLE c.2865-4del Benign/Likely benign ★★ same condition
POLE c.2865-5_2865-4del Benign/Likely benign ★★ same condition
POLE p.Ala1778= Benign ★★ same residue
POLE p.Ala1778Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Ala1778Val Conflicting classifications of pathogenicity ★ ⚠ same residue
POLE p.Ala2030fs Conflicting classifications of pathogenicity ★ same condition
POLE p.Glu537fs Conflicting classifications of pathogenicity ★ 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-ala1778fs (accessed [today's date]).

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