Is AP4E1 p.Glu520fs (c.1558dup) pathogenic?

AP4E1 p.Glu520fs (c.1558dup) is classified Likely pathogenic in AP4E1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). No gnomAD frequency available for this variant; Associated with hereditary spastic paraplegia 51.

What condition is associated with AP4E1 p.Glu520fs (c.1558dup)?

AP4E1 p.Glu520fs (c.1558dup) is associated with hereditary spastic paraplegia 51 (ClinVar).

How common is AP4E1 p.Glu520fs (c.1558dup) in the general population?

AP4E1 p.Glu520fs (c.1558dup) is no gnomAD frequency available for this variant (gnomAD).

AP4E1 p.Glu520fs

Q: How is Severe intellectual disability and progressive spastic paraplegia inherited?

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

c.1558dup · rs2504796812 · VCV1709784

Likely pathogenic Single submitter

Classification

Likely pathogenic

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 spastic paraplegia 51

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 14 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.1	GERP -2.9, phastCons 0.99

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: AP4E1
Protein: p.Glu520fs
Coding: c.1558dup
MANE Select: NM_007347
dbSNP: rs2504796812
Type: Duplication
Location: chr15:50958497 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.42 · 4 PDB

Full AP4E1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 51 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe intellectual disability and progressive spastic paraplegia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

AP4E1 c.3096-57dup Benign ★★ same condition
AP4E1 c.942_943+3delinsCC Pathogenic/Likely pathogenic ★★ same condition
AP4E1 p.Arg1105Ter Pathogenic ★★ same condition
AP4E1 p.His128Tyr Uncertain significance ★★ ⚠ same condition
AP4E1 p.Lys181Gln Uncertain significance ★★ ⚠ same condition
AP4E1 p.Pro717Ser Uncertain significance ★★ ⚠ same condition
AP4E1 p.Thr559Pro Uncertain significance ★★ ⚠ same condition
AP4E1 p.Thr911Ala 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/ap4e1-p-glu520fs (accessed [today's date]).

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