Hereditary spastic paraplegia 51

Summary

Hereditary spastic paraplegia 51 (MONDO:0013401) is a disease caused by AP4E1 (GenCC Definitive), with 1 cohort gene and 2 clinical trials.

At a glance

• Causal gene: AP4E1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 44
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 51
Mondo ID	MONDO:0013401
OMIM	613744
DOID	DOID:0110803
UMLS	C3151056
MedGen	462406
GARD	0013737
NORD	1990
Is cancer (heuristic)	no

Also known as: AP4E1 hereditary spastic paraplegia · cerebral palsy, spastic quadriplegic, 4 · hereditary spastic paraplegia caused by mutation in AP4E1 · hereditary spastic paraplegia type 51 · Spastic Paraplegia 51 · spastic paraplegia 51, autosomal recessive · SPG51

Data availability: 44 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › palsy › paraplegia › hereditary spastic paraplegia › hereditary spastic paraplegia 51

Related subtypes (44): hereditary spastic paraplegia 3A, hereditary spastic paraplegia 4, mast syndrome, hereditary spastic paraplegia 5A, hereditary spastic paraplegia 16, hereditary spastic paraplegia 2, macrocephaly-spastic paraplegia-dysmorphism syndrome, Charcot-Marie-Tooth disease type 5, hereditary spastic paraplegia 6, hereditary spastic paraplegia 10, hereditary spastic paraplegia 14, hereditary spastic paraplegia 13, hereditary spastic paraplegia 7, hereditary spastic paraplegia 33, hereditary spastic paraplegia 31, hereditary spastic paraplegia 30, hereditary spastic paraplegia 35, hereditary spastic paraplegia 50, hereditary spastic paraplegia 48, hereditary spastic paraplegia 47, hereditary spastic paraplegia 52, hereditary spastic paraplegia 56, early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, hereditary spastic paraplegia 77, pure hereditary spastic paraplegia, complex hereditary spastic paraplegia, pure or complex hereditary spastic paraplegia, spastic paraplegia 87, autosomal recessive, spastic paraplegia 80, autosomal dominant, spastic paraplegia 81, autosomal recessive, spastic paraplegia 82, autosomal recessive, spastic paraplegia 83, autosomal recessive, spastic paraplegia 88, autosomal dominant, spastic paraplegia 79A, autosomal dominant, with ataxia, spastic paraplegia 89, autosomal recessive, spastic paraplegia 90A, autosomal dominant, spastic paraplegia 90B, autosomal recessive, spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia, spastic paraplegia 72b, autosomal recessive, spastic paraplegia 92, autosomal recessive, spastic paraplegia 93, autosomal recessive, IFIH1-related hereditary spastic paraplegia, RNASEH2B-related hereditary spastic paraplegia, ADAR-related hereditary spastic paraplegia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

44 retrieved; paginated sample, class counts are floors:

13 benign, 9 uncertain significance, 9 benign/likely benign, 6 pathogenic, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031734	NM_007347.5(AP4E1):c.3313C>T (p.Arg1105Ter)	AP4E1	Pathogenic	criteria provided, multiple submitters, no conflicts
1064645	NM_007347.5(AP4E1):c.942_943+3delinsCC	AP4E1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344794	NM_007347.5(AP4E1):c.542+5_542+8del	AP4E1	Pathogenic/Likely pathogenic	no assertion criteria provided
1696296	NM_007347.5(AP4E1):c.2804G>A (p.Trp935Ter)	AP4E1	Pathogenic	criteria provided, single submitter
2579247	GRCh38/hg38 15q21.2(chr15:50923067-50925830)x0	AP4E1	Pathogenic	criteria provided, single submitter
30659	NC_000015.10:g.50755991_50948682del	AP4E1	Pathogenic	no assertion criteria provided
30661	NM_007347.5(AP4E1):c.1359_1360insNN (p.Val454fs)	AP4E1	Pathogenic	no assertion criteria provided
4292135	NM_007347.5(AP4E1):c.319C>T (p.Gln107Ter)	AP4E1	Pathogenic	criteria provided, single submitter
1709784	NM_007347.5(AP4E1):c.1558dup (p.Glu520fs)	AP4E1	Likely pathogenic	criteria provided, single submitter
4277971	NM_007347.5(AP4E1):c.328del (p.Leu110fs)	AP4E1	Likely pathogenic	criteria provided, single submitter
635026	NM_007347.5(AP4E1):c.1317-2A>C	AP4E1	Likely pathogenic	criteria provided, single submitter
128402	NM_007347.5(AP4E1):c.613C>A (p.His205Asn)	AP4E1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240837	NM_007347.5(AP4E1):c.1852G>A (p.Val618Ile)	AP4E1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029158	NM_007347.5(AP4E1):c.326A>G (p.Asn109Ser)	AP4E1	Uncertain significance	criteria provided, single submitter
1383328	NM_007347.5(AP4E1):c.382C>T (p.His128Tyr)	AP4E1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2500948	NM_007347.5(AP4E1):c.1429+1G>T	AP4E1	Uncertain significance	criteria provided, single submitter
2582319	NM_007347.5(AP4E1):c.773A>G (p.Lys258Arg)	AP4E1	Uncertain significance	criteria provided, single submitter
3577352	NM_007347.5(AP4E1):c.2731A>G (p.Thr911Ala)	AP4E1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3775854	NM_007347.5(AP4E1):c.1177-4A>G	AP4E1	Uncertain significance	criteria provided, single submitter
434233	NM_007347.5(AP4E1):c.1675A>C (p.Thr559Pro)	AP4E1	Uncertain significance	criteria provided, multiple submitters, no conflicts
458249	NM_007347.5(AP4E1):c.2149C>T (p.Pro717Ser)	AP4E1	Uncertain significance	criteria provided, multiple submitters, no conflicts
946834	NM_007347.5(AP4E1):c.541A>C (p.Lys181Gln)	AP4E1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1243701	NM_007347.5(AP4E1):c.1967-91A>G	AP4E1	Benign	criteria provided, multiple submitters, no conflicts
1245233	NM_007347.5(AP4E1):c.3096-57dup	AP4E1	Benign	criteria provided, multiple submitters, no conflicts
1277493	NM_007347.5(AP4E1):c.222+48_222+49insT	AP4E1	Benign	criteria provided, multiple submitters, no conflicts
1278582	NM_007347.5(AP4E1):c.1316+44_1316+54del	AP4E1	Benign	criteria provided, multiple submitters, no conflicts
128392	NM_007347.5(AP4E1):c.1085A>G (p.Tyr362Cys)	AP4E1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
128393	NM_007347.5(AP4E1):c.1283A>G (p.Asn428Ser)	AP4E1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
128395	NM_007347.5(AP4E1):c.2429C>T (p.Thr810Ile)	AP4E1	Benign	criteria provided, multiple submitters, no conflicts
128398	NM_007347.5(AP4E1):c.2755A>G (p.Met919Val)	AP4E1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
AP4E1	Definitive	Autosomal recessive	hereditary spastic paraplegia 51	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AP4E1	Orphanet:280763	Severe intellectual disability and progressive spastic paraplegia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AP4E1	HGNC:573	ENSG00000081014	Q9UPM8	AP-4 complex subunit epsilon-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AP4E1	AP-4 complex subunit epsilon-1	Component of the adaptor protein complex 4 (AP-4).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AP4E1	Other/Unknown	no		Clathrin/coatomer_adapt-like_N, ARM-like, ARM-type_fold

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
esophagus squamous epithelium	1
gingival epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AP4E1	262	ubiquitous	yes	gingival epithelium, esophagus squamous epithelium, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AP4E1	2,108

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AP4E1	Q9UPM8	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Lysosome Vesicle Biogenesis	1	326.3×	0.008	AP4E1
trans-Golgi Network Vesicle Budding	1	253.8×	0.008	AP4E1
Golgi Associated Vesicle Biogenesis	1	200.3×	0.008	AP4E1
Membrane Trafficking	1	37.1×	0.029	AP4E1
Vesicle-mediated transport	1	34.8×	0.029	AP4E1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein targeting	1	366.4×	0.011	AP4E1
intracellular protein localization	1	104.7×	0.014	AP4E1
vesicle-mediated transport	1	96.3×	0.014	AP4E1
intracellular protein transport	1	64.8×	0.015	AP4E1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AP4E1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	AP4E1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
AP4E1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia