Hereditary spastic paraplegia 47

Summary

Hereditary spastic paraplegia 47 (MONDO:0013551) is a disease caused by AP4B1 (GenCC Strong), with 4 cohort genes and 2 clinical trials.

At a glance

• Causal gene: AP4B1 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 334
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 47
Mondo ID	MONDO:0013551
OMIM	614066
DOID	DOID:0110799
NCIT	C164224
UMLS	C3279738
MedGen	481368
GARD	0015749
NORD	1993
Is cancer (heuristic)	no

Also known as: AP4B1 hereditary spastic paraplegia · cerebral palsy, spastic quadriplegic, 5 · hereditary spastic paraplegia 47 · hereditary spastic paraplegia caused by mutation in AP4B1 · hereditary spastic paraplegia type 47 · Spastic Paraplegia 47 · spastic paraplegia 47, autosomal recessive · SPG47

Data availability: 334 ClinVar variants · 4 GenCC gene-disease records · 3 cell lines.

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 47

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 51, 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

334 retrieved; paginated sample, class counts are floors:

146 uncertain significance, 105 likely benign, 35 pathogenic, 18 conflicting classifications of pathogenicity, 10 benign, 8 benign/likely benign, 7 pathogenic/likely pathogenic, 5 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2425617	NC_000001.10:g.(?112318699)(115576848_?)del	AMPD1	Pathogenic	criteria provided, single submitter
1032462	NM_001253852.3(AP4B1):c.1540C>T (p.Arg514Ter)	AP4B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299776	NM_001253852.3(AP4B1):c.616C>T (p.Arg206Ter)	AP4B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334912	NM_001253852.3(AP4B1):c.1459C>T (p.Arg487Ter)	AP4B1	Pathogenic	no assertion criteria provided
1335806	NM_001253852.3(AP4B1):c.1365T>A (p.Tyr455Ter)	AP4B1	Pathogenic	no assertion criteria provided
1335882	NM_001253852.3(AP4B1):c.967del (p.Ser323fs)	AP4B1	Pathogenic	no assertion criteria provided
1344774	NM_001253852.3(AP4B1):c.304C>T (p.Arg102Ter)	AP4B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1344775	NM_001253852.3(AP4B1):c.487_488insTAT (p.Glu163delinsValTer)	AP4B1	Pathogenic/Likely pathogenic	no assertion criteria provided
1362359	NM_001253852.3(AP4B1):c.985A>T (p.Lys329Ter)	AP4B1	Pathogenic	criteria provided, single submitter
1454422	NM_001253852.3(AP4B1):c.926del (p.Gly309fs)	AP4B1	Pathogenic	criteria provided, single submitter
1456718	NM_001253852.3(AP4B1):c.1057C>T (p.Arg353Ter)	AP4B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1457254	NM_001253852.3(AP4B1):c.352C>T (p.Gln118Ter)	AP4B1	Pathogenic	criteria provided, single submitter
1526026	NM_001253852.3(AP4B1):c.219C>A (p.Cys73Ter)	AP4B1	Pathogenic	criteria provided, single submitter
156414	NM_001253852.3(AP4B1):c.1160_1161del (p.Thr387fs)	AP4B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
157721	NM_001253852.3(AP4B1):c.313del (p.Ala105fs)	AP4B1	Pathogenic	criteria provided, single submitter
1704352	NM_001253852.3(AP4B1):c.1317dup (p.Ile440fs)	AP4B1	Pathogenic	criteria provided, single submitter
1993044	NM_001253852.3(AP4B1):c.1122_1123insTTGTAGGTGCCAGGACTTCTTTTGTAGGT (p.Ala375delinsLeuTer)	AP4B1	Pathogenic	criteria provided, single submitter
1993045	NM_001253852.3(AP4B1):c.1112_1113insGGAGC (p.Ile371fs)	AP4B1	Pathogenic	criteria provided, single submitter
2008841	NM_001253852.3(AP4B1):c.388_389dup (p.Asp131fs)	AP4B1	Pathogenic	criteria provided, single submitter
209982	NM_006594.5:c.667del	AP4B1	Pathogenic	no assertion criteria provided
210195	NM_001253852.3(AP4B1):c.311_312delinsC (p.Leu104fs)	AP4B1	Pathogenic	criteria provided, multiple submitters, no conflicts
2106782	NM_001253852.3(AP4B1):c.876_877del (p.Cys293fs)	AP4B1	Pathogenic	criteria provided, single submitter
2144496	NM_001253852.3(AP4B1):c.1240C>T (p.Gln414Ter)	AP4B1	Pathogenic	criteria provided, multiple submitters, no conflicts
252667	NM_001253852.3(AP4B1):c.114-2A>C	AP4B1	Pathogenic	criteria provided, multiple submitters, no conflicts
2578580	NM_001253852.3(AP4B1):c.992_999del (p.Gln331fs)	AP4B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2752455	NM_001253852.3(AP4B1):c.1324_1331del (p.Leu442fs)	AP4B1	Pathogenic	criteria provided, single submitter
2911976	NM_001253852.3(AP4B1):c.444dup (p.Asn149Ter)	AP4B1	Pathogenic	criteria provided, single submitter
2971411	NM_001253852.3(AP4B1):c.52_53del (p.Cys18fs)	AP4B1	Pathogenic	criteria provided, multiple submitters, no conflicts
3632851	NM_001253852.3(AP4B1):c.1098dup (p.Ala367fs)	AP4B1	Pathogenic	criteria provided, single submitter
422147	NM_001253852.3(AP4B1):c.1216C>T (p.Arg406Ter)	AP4B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
AP4B1	Strong	Autosomal recessive	hereditary spastic paraplegia 47	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AP4B1	Orphanet:280763	Severe intellectual disability and progressive spastic paraplegia
AMPD1	Orphanet:45	Adenosine monophosphate deaminase deficiency

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AP4B1	HGNC:572	ENSG00000134262	Q9Y6B7	AP-4 complex subunit beta-1	gencc,clinvar
DCLRE1B	HGNC:17641	ENSG00000118655	Q9H816	5’ exonuclease Apollo	clinvar
AP4B1-AS1	HGNC:44114	ENSG00000226167		AP4B1 antisense RNA 1	clinvar
AMPD1	HGNC:468	ENSG00000116748	P23109	AMP deaminase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AP4B1	AP-4 complex subunit beta-1	Component of the adaptor protein complex 4 (AP-4).
DCLRE1B	5’ exonuclease Apollo	5’-3’ exonuclease that plays a central role in telomere maintenance and protection during S-phase.
AMPD1	AMP deaminase 1	AMP deaminase plays a critical role in energy metabolism.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Enzyme (other)	1	3.0×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AP4B1	Other/Unknown	no		Clathrin/coatomer_adapt-like_N, ARM-like, TBP_dom_sf
DCLRE1B	Other/Unknown	no		DRMBL, RibonucZ/Hydroxyglut_hydro
AP4B1-AS1	Other/Unknown	no
AMPD1	Enzyme (other)	yes	3.5.4.6	AMPD, A/AMP_deam_AS, Metal_Hydrolase

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
primordial germ cell in gonad	2
cerebellar hemisphere	1
right hemisphere of cerebellum	1
oocyte	1
secondary oocyte	1
lymph node	1
quadriceps femoris	1
triceps brachii	1
vastus lateralis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AP4B1	258	ubiquitous	marker	granulocyte, cerebellar hemisphere, right hemisphere of cerebellum
DCLRE1B	224	ubiquitous	yes	secondary oocyte, primordial germ cell in gonad, oocyte
AP4B1-AS1	130	broad	yes	primordial germ cell in gonad, granulocyte, lymph node
AMPD1	175	tissue_specific	marker	triceps brachii, vastus lateralis, quadriceps femoris

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AMPD1	1,830
AP4B1	1,772
DCLRE1B	1,528
AP4B1-AS1	0

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AP4B1	Q9Y6B7	5
DCLRE1B	Q9H816	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AMPD1	P23109	86.84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Nucleotide salvage	1	380.7×	0.017	AMPD1
Purine salvage	1	292.8×	0.017	AMPD1
Lysosome Vesicle Biogenesis	1	108.8×	0.020	AP4B1
Metabolism of nucleotides	1	100.2×	0.020	AMPD1
Fanconi Anemia Pathway	1	92.8×	0.020	DCLRE1B
trans-Golgi Network Vesicle Budding	1	84.6×	0.020	AP4B1
Golgi Associated Vesicle Biogenesis	1	66.8×	0.021	AP4B1
Membrane Trafficking	1	12.4×	0.093	AP4B1
Vesicle-mediated transport	1	11.6×	0.093	AP4B1
Metabolism	1	3.9×	0.237	AMPD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein localization to somatodendritic compartment	1	5617.3×	0.003	AP4B1
telomeric loop formation	1	2808.7×	0.003	DCLRE1B
IMP biosynthetic process	1	1872.4×	0.003	AMPD1
telomeric 3’ overhang formation	1	1404.3×	0.003	DCLRE1B
IMP salvage	1	1123.5×	0.003	AMPD1
GMP salvage	1	936.2×	0.003	AMPD1
protection from non-homologous end joining at telomere	1	802.5×	0.003	DCLRE1B
telomere maintenance via telomere lengthening	1	624.1×	0.003	DCLRE1B
AMP metabolic process	1	624.1×	0.003	AMPD1
telomere capping	1	432.1×	0.004	DCLRE1B
interstrand cross-link repair	1	144.0×	0.010	DCLRE1B
double-strand break repair via nonhomologous end joining	1	140.4×	0.010	DCLRE1B
protein targeting	1	122.1×	0.011	AP4B1
telomere maintenance	1	89.2×	0.014	DCLRE1B
intracellular protein localization	1	34.9×	0.032	AP4B1
vesicle-mediated transport	1	32.1×	0.033	AP4B1
intracellular protein transport	1	21.6×	0.046	AP4B1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AP4B1	0	0
DCLRE1B	0	0
AP4B1-AS1	0	0
AMPD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
AMPD1	3	Binding:3
DCLRE1B	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AMPD1	3.5.4.6	AMP deaminase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	AMPD1
E	Difficult family or no structure, no drug	3	AP4B1, DCLRE1B, AP4B1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AP4B1	0	—
DCLRE1B	1	—
AP4B1-AS1	0	—
AMPD1	3	—

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