Hereditary spastic paraplegia 48

Summary

Hereditary spastic paraplegia 48 (MONDO:0013342) is a disease caused by AP5Z1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AP5Z1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 899
• Phenotypes (HPO): 19

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0002079	Hypoplasia of the corpus callosum	Very frequent (80-99%)
HP:0007020	Progressive spastic paraplegia	Very frequent (80-99%)
HP:0000020	Urinary incontinence	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0002839	Urinary bladder sphincter dysfunction	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003319	Abnormality of the cervical spine	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000488	Retinopathy	Occasional (5-29%)
HP:0001300	Parkinsonism	Occasional (5-29%)
HP:0002136	Broad-based gait	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 48
Mondo ID	MONDO:0013342
OMIM	613647
Orphanet	306511
DOID	DOID:0110800
SNOMED CT	763367009
UMLS	C3150901
MedGen	462251
GARD	0017378
Is cancer (heuristic)	no

Also known as: AP5Z1 hereditary spastic paraplegia · autosomal recessive spastic paraplegia type 48 · hereditary spastic paraplegia caused by mutation in AP5Z1 · hereditary spastic paraplegia type 48 · spastic paraplegia 48, autosomal recessive · SPG48

Data availability: 899 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › lysosomal storage disease › hereditary spastic paraplegia 48

Related subtypes (10): lysosomal acid phosphatase deficiency, glycoprotein storage disease, pycnodysostosis, late infantile neuronal ceroid lipofuscinosis, glycoproteinosis, disorder of sialic acid metabolism, lysosomal glycogen storage disease, lysosomal lipid storage disorder, inborn disorder of lysosomal amino acid transport, mucopolysaccharidosis

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

600 retrieved; paginated sample, class counts are floors:

234 likely benign, 224 uncertain significance, 51 conflicting classifications of pathogenicity, 28 benign, 21 benign/likely benign, 18 likely pathogenic, 18 pathogenic, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033302	NM_014855.3(AP5Z1):c.158C>A (p.Ser53Ter)	AP5Z1	Pathogenic	criteria provided, single submitter
1175065	NM_014855.3(AP5Z1):c.1312-2A>G	AP5Z1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323294	NM_014855.3(AP5Z1):c.1323G>A (p.Trp441Ter)	AP5Z1	Pathogenic	criteria provided, single submitter
1366715	NM_014855.3(AP5Z1):c.2079_2100del (p.Cys693_Pro694insTer)	AP5Z1	Pathogenic	criteria provided, single submitter
1458218	NM_014855.3(AP5Z1):c.49C>T (p.Gln17Ter)	AP5Z1	Pathogenic	criteria provided, single submitter
2	NM_014855.3(AP5Z1):c.80_83delinsTGCTGTAAACTGTAACTGTAAA (p.Arg27_Ile28delinsLeuLeuTer)	AP5Z1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2007501	NM_014855.3(AP5Z1):c.896_902dup (p.Cys301Ter)	AP5Z1	Pathogenic	criteria provided, single submitter
2041213	NM_014855.3(AP5Z1):c.2079_2091del (p.Cys693fs)	AP5Z1	Pathogenic	criteria provided, single submitter
2151423	NM_014855.3(AP5Z1):c.67A>T (p.Lys23Ter)	AP5Z1	Pathogenic	criteria provided, single submitter
2853047	NM_014855.3(AP5Z1):c.704del (p.Asp235fs)	AP5Z1	Pathogenic	criteria provided, single submitter
2862357	NM_014855.3(AP5Z1):c.1954G>T (p.Glu652Ter)	AP5Z1	Pathogenic	criteria provided, single submitter
2997932	NM_014855.3(AP5Z1):c.2079del (p.Gln696fs)	AP5Z1	Pathogenic	criteria provided, single submitter
3	NM_014855.3(AP5Z1):c.1413_1426del (p.Leu473fs)	AP5Z1	Pathogenic	no assertion criteria provided
3653876	NM_014855.3(AP5Z1):c.670dup (p.Thr224fs)	AP5Z1	Pathogenic	criteria provided, single submitter
3685198	NM_014855.3(AP5Z1):c.1042_1043del (p.Ser348fs)	AP5Z1	Pathogenic	criteria provided, single submitter
3693922	NM_014855.3(AP5Z1):c.950dup (p.Asp317fs)	AP5Z1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3716976	NM_014855.3(AP5Z1):c.1499_1500del (p.Leu500fs)	AP5Z1	Pathogenic	criteria provided, single submitter
375313	NM_014855.3(AP5Z1):c.1322G>A (p.Trp441Ter)	AP5Z1	Pathogenic	criteria provided, multiple submitters, no conflicts
375314	NM_014855.3(AP5Z1):c.412C>T (p.Arg138Ter)	AP5Z1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375316	NM_014855.3(AP5Z1):c.1732C>T (p.Gln578Ter)	AP5Z1	Pathogenic	criteria provided, multiple submitters, no conflicts
3777713	NM_014855.3(AP5Z1):c.805C>T (p.Gln269Ter)	AP5Z1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446850	NM_014855.3(AP5Z1):c.355_358dup (p.Leu120fs)	AP5Z1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4723357	NM_014855.3(AP5Z1):c.1308dup (p.Lys437Ter)	AP5Z1	Pathogenic	criteria provided, single submitter
4738340	NM_014855.3(AP5Z1):c.2086del (p.Gln696fs)	AP5Z1	Pathogenic	criteria provided, single submitter
1030377	NM_014855.3(AP5Z1):c.179+1G>T	AP5Z1	Likely pathogenic	criteria provided, single submitter
1067378	NC_000007.13:g.(?_4816199)_4825153del	AP5Z1	Likely pathogenic	criteria provided, single submitter
1493192	NM_014855.3(AP5Z1):c.1132+1_1132+3del	AP5Z1	Likely pathogenic	criteria provided, single submitter
1947244	NM_014855.3(AP5Z1):c.970-1G>A	AP5Z1	Likely pathogenic	criteria provided, single submitter
2288799	NM_014855.3(AP5Z1):c.1707+1G>A	AP5Z1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2505272	NM_014855.3(AP5Z1):c.505C>T (p.Gln169Ter)	AP5Z1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
AP5Z1	Strong	Autosomal recessive	hereditary spastic paraplegia 48	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AP5Z1	Orphanet:306511	Autosomal recessive spastic paraplegia type 48

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
AP5Z1	HGNC:22197	ENSG00000242802	O43299	AP-5 complex subunit zeta-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AP5Z1	AP-5 complex subunit zeta-1	As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport.

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)
AP5Z1	Other/Unknown	no		ARM-like, AP5Z1, AP5Z1_ARM

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
granulocyte	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AP5Z1	233	ubiquitous	marker	granulocyte, tendon of biceps brachii, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AP5Z1	1,000

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AP5Z1	O43299	85.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
late endosome to Golgi transport	1	2808.7×	0.004	AP5Z1
lysosomal protein catabolic process	1	1053.2×	0.005	AP5Z1
axon development	1	455.5×	0.008	AP5Z1
lysosome organization	1	306.4×	0.008	AP5Z1
endosomal transport	1	244.2×	0.008	AP5Z1
autophagosome assembly	1	224.7×	0.008	AP5Z1
double-strand break repair via homologous recombination	1	156.0×	0.010	AP5Z1
Golgi organization	1	133.8×	0.010	AP5Z1
vesicle-mediated transport	1	96.3×	0.013	AP5Z1
gene expression	1	79.9×	0.014	AP5Z1
intracellular protein transport	1	64.8×	0.015	AP5Z1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AP5Z1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
AP5Z1	6	Binding:6

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	AP5Z1

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)
AP5Z1	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.