Hereditary spastic paraplegia 50

Summary

Hereditary spastic paraplegia 50 (MONDO:0013048) is a disease caused by AP4M1 (GenCC Definitive), with 3 cohort genes and 4 clinical trials.

At a glance

• Causal gene: AP4M1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 357
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 50
Mondo ID	MONDO:0013048
MeSH	C567858
OMIM	612936
DOID	DOID:0110802
UMLS	C2752008
MedGen	442869
GARD	0015592
NORD	1989
Is cancer (heuristic)	no

Also known as: AP4M1 hereditary spastic paraplegia · cerebral palsy, spastic quadriplegic, 3 · hereditary spastic paraplegia caused by mutation in AP4M1 · hereditary spastic paraplegia type 50 · Spastic Paraplegia 50 · spastic paraplegia 50, autosomal recessive · SPG50

Data availability: 357 ClinVar variants · 5 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 50

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 48, hereditary spastic paraplegia 51, 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

357 retrieved; paginated sample, class counts are floors:

157 likely benign, 114 uncertain significance, 26 pathogenic, 19 conflicting classifications of pathogenicity, 13 likely pathogenic, 12 benign, 9 pathogenic/likely pathogenic, 7 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1174617	NM_004722.4(AP4M1):c.1137+1G>T	AP4M1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1377569	NM_004722.4(AP4M1):c.555_556del (p.Asn185fs)	AP4M1	Pathogenic	criteria provided, single submitter
1430466	NM_004722.4(AP4M1):c.1317G>A (p.Trp439Ter)	AP4M1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1437494	NM_004722.4(AP4M1):c.1320dup (p.Arg441fs)	AP4M1	Pathogenic	criteria provided, single submitter
1457475	NM_004722.4(AP4M1):c.776_777del (p.Val259fs)	AP4M1	Pathogenic	criteria provided, single submitter
1497146	NM_004722.4(AP4M1):c.52_58+6del	AP4M1	Pathogenic	criteria provided, single submitter
1697248	NM_004722.4(AP4M1):c.142del (p.Val48fs)	AP4M1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1699331	NM_004722.4(AP4M1):c.1012del (p.Arg338fs)	AP4M1	Pathogenic	criteria provided, single submitter
183357	NM_004722.4(AP4M1):c.952C>T (p.Arg318Ter)	AP4M1	Pathogenic	criteria provided, multiple submitters, no conflicts
2047850	NM_004722.4(AP4M1):c.1183_1196del (p.Thr395fs)	AP4M1	Pathogenic	criteria provided, single submitter
209980	NM_004722.4(AP4M1):c.1012C>T (p.Arg338Ter)	AP4M1	Pathogenic	criteria provided, multiple submitters, no conflicts
210211	NM_004722.4(AP4M1):c.32del (p.Lys11fs)	AP4M1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
210216	NM_004722.4(AP4M1):c.955T>C (p.Cys319Arg)	AP4M1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2143466	NM_004722.4(AP4M1):c.697G>T (p.Glu233Ter)	AP4M1	Pathogenic	criteria provided, single submitter
2682288	NM_004722.4(AP4M1):c.568del (p.Asp190fs)	AP4M1	Pathogenic	criteria provided, single submitter
2749126	NM_004722.4(AP4M1):c.861dup (p.Asp288fs)	AP4M1	Pathogenic	criteria provided, single submitter
3016128	NM_004722.4(AP4M1):c.63_64del (p.Asp23fs)	AP4M1	Pathogenic	criteria provided, single submitter
3017395	NM_004722.4(AP4M1):c.403C>T (p.Gln135Ter)	AP4M1	Pathogenic	criteria provided, single submitter
30264	NM_004722.4(AP4M1):c.577G>A (p.Glu193Lys)	AP4M1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3245785	NC_000007.13:g.(?99703861)(99704170_?)del	AP4M1	Pathogenic	criteria provided, single submitter
3245786	NC_000007.13:g.(?99699407)(99704283_?)del	AP4M1	Pathogenic	criteria provided, single submitter
3775613	NM_004722.4(AP4M1):c.128_132del (p.Asp43fs)	AP4M1	Pathogenic	criteria provided, single submitter
429735	NM_004722.4(AP4M1):c.923C>G (p.Ser308Ter)	AP4M1	Pathogenic	criteria provided, multiple submitters, no conflicts
450738	NM_004722.4(AP4M1):c.842_843del (p.Val281fs)	AP4M1	Pathogenic	criteria provided, multiple submitters, no conflicts
450739	NM_004722.4(AP4M1):c.218dup (p.Asn73fs)	AP4M1	Pathogenic	criteria provided, multiple submitters, no conflicts
4687481	NC_000007.13:g.(99703627_99703863)_(99704138_99704280)del	AP4M1	Pathogenic	criteria provided, single submitter
4721295	NM_004722.4(AP4M1):c.912G>A (p.Trp304Ter)	AP4M1	Pathogenic	criteria provided, single submitter
4813589	NM_004722.4(AP4M1):c.893T>C (p.Leu298Pro)	AP4M1	Pathogenic	criteria provided, single submitter
522944	NM_004722.4(AP4M1):c.802C>T (p.Arg268Ter)	AP4M1	Pathogenic	criteria provided, multiple submitters, no conflicts
561150	NM_004722.4(AP4M1):c.916C>T (p.Arg306Ter)	AP4M1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · 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
AP4M1	Definitive	Autosomal recessive	hereditary spastic paraplegia 50	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AP4M1	Orphanet:280763	Severe intellectual disability and progressive spastic paraplegia
DNAAF19	Orphanet:244	Primary ciliary dyskinesia
APOA1	Orphanet:425	Apolipoprotein A-I deficiency
APOA1	Orphanet:93560	AApoAI amyloidosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AP4M1	HGNC:574	ENSG00000221838	O00189	AP-4 complex subunit mu-1	gencc,clinvar
DNAAF19	HGNC:32700	ENSG00000167131	Q8IW40	Dynein axonemal assembly factor 19	clinvar
APOA1	HGNC:600	ENSG00000118137	P02647	Apolipoprotein A-I	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AP4M1	AP-4 complex subunit mu-1	Component of the adaptor protein complex 4 (AP-4).
DNAAF19	Dynein axonemal assembly factor 19	Dynein-attachment factor required for cilia motility.
APOA1	Apolipoprotein A-I	Participates in the reverse transport of cholesterol from tissues to the liver for excretion by promoting cholesterol efflux from tissues and by acting as a cofactor for the lecithin cholesterol acyltransferase (LCAT).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AP4M1	Other/Unknown	no		Clathrin_mu, Longin-like_dom_sf, Clathrin_mu_CS
DNAAF19	Other/Unknown	no		RPAP3-like_C, Dynein_attach_N, CC103
APOA1	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	2
right testis	1
right uterine tube	1
male germ line stem cell (sensu Vertebrata) in testis	1
testis	1
jejunal mucosa	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AP4M1	187	ubiquitous	marker	left testis, right testis, right uterine tube
DNAAF19	130	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, left testis, testis
APOA1	170	broad	marker	jejunal mucosa, right lobe of liver, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOA1	3,608
AP4M1	1,525
DNAAF19	764

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APOA1	P02647	31
AP4M1	O00189	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAAF19	Q8IW40	80.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 48. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCA1 causes TGD	1	2855.0×	0.012	APOA1
HDL clearance	1	1142.0×	0.012	APOA1
HDL assembly	1	713.8×	0.012	APOA1
Chylomicron assembly	1	571.0×	0.012	APOA1
Chylomicron remodeling	1	571.0×	0.012	APOA1
HDL remodeling	1	571.0×	0.012	APOA1
Scavenging by Class B Receptors	1	519.1×	0.012	APOA1
Vesicle-mediated transport	2	34.8×	0.012	AP4M1, APOA1
Scavenging of heme from plasma	1	439.2×	0.012	APOA1
Plasma lipoprotein assembly	1	356.9×	0.013	APOA1
ABC transporters in lipid homeostasis	1	300.5×	0.013	APOA1
Scavenging by Class A Receptors	1	300.5×	0.013	APOA1
Binding and Uptake of Ligands by Scavenger Receptors	1	271.9×	0.013	APOA1
Plasma lipoprotein remodeling	1	237.9×	0.013	APOA1
Plasma lipoprotein clearance	1	237.9×	0.013	APOA1
ABC transporter disorders	1	219.6×	0.014	APOA1
Metabolism of fat-soluble vitamins	1	190.3×	0.015	APOA1
Dengue virus activates/modulates innate and adaptive immune responses	1	167.9×	0.015	APOA1
Lysosome Vesicle Biogenesis	1	163.1×	0.015	AP4M1
Visual phototransduction	1	129.8×	0.018	APOA1
trans-Golgi Network Vesicle Budding	1	126.9×	0.018	AP4M1
Retinoid metabolism and transport	1	124.1×	0.018	APOA1
Plasma lipoprotein assembly, remodeling, and clearance	1	114.2×	0.018	APOA1
Heme signaling	1	107.7×	0.018	APOA1
Maturation of DENV proteins	1	105.7×	0.018	APOA1
Response to elevated platelet cytosolic Ca2+	1	81.6×	0.023	APOA1
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.025	APOA1
Disorders of transmembrane transporters	1	69.6×	0.025	APOA1
ABC-family protein mediated transport	1	60.7×	0.027	APOA1
Metabolism of vitamins and cofactors	1	58.3×	0.027	APOA1

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 oxidation	1	1872.4×	0.004	APOA1
peptidyl-methionine modification	1	1872.4×	0.004	APOA1
protein localization to basolateral plasma membrane	1	1872.4×	0.004	AP4M1
regulation of intestinal cholesterol absorption	1	1404.3×	0.004	APOA1
positive regulation of phospholipid efflux	1	1404.3×	0.004	APOA1
acylglycerol homeostasis	1	1123.5×	0.004	APOA1
negative regulation of cell adhesion molecule production	1	1123.5×	0.004	APOA1
cellular response to lipoprotein particle stimulus	1	1123.5×	0.004	APOA1
negative regulation of cytokine production involved in immune response	1	936.2×	0.004	APOA1
glucocorticoid metabolic process	1	936.2×	0.004	APOA1
negative regulation of very-low-density lipoprotein particle remodeling	1	936.2×	0.004	APOA1
lipoprotein biosynthetic process	1	936.2×	0.004	APOA1
vitamin transport	1	936.2×	0.004	APOA1
negative regulation of response to cytokine stimulus	1	936.2×	0.004	APOA1
cholesterol import	1	936.2×	0.004	APOA1
determination of digestive tract left/right asymmetry	1	936.2×	0.004	DNAAF19
high-density lipoprotein particle clearance	1	802.5×	0.005	APOA1
positive regulation of cholesterol metabolic process	1	702.2×	0.005	APOA1
negative regulation of heterotypic cell-cell adhesion	1	624.1×	0.005	APOA1
amyloid-beta formation	1	624.1×	0.005	APOA1
high-density lipoprotein particle assembly	1	561.7×	0.006	APOA1
Golgi to lysosome transport	1	510.7×	0.006	AP4M1
regulation of Cdc42 protein signal transduction	1	468.1×	0.006	APOA1
blood vessel endothelial cell migration	1	468.1×	0.006	APOA1
epithelial cilium movement involved in determination of left/right asymmetry	1	432.1×	0.006	DNAAF19
phospholipid efflux	1	374.5×	0.006	APOA1
post-Golgi vesicle-mediated transport	1	351.1×	0.006	AP4M1
Golgi to endosome transport	1	351.1×	0.006	AP4M1
axonemal dynein complex assembly	1	351.1×	0.006	DNAAF19
phospholipid homeostasis	1	330.4×	0.007	APOA1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AP4M1	0	0
DNAAF19	0	0
APOA1	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
APOA1	2	Binding:2

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	0
E	Difficult family or no structure, no drug	3	AP4M1, DNAAF19, APOA1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AP4M1	0	—
DNAAF19	0	—
APOA1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	2
PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06692712	PHASE3	RECRUITING	Phase 3 Efficacy Study With Concurrent Control of IT MELPIDA in SPG50.Concurrent Controls.
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
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