Hereditary spastic paraplegia 52

Summary

Hereditary spastic paraplegia 52 (MONDO:0013552) is a disease caused by AP4S1 (GenCC Strong), with 2 cohort genes and 2 clinical trials.

At a glance

• Causal gene: AP4S1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 25
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 52
Mondo ID	MONDO:0013552
OMIM	614067
DOID	DOID:0110804
UMLS	C3279743
MedGen	481373
GARD	0015750
NORD	1991
Is cancer (heuristic)	no

Also known as: AP4S1 hereditary spastic paraplegia · cerebral palsy, spastic quadriplegic, 6 · hereditary spastic paraplegia 52 · hereditary spastic paraplegia caused by mutation in AP4S1 · hereditary spastic paraplegia type 52 · Spastic Paraplegia 52 · spastic paraplegia 52, autosomal recessive · SPG52

Data availability: 25 ClinVar variants · 3 GenCC gene-disease records · 2 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 52

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 47, 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

25 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 5 pathogenic, 4 benign, 4 pathogenic/likely pathogenic, 3 likely pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
210218	NM_001128126.3(AP4S1):c.295-3C>A	AP4S1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
234924	NM_001128126.3(AP4S1):c.289C>T (p.Arg97Ter)	AP4S1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
234925	NM_001128126.3(AP4S1):c.138+3_138+6del	AP4S1	Pathogenic	criteria provided, multiple submitters, no conflicts
2581133	NM_001128126.3(AP4S1):c.365_366delinsAG (p.Cys122Ter)	AP4S1	Pathogenic	no assertion criteria provided
279680	NM_001128126.3(AP4S1):c.294+1G>T	AP4S1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30658	NM_001128126.3(AP4S1):c.124C>T (p.Arg42Ter)	AP4S1	Pathogenic	criteria provided, multiple submitters, no conflicts
3242526	Single allele	AP4S1	Pathogenic	criteria provided, single submitter
577104	NM_001128126.3(AP4S1):c.43C>T (p.Arg15Ter)	AP4S1	Pathogenic	criteria provided, multiple submitters, no conflicts
17524	NM_000078.3(CETP):c.1321+1G>A	CETP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344801	NM_001128126.3(AP4S1):c.139-2A>G	AP4S1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685242	NM_001128126.3(AP4S1):c.295-1G>A	AP4S1	Likely pathogenic	criteria provided, single submitter
417874	NM_001128126.3(AP4S1):c.138+2T>G	AP4S1	Likely pathogenic	criteria provided, single submitter
434248	NM_001128126.3(AP4S1):c.29A>G (p.Lys10Arg)	AP4S1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
807104	NM_001128126.3(AP4S1):c.306+3006del	AP4S1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1699110	NM_001128126.3(AP4S1):c.306+4281A>G	AP4S1	Uncertain significance	criteria provided, single submitter
2431495	NM_001128126.3(AP4S1):c.44G>A (p.Arg15Gln)	AP4S1	Uncertain significance	criteria provided, single submitter
2439139	NM_001128126.3(AP4S1):c.152A>G (p.Glu51Gly)	AP4S1	Uncertain significance	criteria provided, single submitter
3067846	NM_001254729.1(AP4S1):c.226_294del	AP4S1	Uncertain significance	criteria provided, single submitter
4077997	NM_001128126.3(AP4S1):c.-71-11661C>T	AP4S1	Uncertain significance	criteria provided, single submitter
4077998	NM_001128126.3(AP4S1):c.-72+11228T>C	AP4S1	Uncertain significance	criteria provided, single submitter
527988	NM_001128126.3(AP4S1):c.83G>A (p.Arg28His)	AP4S1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1192441	NM_001128126.3(AP4S1):c.138+63G>C	AP4S1	Benign	criteria provided, multiple submitters, no conflicts
1192442	NM_001128126.3(AP4S1):c.139-65C>G	AP4S1	Benign	criteria provided, multiple submitters, no conflicts
1192443	NM_001128126.3(AP4S1):c.295-34T>G	AP4S1	Benign	criteria provided, multiple submitters, no conflicts
678006	NM_001128126.3(AP4S1):c.139-110A>G	AP4S1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
AP4S1	Strong	Autosomal recessive	hereditary spastic paraplegia 52	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AP4S1	Orphanet:280763	Severe intellectual disability and progressive spastic paraplegia
CETP	Orphanet:181428	Familial Hyperalphalipoproteinemia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AP4S1	HGNC:575	ENSG00000100478	Q9Y587	AP-4 complex subunit sigma-1	gencc,clinvar
CETP	HGNC:1869	ENSG00000087237	P11597	Cholesteryl ester transfer protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AP4S1	AP-4 complex subunit sigma-1	Component of the adaptor protein complex 4 (AP-4).
CETP	Cholesteryl ester transfer protein	Involved in the transfer of neutral lipids, including cholesteryl ester and triglyceride, among lipoprotein particles.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AP4S1	Other/Unknown	no		Longin-like_dom_sf, AP_complex_ssu, AP_mu_sigma_su
CETP	Other/Unknown	no		Lipid-bd_serum_glycop_C, Cholesteryl_ester_transfer, Lipid-bd_serum_glycop_N

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
calcaneal tendon	1
endothelial cell	1
liver	1
lymph node	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AP4S1	268	ubiquitous	marker	endothelial cell, calcaneal tendon, Brodmann (1909) area 23
CETP	165	broad	marker	lymph node, spleen, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CETP	1,391
AP4S1	935

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AP4S1	Q9Y587	4
CETP	P11597	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 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
LDL remodeling	1	951.7×	0.006	CETP
HDL remodeling	1	571.0×	0.006	CETP
Lysosome Vesicle Biogenesis	1	163.1×	0.011	AP4S1
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	154.3×	0.011	CETP
trans-Golgi Network Vesicle Budding	1	126.9×	0.011	AP4S1
Membrane Trafficking	1	18.5×	0.057	AP4S1
Vesicle-mediated transport	1	17.4×	0.057	AP4S1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
triglyceride transport	1	2106.5×	0.004	CETP
regulation of cholesterol efflux	1	1203.7×	0.004	CETP
positive regulation of cholesterol transport	1	1203.7×	0.004	CETP
positive regulation of phospholipid transport	1	1203.7×	0.004	CETP
very-low-density lipoprotein particle remodeling	1	1053.2×	0.004	CETP
negative regulation of macrophage derived foam cell differentiation	1	648.1×	0.005	CETP
low-density lipoprotein particle remodeling	1	526.6×	0.005	CETP
phospholipid homeostasis	1	495.6×	0.005	CETP
reverse cholesterol transport	1	468.1×	0.005	CETP
high-density lipoprotein particle remodeling	1	401.2×	0.005	CETP
phosphatidylcholine metabolic process	1	401.2×	0.005	CETP
cholesterol transport	1	366.4×	0.005	CETP
triglyceride homeostasis	1	240.7×	0.007	CETP
triglyceride metabolic process	1	221.7×	0.007	CETP
protein targeting	1	183.2×	0.008	AP4S1
lipid homeostasis	1	168.5×	0.008	CETP
lipid transport	1	131.7×	0.010	CETP
cholesterol metabolic process	1	98.0×	0.012	CETP
cholesterol homeostasis	1	78.0×	0.015	CETP
intracellular protein localization	1	52.3×	0.021	AP4S1
vesicle-mediated transport	1	48.1×	0.022	AP4S1
protein transport	1	21.9×	0.045	AP4S1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
CETP	5	3
AP4S1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ANACETRAPIB	3	CETP
EVACETRAPIB	3	CETP
DALCETRAPIB	3	CETP
TORCETRAPIB	3	CETP
URSOLIC ACID	2	CETP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CETP	132	Binding:127, Functional:5
AP4S1	1	Binding:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CETP	132

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

5 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.

Compound	Max phase	Cohort target (bioactivity)
ANACETRAPIB	3	CETP
EVACETRAPIB	3	CETP
DALCETRAPIB	3	CETP
TORCETRAPIB	3	CETP
URSOLIC ACID	2	CETP

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	1	CETP
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	AP4S1

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)
AP4S1	1	—

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