Hereditary spastic paraplegia

Summary

Hereditary spastic paraplegia (MONDO:0019064) is a disease (an umbrella term covering 45 Mondo subtypes) caused by variants in ABCD1, ALDH18A1, and RINT1, with 75 cohort genes and 51 clinical trials. The dominant Reactome pathway is Membrane Trafficking (12 cohort genes). Top therapeutic interventions include cycloserine, dalfampridine, and miglustat.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal genes: ABCD1 (GenCC Strong), ALDH18A1 (GenCC Strong), RINT1 (GenCC Strong)
• Umbrella term: 45 Mondo subtypes
• Cohort genes: 75
• ClinVar variants: 2,128
• Clinical trials: 51

Clinical features

Epidemiology

Prevalence records

10 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	4.2	Worldwide	Validated
Point prevalence	1-9 / 100 000	4.8	Europe	Validated
Point prevalence	1-9 / 100 000	9.6	Spain	Validated
Point prevalence	1-9 / 100 000	4.1	Portugal	Validated
Point prevalence	1-9 / 100 000	5.75	Tunisia	Validated
Point prevalence	1-9 / 100 000	7.4	Norway	Validated
Point prevalence	1-9 / 100 000	2.7	Italy	Validated
Point prevalence	1-9 / 100 000	4.4	Estonia	Validated
Point prevalence	1-9 / 100 000	2.1	Libyan Arab Jamahiriya	Validated
Point prevalence	1-9 / 100 000	1.3	Sweden	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia
Mondo ID	MONDO:0019064
MeSH	D015419
OMIM	303350
Orphanet	685
DOID	DOID:2476
ICD-10-CM	G11.4
ICD-11	810807375
NCIT	C140267
SNOMED CT	39912006
UMLS	C0037773
MedGen	20844
GARD	0006637
MedDRA	10019903
NORD	1238
Is cancer (heuristic)	no

Also known as: familial spastic paraparesis · familial spastic paraplegia · FSP · hereditary spastic paraparesis · HSP · spastic paraplegia · SPG · Strümpell-Lorrain disease

Data availability: 2,128 ClinVar variants · 12 GenCC gene-disease records · 32 cell lines.

Disease family

An umbrella term covering 45 Mondo subtypes.

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

Related subtypes (1): Brown-Sequard syndrome

Subtypes (45): 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 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

600 retrieved; paginated sample, class counts are floors:

306 uncertain significance, 128 conflicting classifications of pathogenicity, 52 benign, 32 benign/likely benign, 24 likely pathogenic, 21 pathogenic/likely pathogenic, 20 pathogenic, 11 likely benign, 6 affects

ClinVar	Variant (HGVS)	Gene	Classification	Review
1344210	NM_002860.4(ALDH18A1):c.1111C>T (p.Arg371Ter)	ALDH18A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344261	NM_031448.6(C19orf12):c.166del	C19orf12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068252	NM_183075.3(CYP2U1):c.343G>A (p.Gly115Ser)	CYP2U1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344268	NM_183075.3(CYP2U1):c.1288+1G>A	CYP2U1	Pathogenic	criteria provided, single submitter
120179	NM_004820.5(CYP7B1):c.889A>G (p.Thr297Ala)	CYP7B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1344306	NM_015214.3(DDHD2):c.856C>T (p.Gln286Ter)	DDHD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027474	NM_001166114.2(PNPLA6):c.4051C>T (p.Arg1351Ter)	PNPLA6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073769	NM_001371279.1(REEP1):c.417+1G>A	REEP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1343954	NM_001371279.1(REEP1):c.344dup (p.Tyr115Ter)	REEP1	Pathogenic	criteria provided, single submitter
1262	NM_024570.4(RNASEH2B):c.529G>A (p.Ala177Thr)	RNASEH2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1202576	NM_014363.6(SACS):c.4756_4760del (p.Asn1586fs)	SACS	Pathogenic	criteria provided, multiple submitters, no conflicts
1343983	NM_014363.6(SACS):c.237dup (p.Ser80fs)	SACS	Pathogenic	criteria provided, multiple submitters, no conflicts
1344003	NM_014363.6(SACS):c.8584A>T (p.Lys2862Ter)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344006	NM_014363.6(SACS):c.9081dup (p.Asp3028Ter)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344007	NM_014363.6(SACS):c.9119dup (p.Asn3040fs)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065559	NM_014946.4(SPAST):c.1606C>T (p.Gln536Ter)	SPAST	Pathogenic	no assertion criteria provided
1177434	NM_014946.4(SPAST):c.1414-2A>T	SPAST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344035	NM_014946.4(SPAST):c.1005-1G>C	SPAST	Pathogenic	criteria provided, single submitter
1344039	NM_014946.4(SPAST):c.1151C>G (p.Pro384Arg)	SPAST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344040	NM_014946.4(SPAST):c.1208_1212del (p.Thr402_Phe403insTer)	SPAST	Pathogenic	criteria provided, single submitter
1344042	NM_014946.4(SPAST):c.1215_1218del (p.Asn405fs)	SPAST	Pathogenic	criteria provided, single submitter
1344045	NM_014946.4(SPAST):c.1321+1G>T	SPAST	Pathogenic	criteria provided, single submitter
1344050	NM_014946.4(SPAST):c.1382del (p.Leu461fs)	SPAST	Pathogenic	criteria provided, single submitter
1344054	NM_014946.4(SPAST):c.1536G>T (p.Glu512Asp)	SPAST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344058	NM_014946.4(SPAST):c.1840del (p.Thr614fs)	SPAST	Pathogenic	criteria provided, single submitter
1344062	NM_014946.4(SPAST):c.361A>T (p.Lys121Ter)	SPAST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344063	NM_014946.4(SPAST):c.390_391del (p.Leu131fs)	SPAST	Pathogenic	criteria provided, single submitter
1344064	NM_014946.4(SPAST):c.391_392insGGT (p.Ala130_Leu131insArg)	SPAST	Pathogenic	criteria provided, single submitter
1344068	NM_014946.4(SPAST):c.843_846dup (p.Gly283fs)	SPAST	Pathogenic	criteria provided, single submitter
1344071	NM_014946.4(SPAST):c.871-1G>A	SPAST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 89 · Orphanet: 116 · 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
ALDH18A1	Definitive	Autosomal dominant	autosomal recessive complex spastic paraplegia type 9B	25
ABCD1	Strong	X-linked	hereditary spastic paraplegia	11
REEP2	Strong	Autosomal dominant	hereditary spastic paraplegia 72	8
RINT1	Strong	Autosomal recessive	hereditary spastic paraplegia	8
SPTAN1	Strong	Autosomal dominant	spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia	10
ATP2B4	Moderate	Autosomal dominant	hereditary spastic paraplegia
USP8	Moderate	Autosomal recessive	hereditary spastic paraplegia	5
ZFR	Supportive	Autosomal recessive	autosomal recessive spastic paraplegia type 71	2
DNM2	Limited	Autosomal dominant	hereditary spastic paraplegia	14
IFRD1	Limited	Autosomal dominant	hereditary spastic paraplegia	2
SREBF2	Limited	Autosomal recessive	hereditary spastic paraplegia	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPTAN1	Orphanet:697160	Infantile epileptic spasms syndrome
USP8	Orphanet:401795	Autosomal recessive spastic paraplegia type 59
USP8	Orphanet:96253	Cushing disease
ZFR	Orphanet:401840	Autosomal recessive spastic paraplegia type 71
ALDH18A1	Orphanet:35664	ALDH18A1-related De Barsy syndrome
ALDH18A1	Orphanet:447753	Autosomal dominant spastic paraplegia type 9A
ALDH18A1	Orphanet:447757	Autosomal dominant spastic paraplegia type 9B
ALDH18A1	Orphanet:447760	Autosomal recessive spastic paraplegia type 9B
ALDH18A1	Orphanet:90348	Autosomal dominant cutis laxa
REEP2	Orphanet:401849	Autosomal spastic paraplegia type 72
RINT1	Orphanet:464724	Fever-associated acute infantile liver failure syndrome
DNM2	Orphanet:100044	Autosomal dominant intermediate Charcot-Marie-Tooth disease type B
DNM2	Orphanet:169189	Autosomal dominant centronuclear myopathy
DNM2	Orphanet:228179	Autosomal dominant Charcot-Marie-Tooth disease type 2M
DNM2	Orphanet:363409	Fetal akinesia-cerebral and retinal hemorrhage syndrome
IFRD1	Orphanet:98771	Spinocerebellar ataxia type 18
ABCD1	Orphanet:139396	X-linked cerebral adrenoleukodystrophy
ABCD1	Orphanet:139399	Adrenomyeloneuropathy
ABCD1	Orphanet:369942	CADDS
ABCD1	Orphanet:388	Hirschsprung disease
CNNM2	Orphanet:620363	Primary hypomagnesemia-generalized seizures-intellectual disability-obesity syndrome
RTN2	Orphanet:100993	Autosomal dominant spastic paraplegia type 12
SACS	Orphanet:98	Autosomal recessive spastic ataxia of Charlevoix-Saguenay
SLC16A2	Orphanet:59	Allan-Herndon-Dudley syndrome
SPG11	Orphanet:2822	Autosomal recessive spastic paraplegia type 11
SPG11	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
SPG11	Orphanet:466775	Autosomal recessive Charcot-Marie-Tooth disease type 2X
ATL1	Orphanet:100984	Autosomal dominant spastic paraplegia type 3
ATL1	Orphanet:36386	Hereditary sensory and autonomic neuropathy type 1
SPAST	Orphanet:100985	Autosomal dominant spastic paraplegia type 4
SPG7	Orphanet:35689	Primary lateral sclerosis
SPG7	Orphanet:99013	Spastic paraplegia type 7
SPTBN2	Orphanet:352403	Spectrin-associated autosomal recessive cerebellar ataxia
SPTBN2	Orphanet:98766	Spinocerebellar ataxia type 5
TWNK	Orphanet:1186	Infantile-onset spinocerebellar ataxia
TWNK	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
TWNK	Orphanet:363534	Mitochondrial DNA depletion syndrome, hepatocerebrorenal form
TWNK	Orphanet:642945	Perrault syndrome type 1
TWNK	Orphanet:642976	Perrault syndrome type 2
TWNK	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
UBAP1	Orphanet:100993	Autosomal dominant spastic paraplegia type 12
UBAP1	Orphanet:631068	Autosomal dominant spastic paraplegia type 80
ERLIN2	Orphanet:209951	Autosomal spastic paraplegia type 18
ERLIN2	Orphanet:247604	Juvenile primary lateral sclerosis
ERLIN2	Orphanet:280384	Recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome
PTPN23	Orphanet:528084	Non-specific syndromic intellectual disability
BSCL2	Orphanet:100998	Autosomal dominant spastic paraplegia type 17
BSCL2	Orphanet:139536	Distal hereditary motor neuropathy type 5
BSCL2	Orphanet:363400	Progressive encephalopathy-severe neurodegeneration-lipodystrophy syndrome
BSCL2	Orphanet:696289	Congenital generalized lipodystrophy type 2

Cohort genes → proteins

75 cohort genes, 74 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	75

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPTAN1	HGNC:11273	ENSG00000197694	Q13813	Spectrin alpha chain, non-erythrocytic 1	gencc,clinvar
USP8	HGNC:12631	ENSG00000138592	P40818	Ubiquitin carboxyl-terminal hydrolase 8	gencc,clinvar
ZFR	HGNC:17277	ENSG00000056097	Q96KR1	Zinc finger RNA-binding protein	gencc,clinvar
ALDH18A1	HGNC:9722	ENSG00000059573	P54886	Delta-1-pyrroline-5-carboxylate synthase	gencc,clinvar
SREBF2	HGNC:11290	ENSG00000198911	Q12772	Sterol regulatory element-binding protein 2	gencc
REEP2	HGNC:17975	ENSG00000132563	Q9BRK0	Receptor expression-enhancing protein 2	gencc
RINT1	HGNC:21876	ENSG00000135249	Q6NUQ1	RAD50-interacting protein 1	gencc
DNM2	HGNC:2974	ENSG00000079805	P50570	Dynamin-2	gencc
IFRD1	HGNC:5456	ENSG00000006652	O00458	Interferon-related developmental regulator 1	gencc
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	gencc
ATP2B4	HGNC:817	ENSG00000058668	P23634	Plasma membrane calcium-transporting ATPase 4	gencc
CNNM2	HGNC:103	ENSG00000148842	Q9H8M5	Metal transporter CNNM2	clinvar
RTN2	HGNC:10468	ENSG00000125744	O75298	Reticulon-2	clinvar
SACS	HGNC:10519	ENSG00000151835	Q9NZJ4	Sacsin	clinvar
SLC16A2	HGNC:10923	ENSG00000147100	P36021	Monocarboxylate transporter 8	clinvar
SLC1A5	HGNC:10943	ENSG00000105281	Q15758	Neutral amino acid transporter B(0)	clinvar
SPG11	HGNC:11226	ENSG00000104133	Q96JI7	Spatacsin	clinvar
ATL1	HGNC:11231	ENSG00000198513	Q8WXF7	Atlastin-1	clinvar
SPAST	HGNC:11233	ENSG00000021574	Q9UBP0	Spastin	clinvar
SPG7	HGNC:11237	ENSG00000197912	Q9UQ90	Mitochondrial inner membrane m-AAA protease component paraplegin	clinvar
SPTBN2	HGNC:11276	ENSG00000173898	O15020	Spectrin beta chain, non-erythrocytic 2	clinvar
TWNK	HGNC:1160	ENSG00000107815	Q96RR1	Twinkle mtDNA helicase	clinvar
UBAP1	HGNC:12461	ENSG00000165006	Q9NZ09	Ubiquitin-associated protein 1	clinvar
ERLIN2	HGNC:1356	ENSG00000147475	O94905	Erlin-2	clinvar
RAB9B	HGNC:14090	ENSG00000123570	Q9NP90	Ras-related protein Rab-9B	clinvar
ARHGAP9	HGNC:14130	ENSG00000123329	Q9BRR9	Rho GTPase-activating protein 9	clinvar
PTPN23	HGNC:14406	ENSG00000076201	Q9H3S7	Tyrosine-protein phosphatase non-receptor type 23	clinvar
COL5A3	HGNC:14864	ENSG00000080573	P25940	Collagen alpha-3(V) chain	clinvar
BSCL2	HGNC:15832	ENSG00000168000	Q96G97	Seipin	clinvar
CCT5	HGNC:1618	ENSG00000150753	P48643	T-complex protein 1 subunit epsilon	clinvar
PNPLA6	HGNC:16268	ENSG00000032444	Q8IY17	Patatin-like phospholipase domain-containing protein 6	clinvar
ERLIN1	HGNC:16947	ENSG00000107566	O75477	Erlin-1	clinvar
NIPA1	HGNC:17043	ENSG00000170113	Q7RTP0	Magnesium transporter NIPA1	clinvar
BICD2	HGNC:17208	ENSG00000185963	Q8TD16	Protein bicaudal D homolog 2	clinvar
GJC2	HGNC:17494	ENSG00000198835	Q5T442	Gap junction gamma-2 protein	clinvar
SPART	HGNC:18514	ENSG00000133104	Q8N0X7	Spartin	clinvar
CPT1C	HGNC:18540	ENSG00000169169	Q8TCG5	Palmitoyl thioesterase CPT1C	clinvar
GBA2	HGNC:18986	ENSG00000070610	Q9HCG7	Non-lysosomal glucosylceramidase	clinvar
COQ4	HGNC:19693	ENSG00000167113	Q9Y3A0	Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial	clinvar
DDHD1	HGNC:19714	ENSG00000100523	Q8NEL9	Phospholipase DDHD1	clinvar
TECPR2	HGNC:19957	ENSG00000196663	O15040	Tectonin beta-propeller repeat-containing protein 2	clinvar
USP50	HGNC:20079	ENSG00000170236	Q70EL3	Ubiquitin carboxyl-terminal hydrolase 50	clinvar
SPG21	HGNC:20373	ENSG00000090487	Q9NZD8	Maspardin	clinvar
CYP2U1	HGNC:20582	ENSG00000155016	Q7Z449	Cytochrome P450 2U1	clinvar
ZFYVE26	HGNC:20761	ENSG00000072121	Q68DK2	Zinc finger FYVE domain-containing protein 26	clinvar
TUBB4A	HGNC:20774	ENSG00000104833	P04350	Tubulin beta-4A chain	clinvar
FA2H	HGNC:21197	ENSG00000103089	Q7L5A8	Fatty acid 2-hydroxylase	clinvar
AP5Z1	HGNC:22197	ENSG00000242802	O43299	AP-5 complex subunit zeta-1	clinvar
ADAR	HGNC:225	ENSG00000160710	P55265	Double-stranded RNA-specific adenosine deaminase	clinvar
VPS37A	HGNC:24928	ENSG00000155975	Q8NEZ2	Vacuolar protein sorting-associated protein 37A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPTAN1	Spectrin alpha chain, non-erythrocytic 1	Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.
USP8	Ubiquitin carboxyl-terminal hydrolase 8	Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation.
ZFR	Zinc finger RNA-binding protein	Involved in postimplantation and gastrulation stages of development.
ALDH18A1	Delta-1-pyrroline-5-carboxylate synthase	Bifunctional enzyme that converts glutamate to glutamate 5-semialdehyde, an intermediate in the biosynthesis of proline, ornithine and arginine.
SREBF2	Sterol regulatory element-binding protein 2	Precursor of the transcription factor form (Processed sterol regulatory element-binding protein 2), which is embedded in the endoplasmic reticulum membrane.
REEP2	Receptor expression-enhancing protein 2	Required for endoplasmic reticulum (ER) network formation, shaping and remodeling.
RINT1	RAD50-interacting protein 1	Involved in regulation of membrane traffic between the Golgi and the endoplasmic reticulum (ER); the function is proposed to depend on its association in the NRZ complex which is believed to play a role in SNARE assembly at the ER.
DNM2	Dynamin-2	Catalyzes the hydrolysis of GTP and utilizes this energy to mediate vesicle scission at plasma membrane during endocytosis and filament remodeling at many actin structures during organization of the actin cytoskeleton.
IFRD1	Interferon-related developmental regulator 1	Could play a role in regulating gene activity in the proliferative and/or differentiative pathways induced by NGF.
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.
ATP2B4	Plasma membrane calcium-transporting ATPase 4	Calcium/calmodulin-regulated and magnesium-dependent enzyme that catalyzes the hydrolysis of ATP coupled with the transport of calcium out of the cell.
CNNM2	Metal transporter CNNM2	Divalent metal cation transporter.
RTN2	Reticulon-2	Inhibits amyloid precursor protein processing, probably by blocking BACE1 activity.
SACS	Sacsin	Co-chaperone which acts as a regulator of the Hsp70 chaperone machinery and may be involved in the processing of other ataxia-linked proteins.
SLC16A2	Monocarboxylate transporter 8	Specific thyroid hormone transmembrane transporter, that mediates both uptake and efflux of thyroid hormones across the cell membrane independently of pH or a Na(+) gradient.
SLC1A5	Neutral amino acid transporter B(0)	Sodium-coupled antiporter of neutral amino acids.
SPG11	Spatacsin	May play a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport.
ATL1	Atlastin-1	Atlastin-1 (ATL1) is a membrane-anchored GTPase that mediates the GTP-dependent fusion of endoplasmic reticulum (ER) membranes, maintaining the continuous ER network.
SPAST	Spastin	ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated.
SPG7	Mitochondrial inner membrane m-AAA protease component paraplegin	Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development.
SPTBN2	Spectrin beta chain, non-erythrocytic 2	Probably plays an important role in neuronal membrane skeleton.
TWNK	Twinkle mtDNA helicase	Mitochondrial helicase involved in mtDNA replication and repair.
UBAP1	Ubiquitin-associated protein 1	Component of the ESCRT-I complex, a regulator of vesicular trafficking process.
ERLIN2	Erlin-2	Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs) such as ITPR1.
RAB9B	Ras-related protein Rab-9B	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.
ARHGAP9	Rho GTPase-activating protein 9	GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.
PTPN23	Tyrosine-protein phosphatase non-receptor type 23	Plays a role in sorting of endocytic ubiquitinated cargos into multivesicular bodies (MVBs) via its interaction with the ESCRT-I complex (endosomal sorting complex required for transport I), and possibly also other ESCRT complexes.
COL5A3	Collagen alpha-3(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
BSCL2	Seipin	Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis.
CCT5	T-complex protein 1 subunit epsilon	Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of actin, tubulin and other proteins upon ATP hydrolysis.
PNPLA6	Patatin-like phospholipase domain-containing protein 6	Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho).
ERLIN1	Erlin-1	Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs).
NIPA1	Magnesium transporter NIPA1	Acts as a Mg(2+) transporter.
BICD2	Protein bicaudal D homolog 2	Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin.
GJC2	Gap junction gamma-2 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
SPART	Spartin	Lipophagy receptor that plays an important role in lipid droplet (LD) turnover in motor neurons.
CPT1C	Palmitoyl thioesterase CPT1C	Palmitoyl thioesterase specifically expressed in the endoplasmic reticulum of neurons.
GBA2	Non-lysosomal glucosylceramidase	Non-lysosomal glucosylceramidase that catalyzes the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine) to free glucose and ceramides (such as N-acylsphing-4-enine).
COQ4	Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial	Lyase that catalyzes the C1-decarboxylation of 4-hydroxy-3-methoxy-5-(all-trans-decaprenyl)benzoic acid into 2-methoxy-6-(all-trans-decaprenyl)phenol during ubiquinone biosynthesis.
DDHD1	Phospholipase DDHD1	Phospholipase A1 (PLA1) that hydrolyzes ester bonds at the sn-1 position of glycerophospholipids producing a free fatty acid and a lysophospholipid.
TECPR2	Tectonin beta-propeller repeat-containing protein 2	Probably plays a role as positive regulator of autophagy.
USP50	Ubiquitin carboxyl-terminal hydrolase 50	Deubiquitinating enzyme that removes conjugated ubiquitin from specific proteins to regulate different cellular processes.
SPG21	Maspardin	May play a role as a negative regulatory factor in CD4-dependent T-cell activation.
CYP2U1	Cytochrome P450 2U1	A cytochrome P450 monooxygenase involved in the metabolism of arachidonic acid and its conjugates.
ZFYVE26	Zinc finger FYVE domain-containing protein 26	Phosphatidylinositol 3-phosphate-binding protein required for the abscission step in cytokinesis: recruited to the midbody during cytokinesis and acts as a regulator of abscission.
TUBB4A	Tubulin beta-4A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
FA2H	Fatty acid 2-hydroxylase	Catalyzes the hydroxylation of free fatty acids at the C-2 position to produce 2-hydroxy fatty acids, which are building blocks of sphingolipids and glycosphingolipids common in neural tissue and epidermis.
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.
ADAR	Double-stranded RNA-specific adenosine deaminase	Catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing.
VPS37A	Vacuolar protein sorting-associated protein 37A	Component of the ESCRT-I complex, a regulator of vesicular trafficking process.

Protein-family classification

Druggable: 23 · Difficult: 13 · Unknown: 39 · Druggable fraction: 0.31

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)	13	2.1×	0.078
Scaffold/PPI	9	2.1×	0.129
Phosphatase	2	2.2×	0.564
Transporter	2	2.1×	0.564
Protease	3	1.5×	0.606
Other/Unknown	39	0.9×	0.985
Antibody/Immunoglobulin	2	0.8×	0.985
Transcription factor	4	0.4×	0.985
Kinase	1	0.4×	0.985

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPTAN1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
USP8	Protease	yes	3.4.19.12	Peptidase_C19_UCH, Rhodanese-like_dom, USP8_dimer
ZFR	Transcription factor	no		Matrin/U1-like-C_Znf_C2H2, DZF_dom, Znf_C2H2_type
ALDH18A1	Kinase	yes		GPR_dom, Asp/Glu/Uridylate_kinase, Glu/AcGlu_kinase
SREBF2	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf
REEP2	Other/Unknown	no		TB2_DP1_HVA22
RINT1	Other/Unknown	no		RINT1_Tip20, EXOC6PINT-1/Sec15/Tip20_C_dom2
DNM2	Scaffold/PPI	no	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, PH_domain
IFRD1	Other/Unknown	no		Interferon-rel_develop_reg_C, Interferon-rel_develop_reg_N, ARM-like
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter
ATP2B4	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, ATPase_P-typ_cation-transptr_C
CNNM2	Other/Unknown	no		CBS_dom, CNNM, RmlC-like_jellyroll
RTN2	Other/Unknown	no		Reticulon, RTN1-4
SACS	Other/Unknown	no		Ubiquitin-like_dom, DnaJ_domain, HEPN_dom
SLC16A2	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
SLC1A5	Other/Unknown	no		Na-dicarboxylate_symporter, Na-dicarboxylate_symporter_CS, Na:dicarbo_symporter_sf
SPG11	Other/Unknown	no		Spatacsin, Spatacsin_C_dom
ATL1	Other/Unknown	no		Guanylate-bd_N, P-loop_NTPase, G_GB1_RHD3_dom
SPAST	Enzyme (other)	yes	5.6.1.1	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
SPG7	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
SPTBN2	Scaffold/PPI	no		Actinin_actin-bd_CS, PH_dom-spectrin-type, CH_dom
TWNK	Enzyme (other)	yes	3.6.4.12	DNA_helicase_DnaB-like_C, Twinkle-like, P-loop_NTPase
UBAP1	Other/Unknown	no		UBA-like_sf, UBA, UMA
ERLIN2	Other/Unknown	no		Band_7, Erlin1/2, Band_7/SPFH_dom_sf
RAB9B	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
ARHGAP9	Scaffold/PPI	no		RhoGAP_dom, WW_dom, SH3_domain
PTPN23	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat
COL5A3	Other/Unknown	no		Fib_collagen_C, Collagen, ConA-like_dom_sf
BSCL2	Other/Unknown	no		Seipin
CCT5	Enzyme (other)	yes	3.6.4.B10	Chaperonin_TCP-1_CS, Cpn60/GroEL/TCP-1, Chap_CCT_epsi
PNPLA6	Other/Unknown	no		cNMP-bd_dom, LysoPLipase_patatin_CS, PNPLA_dom
ERLIN1	Other/Unknown	no		Band_7, Erlin1/2, Band_7/SPFH_dom_sf
NIPA1	Other/Unknown	no		Mg_trans_NIPA, EmrE-like
BICD2	Other/Unknown	no		BICD
GJC2	Other/Unknown	no		Connexin, Connexin_N, Connexin_CS
SPART	Other/Unknown	no		MIT_dom, Senescence/spartin_C, MIT_dom_sf
CPT1C	Enzyme (other)	yes	2.3.1.21	Carn_acyl_trans, CAT-like_dom_sf, CPT_N
GBA2	Enzyme (other)	yes	3.2.1.45	GH116_catalytic, 6-hairpin_glycosidase_sf, 6hp_glycosidase-like_sf
COQ4	Other/Unknown	no		Coq4, Coq4_euk
DDHD1	Enzyme (other)	yes	3.1.1.118	DDHD_dom, PA-PLA1
TECPR2	Scaffold/PPI	no		WD40_rpt, Beta-propeller_rpt_TECPR, RCC1/BLIP-II
USP50	Protease	yes		Peptidase_C19_UCH, USP_CS, USP
SPG21	Other/Unknown	no		AB_hydrolase_1, Maspardin, AB_hydrolase_fold
CYP2U1	Other/Unknown	no		Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_E_grp-I_CYP2D-like
ZFYVE26	Transcription factor	no		Znf_FYVE, Znf_FYVE_PHD, Znf_RING/FYVE/PHD
TUBB4A	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
FA2H	Enzyme (other)	yes	1.14.18.6	Cyt_B5-like_heme/steroid-bd, Fatty_acid_hydroxylase, Scs7
AP5Z1	Other/Unknown	no		ARM-like, AP5Z1, AP5Z1_ARM
ADAR	Enzyme (other)	yes	3.5.4.37	A_deamin, dsRBD_dom, WH-like_DNA-bd_sf
VPS37A	Other/Unknown	no		Mod_r, UBQ-conjugating_enzyme/RWD, Helix_hairpin_bin_sf

Expression context

Cohort genes with no expression data: 0.

65 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)	75
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	8
endothelial cell	8
right hemisphere of cerebellum	7
sural nerve	7
cerebellar hemisphere	6
male germ line stem cell (sensu Vertebrata) in testis	6
cerebellar cortex	5
cortical plate	5
granulocyte	5
secondary oocyte	5
Brodmann (1909) area 23	5
middle temporal gyrus	5
ventricular zone	4
oocyte	4
gastrocnemius	4
stromal cell of endometrium	4
C1 segment of cervical spinal cord	4
corpus callosum	4
monocyte	4
ganglionic eminence	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPTAN1	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
USP8	284	ubiquitous	marker	calcaneal tendon, sural nerve, colonic epithelium
ZFR	300	ubiquitous	marker	CA1 field of hippocampus, germinal epithelium of ovary, dorsal motor nucleus of vagus nerve
ALDH18A1	263	ubiquitous	marker	parotid gland, jejunal mucosa, ileal mucosa
SREBF2	287	ubiquitous	marker	ganglionic eminence, cortical plate, ventricular zone
REEP2	224	ubiquitous	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
RINT1	259	ubiquitous	marker	tibia, male germ line stem cell (sensu Vertebrata) in testis, body of pancreas
DNM2	234	ubiquitous	marker	metanephros cortex, granulocyte, mucosa of transverse colon
IFRD1	299	ubiquitous	marker	body of pancreas, jejunal mucosa, skeletal muscle tissue of rectus abdominis
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland
ATP2B4	292	tissue_specific	marker	saphenous vein, cauda epididymis, body of uterus
CNNM2	234	ubiquitous	marker	secondary oocyte, oocyte, right adrenal gland
RTN2	271	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, hindlimb stylopod muscle, gastrocnemius
SACS	286	ubiquitous	marker	Brodmann (1909) area 23, middle frontal gyrus, frontal pole
SLC16A2	183	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, right lobe of liver
SLC1A5	270	ubiquitous	marker	stromal cell of endometrium, endometrium epithelium, olfactory segment of nasal mucosa
SPG11	295	ubiquitous	marker	bronchial epithelial cell, granulocyte, calcaneal tendon
ATL1	241	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, endothelial cell
SPAST	284	ubiquitous	marker	cortical plate, oocyte, secondary oocyte
SPG7	302	ubiquitous	marker	primordial germ cell in gonad, sural nerve, left lobe of thyroid gland
SPTBN2	238	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
TWNK	211	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, tendon of biceps brachii, gastrocnemius
UBAP1	288	ubiquitous	marker	lower esophagus mucosa, gastrocnemius, muscle of leg
ERLIN2	277	ubiquitous	marker	choroid plexus epithelium, renal medulla, calcaneal tendon
RAB9B	207	broad	yes	left ventricle myocardium, Brodmann (1909) area 23, endothelial cell
ARHGAP9	235	broad	marker	granulocyte, blood, spleen
PTPN23	228	ubiquitous	marker	sural nerve, pituitary gland, upper arm skin
COL5A3	240	broad	marker	sural nerve, apex of heart, endocervix
BSCL2	149	ubiquitous	marker	superior frontal gyrus, primary visual cortex, pituitary gland
CCT5	298	ubiquitous	marker	primordial germ cell in gonad, endometrium epithelium, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 163.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH18A1	7,351
GFAP	6,997
CCT5	6,388
TUBB4A	5,138
DNM2	4,715
GAD1	4,362
SPG7	3,970
SPAST	3,393
ATP2B4	3,368
ADAR	3,166

Intra-cohort edges

A	B	Sources
ABCD1	SPAST	string_interaction
ADAR	RNASEH2B	string_interaction
ALDH18A1	REEP1	string_interaction
ALDH18A1	SPAST	string_interaction
ALDH18A1	WASHC5	string_interaction
AP5B1	AP5Z1	string_interaction
AP5B1	SPG11	biogrid_interaction, intact, string_interaction
AP5B1	ZFYVE26	intact, string_interaction
AP5Z1	ARSI	string_interaction
AP5Z1	CYP2U1	string_interaction
AP5Z1	CYP7B1	string_interaction
AP5Z1	DDHD1	string_interaction
AP5Z1	DDHD2	string_interaction
AP5Z1	GBA2	string_interaction
AP5Z1	GJC2	string_interaction
AP5Z1	MTRFR	string_interaction
AP5Z1	PNPLA6	string_interaction
AP5Z1	REEP2	string_interaction
AP5Z1	RTN2	string_interaction
AP5Z1	SPART	string_interaction
AP5Z1	SPG11	intact, string_interaction
AP5Z1	SPG21	string_interaction
AP5Z1	SPG7	string_interaction
AP5Z1	TECPR2	string_interaction
AP5Z1	VPS37A	string_interaction
AP5Z1	ZFR	string_interaction
AP5Z1	ZFYVE26	intact, string_interaction
ARSI	C19orf12	string_interaction
ARSI	DDHD2	string_interaction
ARSI	MTRFR	string_interaction
ARSI	PGAP1	string_interaction
ARSI	REEP2	string_interaction
ARSI	SPG21	string_interaction
ARSI	TECPR2	string_interaction
ARSI	VPS37A	string_interaction
ARSI	ZFR	string_interaction
ATL1	DNM2	intact
ATL1	NIPA1	string_interaction
ATL1	REEP1	string_interaction
ATL1	REEP2	string_interaction
ATL1	RTN2	string_interaction
ATL1	SPART	string_interaction
ATL1	SPAST	intact, string_interaction
ATL1	SPG11	string_interaction
ATL1	WASHC5	string_interaction
ATL1	ZFYVE26	string_interaction
BSCL2	IFRD1	intact
BSCL2	REEP1	string_interaction
BSCL2	RTN2	string_interaction
BSCL2	SPART	string_interaction

Structural data

PDB: 42 · AlphaFold-only: 32 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CCT5	P48643	69
ERCC2	P18074	51
SLC1A5	Q15758	27
ADAR	P55265	24
WDR48	Q8TAF3	19
ABCD1	P33897	14
ATL1	Q8WXF7	14
PTPN23	Q9H3S7	11
USP8	P40818	9
FANCI	Q9NVI1	8
SPTAN1	Q13813	7
CNNM2	Q9H8M5	7
SACS	Q9NZJ4	7
SLC16A2	P36021	7
SPAST	Q9UBP0	7
ERLIN2	O94905	4
RNASEH2B	Q5TBB1	4
SPG11	Q96JI7	3
SPTBN2	O15020	3
UBAP1	Q9NZ09	3
ARHGAP9	Q9BRR9	3
ERLIN1	O75477	3
CEP63	Q96MT8	3
ATP2B4	P23634	2
TWNK	Q96RR1	2
BICD2	Q8TD16	2
SPART	Q8N0X7	2
AP5B1	Q2VPB7	2
RETREG1	Q9H6L5	2
GAD1	Q99259	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SPG21	Q9NZD8	93.02
TUBB4A	P04350	92.25
CYP7B1	O75881	91.98
ENTPD1	P49961	90.85
WASHC5	Q12768	90.27
GBA2	Q9HCG7	89.77
PGAP1	Q75T13	89.15
COQ4	Q9Y3A0	88.56
CYP2U1	Q7Z449	88.45
ARSI	Q5FYB1	87.35
NIPA1	Q7RTP0	86.00
RINT1	Q6NUQ1	85.97
FA2H	Q7L5A8	85.53
AP5Z1	O43299	85.32
IFRD1	O00458	84.46
USP50	Q70EL3	80.69
SH3TC2	Q8TF17	78.63
DNAJC16	Q9Y2G8	77.54
DDHD2	O94830	74.70
MILR1	Q7Z6M3	74.55
FLRT1	Q9NZU1	73.46
PNPLA6	Q8IY17	69.75
GJC2	Q5T442	68.50
TECPR2	O15040	68.27
REEP1	Q9H902	67.91
DDHD1	Q8NEL9	67.11
REEP2	Q9BRK0	65.05
PLEKHG5	O94827	64.94
ZFR	Q96KR1	62.11
C19orf12	Q9NSK7	59.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 350. Enrichment computed across 104 evidence-associated genes (70 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 70 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Membrane Trafficking	12	6.4×	1e-04	SPTAN1, SPTBN2, BICD2, TUBB4A, ALS2, AP4B1, AP4E1, AP4M1 (+4 more)
Vesicle-mediated transport	12	6.0×	1e-04	SPTAN1, SPTBN2, BICD2, TUBB4A, ALS2, AP4B1, AP4E1, AP4M1 (+4 more)
Lysosome Vesicle Biogenesis	5	23.3×	2e-04	DNM2, AP4B1, AP4E1, AP4M1, AP4S1
Strand-asynchronous mitochondrial DNA replication	3	48.9×	0.002	TWNK, POLG, POLG2
trans-Golgi Network Vesicle Budding	4	14.5×	0.010	AP4B1, AP4E1, AP4M1, AP4S1
Golgi-to-ER retrograde transport	5	9.5×	0.010	BICD2, TUBB4A, KIF1C, KIF5A, KIF1A
COPI-dependent Golgi-to-ER retrograde traffic	5	7.9×	0.021	TUBB4A, RINT1, KIF1C, KIF5A, KIF1A
Intra-Golgi and retrograde Golgi-to-ER traffic	5	7.5×	0.023	BICD2, TUBB4A, KIF1C, KIF5A, KIF1A
Kinesins	4	10.2×	0.024	TUBB4A, KIF1C, KIF5A, KIF1A
Interaction between L1 and Ankyrins	3	15.8×	0.031	SPTAN1, SPTBN2, L1CAM
Downregulation of ERBB2:ERBB3 signaling	2	23.3×	0.076	USP8, NRG1
Membrane binding and targetting of GAG proteins	2	23.3×	0.076	UBAP1, VPS37A
L1CAM interactions	4	6.9×	0.076	SPTAN1, SPTBN2, TUBB4A, L1CAM
Mitochondrial protein degradation	4	6.5×	0.076	ALDH18A1, SPG7, TWNK, HSPD1
Hemostasis	7	3.6×	0.076	TUBB4A, KIF1C, KIF5A, L1CAM, MAG, ATP2B4, KIF1A
Recycling pathway of L1	3	9.6×	0.081	TUBB4A, DNM2, L1CAM
Factors involved in megakaryocyte development and platelet production	5	4.7×	0.083	TUBB4A, IFNA5, KIF1C, KIF5A, KIF1A
Defective CYP2U1 causes SPG56	1	163.1×	0.098	CYP2U1
Defective CYP7B1 causes SPG5A and CBAS3	1	163.1×	0.098	CYP7B1
Defective SLC33A1 causes spastic paraplegia 42 (SPG42)	1	163.1×	0.098	SLC33A1
Golgi Associated Vesicle Biogenesis	3	8.6×	0.098	DNM2, AP4B1, AP4E1
Nervous system development	6	3.7×	0.098	SPTAN1, SPTBN2, SREBF2, TUBB4A, L1CAM, MAG
MHC class II antigen presentation	4	5.1×	0.119	SPTBN2, TUBB4A, DNM2, KIF5A
Defective ABCD1 causes ALD	1	81.6×	0.143	ABCD1
C6 deamination of adenosine	1	81.6×	0.143	ADAR
Formation of editosomes by ADAR proteins	1	81.6×	0.143	ADAR
GABA synthesis	1	81.6×	0.143	GAD1
Basigin interactions	2	12.6×	0.143	L1CAM, MAG
Formation of tubulin folding intermediates by CCT/TriC	2	12.1×	0.143	CCT5, TUBB4A
Budding and maturation of HIV virion	2	11.7×	0.143	UBAP1, VPS37A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 95 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
vesicle-mediated transport	10	10.1×	4e-05	SPTBN2, AP5Z1, AP5B1, AP4B1, AP4E1, AP4M1, AP4S1, KIF1C (+2 more)
retrograde neuronal dense core vesicle transport	3	106.4×	6e-04	KIF1C, KIF5A, KIF1A
SREBP signaling pathway	3	59.1×	0.003	SREBF2, ERLIN2, ERLIN1
mitochondrial DNA replication	3	48.4×	0.005	TWNK, POLG, POLG2
protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	3	33.3×	0.010	UBAP1, PTPN23, VPS37A
lipid droplet organization	3	29.6×	0.010	BSCL2, SPART, DDHD2
endosome organization	4	15.8×	0.010	USP8, USP50, WASHC5, ALS2
protein targeting	4	15.4×	0.010	AP4B1, AP4E1, AP4M1, AP4S1
cholesterol metabolic process	5	10.3×	0.010	SREBF2, ERLIN2, ERLIN1, GBA2, CYP7B1
anterograde neuronal dense core vesicle transport	2	88.7×	0.012	KIF1C, KIF1A
synaptic vesicle transport	3	26.6×	0.012	SPG11, DNM2, KIF5A
lysosome organization	4	12.9×	0.015	SPG11, ZFYVE26, AP5Z1, WASHC5
autophagosome organization	2	71.0×	0.016	SPG11, ZFYVE26
central nervous system myelin formation	2	50.7×	0.024	ERCC2, MAG
negative regulation of cholesterol biosynthetic process	2	50.7×	0.024	ERLIN2, ERLIN1
anterograde axonal transport	3	18.4×	0.024	SPAST, SPG7, KIF1A
DNA-templated DNA replication	3	17.7×	0.024	TWNK, POLG, POLG2
endosomal transport	4	10.3×	0.024	AP5Z1, AP5B1, WASHC5, ALS2
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	3	17.2×	0.025	UBAP1, PTPN23, VPS37A
endoplasmic reticulum tubular network membrane organization	2	44.4×	0.029	RTN2, ATL1
axon development	3	14.4×	0.038	AP5Z1, L1CAM, PLP1
peripheral nervous system myelin maintenance	2	32.2×	0.045	FA2H, SH3TC2
regulation of cholesterol biosynthetic process	2	32.2×	0.045	ERLIN2, ERLIN1
actin filament capping	2	32.2×	0.045	SPTAN1, SPTBN2
membrane fission	3	13.0×	0.045	SPAST, UBAP1, VPS37A
protein hexamerization	2	29.6×	0.052	SPAST, TWNK
intracellular protein localization	5	5.5×	0.055	ALS2, AP4B1, AP4E1, AP4M1, AP4S1
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	3	10.6×	0.068	BICD2, RINT1, KIF1C
astrocyte development	2	23.6×	0.071	GFAP, PLP1
endoplasmic reticulum tubular network organization	2	23.6×	0.071	REEP2, REEP1

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Miglustat.

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 6 · Phased (≥1): 7 · Undrugged: 68

Druggability breadth: 43 of 104 evidence-associated genes (41%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GBA2	MIGLUSTAT
CYP2U1	PAZOPANIB
TUBB4A	COLCHICINE
WDR48	PIMOZIDE
ERCC2	SUNITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBB4A	21	4
ERCC2	16	4
GBA2	6	4
WDR48	4	4
SPTAN1	1	2
CYP2U1	1	4
ENTPD1	1	3
USP8	0	0
ZFR	0	0
ALDH18A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIGLUSTAT	4	GBA2
MIGALASTAT	4	GBA2
PAZOPANIB	4	CYP2U1
COLCHICINE	4	TUBB4A
VINBLASTINE	4	TUBB4A
LEVOFLOXACIN ANHYDROUS	4	TUBB4A
DOCETAXEL	4	TUBB4A
NOSCAPINE	4	TUBB4A
VINBLASTINE SULFATE	4	TUBB4A
PACLITAXEL	4	TUBB4A
LEVOFLOXACIN	4	TUBB4A
VINORELBINE	4	TUBB4A
TIRBANIBULIN	4	TUBB4A
PODOFILOX	4	TUBB4A
VINCRISTINE	4	TUBB4A
DOCETAXEL ANHYDROUS	4	TUBB4A
PIMOZIDE	4	WDR48
TRIFLUOPERAZINE	4	WDR48
SUNITINIB	4	ERCC2
LUCERASTAT	3	GBA2
PATUPILONE	3	TUBB4A
FLUPENTIXOL	3	WDR48
SURAMIN	3	ENTPD1
DINACICLIB	3	ERCC2
DEFACTINIB	3	ERCC2
ALVOCIDIB	3	ERCC2
MOLIBRESIB	2	SPTAN1, WDR48
AFEGOSTAT	2	GBA2
DUVOGLUSTAT	2	GBA2
NIZUBAGLUSTAT	2	GBA2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 18.

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

Symbol	Assays	Type breakdown
TUBB4A	1,758	Binding:1718, Functional:34, ADMET:6
CYP2U1	183	ADMET:181, Binding:2
USP8	54	Binding:51, Functional:3
WDR48	43	Binding:43
GBA2	38	Binding:38
ENTPD1	32	Binding:27, ADMET:5
SREBF2	22	Binding:22
DNM2	15	Binding:15
SLC1A5	13	Binding:13
SPTAN1	7	Binding:7
AP5Z1	6	Binding:6
ALDH18A1	3	Binding:3
CCT5	3	Binding:3
ERCC2	3	Binding:3
ERLIN2	2	Binding:2
FA2H	2	Binding:2
ADAR	2	Binding:2
CYP7B1	2	ADMET:2
DDHD2	2	Functional:2
ZFR	1	Binding:1
SLC16A2	1	Functional:1
SPG11	1	Binding:1
SPAST	1	Binding:1
PNPLA6	1	Binding:1
ERLIN1	1	Binding:1
FANCI	1	Binding:1
WASHC5	1	Binding:1
GAD1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
USP8	3.4.19.12	ubiquitinyl hydrolase 1
DNM2	3.6.5.5	dynamin GTPase
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter
SPAST	5.6.1.1	microtubule-severing ATPase
SPG7	3.4.24.B18
TWNK	3.6.4.12	DNA helicase
PTPN23	3.1.3.48	protein-tyrosine-phosphatase
CCT5	3.6.4.B10
CPT1C	2.3.1.21	carnitine O-palmitoyltransferase
GBA2	3.2.1.45	glucosylceramidase
DDHD1	3.1.1.118, 3.1.1.32	phospholipid sn-1 acylhydrolase, phospholipase A1
FA2H	1.14.18.6	4-hydroxysphinganine ceramide fatty acyl 2-hydroxylase
ADAR	3.5.4.37	double-stranded RNA adenine deaminase
RNASEH2B	3.1.26.4	ribonuclease H
CYP7B1	1.14.14.29	25/26-hydroxycholesterol 7alpha-hydroxylase
ENTPD1	3.6.1.5	apyrase
ERCC2	3.6.4.12	DNA helicase
GAD1	4.1.1.15	glutamate decarboxylase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CYP2U1	183
TUBB4A	1,758

Pharmacogenomics

Cohort genes with a PharmGKB record: 74; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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)
MIGALASTAT	4	GBA2
PAZOPANIB	4	CYP2U1
COLCHICINE	4	TUBB4A
VINBLASTINE	4	TUBB4A
LEVOFLOXACIN ANHYDROUS	4	TUBB4A
DOCETAXEL	4	TUBB4A
NOSCAPINE	4	TUBB4A
VINBLASTINE SULFATE	4	TUBB4A
PACLITAXEL	4	TUBB4A
LEVOFLOXACIN	4	TUBB4A
VINORELBINE	4	TUBB4A
TIRBANIBULIN	4	TUBB4A
PODOFILOX	4	TUBB4A
VINCRISTINE	4	TUBB4A
DOCETAXEL ANHYDROUS	4	TUBB4A
PIMOZIDE	4	WDR48
TRIFLUOPERAZINE	4	WDR48
SUNITINIB	4	ERCC2
LUCERASTAT	3	GBA2
PATUPILONE	3	TUBB4A
FLUPENTIXOL	3	WDR48
SURAMIN	3	ENTPD1
DINACICLIB	3	ERCC2
DEFACTINIB	3	ERCC2
ALVOCIDIB	3	ERCC2
MOLIBRESIB	2	SPTAN1, WDR48
AFEGOSTAT	2	GBA2
DUVOGLUSTAT	2	GBA2
NIZUBAGLUSTAT	2	GBA2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	GBA2, CYP2U1, TUBB4A, WDR48, ERCC2
B	Phased (≥1) drug, not yet approved	2	SPTAN1, ENTPD1
C	Druggable family + PDB, no drug	13	USP8, ALDH18A1, ABCD1, SLC16A2, SPAST, SPG7, TWNK, PTPN23, CCT5, CPT1C (+3 more)
D	Druggable family + AlphaFold only, no drug	7	DDHD1, USP50, FA2H, CYP7B1, MILR1, ARSI, FLRT1
E	Difficult family or no structure, no drug	48	ZFR, SREBF2, REEP2, RINT1, DNM2, IFRD1, ATP2B4, CNNM2, RTN2, SACS (+38 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DDHD2	2	CYP2U1, GBA2
USP8	54	—
ZFR	1	—
ALDH18A1	3	—
SREBF2	22	—
REEP2	0	—
RINT1	0	—
DNM2	15	—
IFRD1	0	—
ABCD1	0	—
ATP2B4	0	—
CNNM2	0	—
RTN2	0	—
SACS	0	—
SLC16A2	1	—
SLC1A5	13	—
SPG11	1	—
ATL1	0	—
SPAST	1	—
SPG7	0	—
SPTBN2	0	—
TWNK	0	—
UBAP1	0	—
ERLIN2	2	—
RAB9B	0	—
ARHGAP9	0	—
PTPN23	0	—
COL5A3	0	—
BSCL2	0	—
CCT5	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 51.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	43
PHASE2	2
PHASE1/PHASE2	2
PHASE4	1
PHASE2/PHASE3	1
PHASE1	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
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)
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT05354622	Not specified	RECRUITING	Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq)
NCT05848271	Not specified	RECRUITING	Natural History Study of Patients with HPDL Mutations
NCT06156813	Not specified	RECRUITING	Turkish Lower-Extremity Motor Activity Log (LE-MAL)
NCT06229626	Not specified	RECRUITING	Evaluation of an Intensive Training Program for Patients with Hereditary Spastic Paraparesis SPG4/Spast
NCT06553976	Not specified	RECRUITING	Spastic Paraplegia - Centers of Excellence Research Network
NCT06572046	Not specified	RECRUITING	STOP-HSP.Net: a Registry for Hereditary Spastic Paraplegia as an Integration Tool for Future Therapeutic Strategies
NCT06573866	Not specified	RECRUITING	Enhancement of Quality of Work And Life
NCT06728787	Not specified	RECRUITING	Robot-assisted Walking Treatment in Hereditary Spastic Paraplegia (HSP)
NCT06742697	Not specified	RECRUITING	Flexibility, Resistance, Aerobic, Movement Execution Training in Adults With Hereditary Spastic Paraplegia
NCT06844734	Not specified	RECRUITING	A Prospective Cohort Study of ITB Treatment for HSP
NCT06936163	Not specified	RECRUITING	A Prospective Cohort Study of Surgical Treatment for Foot Deformities in HSP
NCT07090057	Not specified	RECRUITING	The Effect of Targeting the Plantaris Muscle-tendon in Surgical Correction of Ankle Equinus in Children
NCT07136844	Not specified	RECRUITING	Gait Analysis Parameter and Upper Limb Evaluation in Adult Patients With Neurological or Metabolic Pathology
NCT07417943	Not specified	RECRUITING	Neuromodulation to Enhance Motor Function in HSP
NCT07478172	Not specified	RECRUITING	Effects of Whole-body Electrical Muscle Stimulation Exercise on Adults With Neuromuscular Disease
NCT07561359	Not specified	ENROLLING_BY_INVITATION	12-Week Strength and Functional Exercise Program for Hereditary Spastic Paraplegia Trial (HSPMOVE)
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CYCLOSERINE	4	1
DALFAMPRIDINE	4	1
MIGLUSTAT	4	1
LEVCYCLOSERINE	2	1
SNAP (S-NITROSO-N-ACETYLPENICILLAMINE)	0	1