hereditary spastic paraplegia 5A

Summary

hereditary spastic paraplegia 5A (MONDO:0010047) is a disease caused by CYP7B1 (GenCC Strong), with 7 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: CYP7B1 (GenCC Strong)
• Cohort genes: 7
• ClinVar variants: 97
• Phenotypes (HPO): 24
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0001258	Spastic paraplegia	Very frequent (80-99%)
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0002495	Impaired vibratory sensation	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0007340	Lower limb muscle weakness	Very frequent (80-99%)
HP:0000079	Abnormality of the urinary system	Frequent (30-79%)
HP:0001317	Abnormal cerebellum morphology	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002500	Abnormal cerebral white matter morphology	Frequent (30-79%)
HP:0007210	Lower limb amyotrophy	Frequent (30-79%)
HP:0011448	Ankle clonus	Frequent (30-79%)
HP:0002070	Limb ataxia	Occasional (5-29%)
HP:0002078	Truncal ataxia	Occasional (5-29%)
HP:0006827	Atrophy of the spinal cord	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Very rare (<1-4%)
HP:0000518	Cataract	Very rare (<1-4%)
HP:0000639	Nystagmus	Very rare (<1-4%)
HP:0001260	Dysarthria	Very rare (<1-4%)
HP:0001271	Polyneuropathy	Very rare (<1-4%)
HP:0002015	Dysphagia	Very rare (<1-4%)
HP:0002650	Scoliosis	Very rare (<1-4%)
HP:0003484	Upper limb muscle weakness	Very rare (<1-4%)
HP:0006986	Upper limb spasticity	Very rare (<1-4%)
HP:0009129	Upper limb amyotrophy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 5A
Mondo ID	MONDO:0010047
OMIM	270800
Orphanet	100986
DOID	DOID:0110810
SNOMED CT	763373005
UMLS	C1849115
MedGen	376521
GARD	0004926
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic paraplegia · autosomal recessive spastic paraplegia type 5A · CYP7B1 pure or complex autosomal recessive spastic paraplegia · hereditary spastic paraplegia type 5A · pure or complex autosomal recessive spastic paraplegia caused by mutation in CYP7B1 · spastic paraplegia 5A · spastic paraplegia 5A, autosomal recessive · spastic paraplegia type 5A · spastic paraplegia type 5B, recessive · SPG5A

Data availability: 97 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 5A

Related subtypes (44): hereditary spastic paraplegia 3A, hereditary spastic paraplegia 4, mast syndrome, 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

97 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 28 conflicting classifications of pathogenicity, 13 pathogenic/likely pathogenic, 12 pathogenic, 7 likely pathogenic, 4 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
120179	NM_004820.5(CYP7B1):c.889A>G (p.Thr297Ala)	CYP7B1	Pathogenic	criteria provided, multiple submitters, no conflicts
219912	NM_004820.5(CYP7B1):c.334C>T (p.Arg112Ter)	CYP7B1	Pathogenic	criteria provided, multiple submitters, no conflicts
225337	NM_004820.5(CYP7B1):c.259+2T>C	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
240073	NM_004820.5(CYP7B1):c.321_324del (p.Lys107fs)	CYP7B1	Pathogenic	criteria provided, multiple submitters, no conflicts
2885037	NM_004820.5(CYP7B1):c.650T>A (p.Leu217Ter)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2983280	NM_004820.5(CYP7B1):c.1233+1G>A	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
409026	NM_004820.5(CYP7B1):c.1286dup (p.Lys430fs)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488846	NM_004820.5(CYP7B1):c.187C>T (p.Arg63Ter)	CYP7B1	Pathogenic	criteria provided, multiple submitters, no conflicts
489179	NM_004820.5(CYP7B1):c.1354C>T (p.Arg452Ter)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
586668	NM_004820.5(CYP7B1):c.1249C>T (p.Arg417Cys)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6100	NM_004820.5(CYP7B1):c.1162C>T (p.Arg388Ter)	CYP7B1	Pathogenic	criteria provided, multiple submitters, no conflicts
6101	NM_004820.5(CYP7B1):c.1088C>T (p.Ser363Phe)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6102	NM_004820.5(CYP7B1):c.169G>A (p.Gly57Arg)	CYP7B1	Pathogenic	no assertion criteria provided
6103	NM_004820.5(CYP7B1):c.1250G>A (p.Arg417His)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6104	NM_004820.5(CYP7B1):c.647T>C (p.Phe216Ser)	CYP7B1	Pathogenic	no assertion criteria provided
6105	NM_004820.5(CYP7B1):c.825T>A (p.Tyr275Ter)	CYP7B1	Pathogenic	criteria provided, multiple submitters, no conflicts
6106	NM_004820.5(CYP7B1):c.1408T>A (p.Phe470Ile)	CYP7B1	Pathogenic	no assertion criteria provided
6107	NM_004820.5(CYP7B1):c.1456C>T (p.Arg486Cys)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
849738	NM_004820.5(CYP7B1):c.650dup (p.Leu217fs)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
942745	NM_004820.5(CYP7B1):c.961G>A (p.Glu321Lys)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
989022	NM_004820.5(CYP7B1):c.67del (p.Ala23fs)	CYP7B1	Pathogenic	criteria provided, single submitter
989025	NM_004820.5(CYP7B1):c.260-1G>A	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
989026	NM_004820.5(CYP7B1):c.314dup (p.Asn105fs)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
989028	NM_004820.5(CYP7B1):c.1168G>T (p.Gly390Ter)	CYP7B1	Pathogenic	criteria provided, single submitter
989030	NM_004820.5(CYP7B1):c.1311_1316delinsAGAA (p.Cys437_Leu439delinsTer)	CYP7B1	Pathogenic	criteria provided, single submitter
2428781	NM_004820.5(CYP7B1):c.1162C>G (p.Arg388Gly)	CYP7B1	Likely pathogenic	criteria provided, single submitter
3595818	NM_004820.5(CYP7B1):c.1108C>T (p.Arg370Cys)	CYP7B1	Likely pathogenic	criteria provided, single submitter
3899226	NM_004820.5(CYP7B1):c.1314C>G (p.Tyr438Ter)	CYP7B1	Likely pathogenic	criteria provided, single submitter
4532102	NM_004820.5(CYP7B1):c.1351G>A (p.Gly451Ser)	CYP7B1	Likely pathogenic	criteria provided, single submitter
4537493	NM_004820.5(CYP7B1):c.361_364del (p.Lys121fs)	CYP7B1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 14 · 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
CYP7B1	Strong	Autosomal recessive	hereditary spastic paraplegia 5A	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP7B1	Orphanet:100986	Autosomal recessive spastic paraplegia type 5A
CYP7B1	Orphanet:79302	Congenital bile acid synthesis defect type 3
MCOLN1	Orphanet:578	Mucolipidosis type IV
REEP2	Orphanet:401849	Autosomal spastic paraplegia type 72
GBA2	Orphanet:320391	Autosomal recessive spastic paraplegia type 46
GBA2	Orphanet:352641	Autosomal recessive cerebellar ataxia with late-onset spasticity
CYP2U1	Orphanet:320411	Autosomal recessive spastic paraplegia type 56
C19orf12	Orphanet:289560	Mitochondrial membrane protein-associated neurodegeneration
C19orf12	Orphanet:320370	Autosomal recessive spastic paraplegia type 43
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

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYP7B1	HGNC:2652	ENSG00000172817	O75881	Cytochrome P450 7B1	gencc,clinvar
MCOLN1	HGNC:13356	ENSG00000090674	Q9GZU1	Mucolipin-1	clinvar
REEP2	HGNC:17975	ENSG00000132563	Q9BRK0	Receptor expression-enhancing protein 2	clinvar
GBA2	HGNC:18986	ENSG00000070610	Q9HCG7	Non-lysosomal glucosylceramidase	clinvar
CYP2U1	HGNC:20582	ENSG00000155016	Q7Z449	Cytochrome P450 2U1	clinvar
C19orf12	HGNC:25443	ENSG00000131943	Q9NSK7	Protein C19orf12	clinvar
ALDH18A1	HGNC:9722	ENSG00000059573	P54886	Delta-1-pyrroline-5-carboxylate synthase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP7B1	Cytochrome P450 7B1	A cytochrome P450 monooxygenase involved in the metabolism of endogenous oxysterols and steroid hormones, including neurosteroids.
MCOLN1	Mucolipin-1	Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis.
REEP2	Receptor expression-enhancing protein 2	Required for endoplasmic reticulum (ER) network formation, shaping and remodeling.
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).
CYP2U1	Cytochrome P450 2U1	A cytochrome P450 monooxygenase involved in the metabolism of arachidonic acid and its conjugates.
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.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.43

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)	2	3.4×	0.330
Kinase	1	4.0×	0.340
Other/Unknown	4	1.0×	0.626

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYP7B1	Enzyme (other)	yes	1.14.14.29	Cyt_P450, Cyt_P450_E_grp-IV, Cyt_P450_CYP7A1-type
MCOLN1	Other/Unknown	no		PKD1_2_channel, Mucolipin, ML1_ELD
REEP2	Other/Unknown	no		TB2_DP1_HVA22
GBA2	Enzyme (other)	yes	3.2.1.45	GH116_catalytic, 6-hairpin_glycosidase_sf, 6hp_glycosidase-like_sf
CYP2U1	Other/Unknown	no		Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_E_grp-I_CYP2D-like
C19orf12	Other/Unknown	no		C19orf12
ALDH18A1	Kinase	yes		GPR_dom, Asp/Glu/Uridylate_kinase, Glu/AcGlu_kinase

Expression context

Cohort genes with no expression data: 0.

6 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right hemisphere of cerebellum	2
epithelial cell of pancreas	2
esophagus squamous epithelium	1
oral cavity	1
seminal vesicle	1
right adrenal gland	1
right adrenal gland cortex	1
spleen	1
cerebellar cortex	1
cerebellar hemisphere	1
metanephros cortex	1
small intestine Peyer’s patch	1
germinal epithelium of ovary	1
thymus	1
endothelial cell	1
kidney epithelium	1
ileal mucosa	1
jejunal mucosa	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYP7B1	239	broad	marker	seminal vesicle, oral cavity, esophagus squamous epithelium
MCOLN1	255	ubiquitous	marker	spleen, right adrenal gland cortex, right adrenal gland
REEP2	224	ubiquitous	yes	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
GBA2	248	ubiquitous	marker	metanephros cortex, right hemisphere of cerebellum, small intestine Peyer’s patch
CYP2U1	241	ubiquitous	marker	thymus, germinal epithelium of ovary, epithelial cell of pancreas
C19orf12	253	ubiquitous	marker	endothelial cell, kidney epithelium, epithelial cell of pancreas
ALDH18A1	263	ubiquitous	marker	parotid gland, jejunal mucosa, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH18A1	7,351
CYP7B1	1,891
CYP2U1	1,748
GBA2	1,709
MCOLN1	1,412
REEP2	937
C19orf12	584

Intra-cohort edges

A	B	Sources
C19orf12	GBA2	string_interaction
CYP2U1	GBA2	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCOLN1	Q9GZU1	25
ALDH18A1	P54886	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYP7B1	O75881	91.98
GBA2	Q9HCG7	89.77
CYP2U1	Q7Z449	88.45
REEP2	Q9BRK0	65.05
C19orf12	Q9NSK7	59.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 7 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective CYP2U1 causes SPG56	1	2284.0×	0.004	CYP2U1
Defective CYP7B1 causes SPG5A and CBAS3	1	2284.0×	0.004	CYP7B1
Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE)	1	253.8×	0.019	CYP2U1
Miscellaneous substrates	1	190.3×	0.019	CYP2U1
Glutamate and glutamine metabolism	1	163.1×	0.019	ALDH18A1
Synthesis of bile acids and bile salts via 27-hydroxycholesterol	1	152.3×	0.019	CYP7B1
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	91.4×	0.020	CYP7B1
Synthesis of bile acids and bile salts	1	81.6×	0.020	CYP7B1
TRP channels	1	81.6×	0.020	MCOLN1
Endogenous sterols	1	78.8×	0.020	CYP7B1
Transferrin endocytosis and recycling	1	73.7×	0.020	MCOLN1
Iron uptake and transport	1	69.2×	0.020	MCOLN1
Glycosphingolipid catabolism	1	58.6×	0.022	GBA2
Stimuli-sensing channels	1	27.2×	0.044	MCOLN1
Mitochondrial protein degradation	1	22.8×	0.049	ALDH18A1
Ion channel transport	1	19.2×	0.054	MCOLN1
Transport of small molecules	1	5.0×	0.184	MCOLN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-ornithine biosynthetic process	1	2407.4×	0.010	ALDH18A1
protein transport into membrane raft	1	1203.7×	0.010	REEP2
glucosylceramide catabolic process	1	802.5×	0.010	GBA2
L-citrulline biosynthetic process	1	601.9×	0.010	ALDH18A1
calcium ion export	1	601.9×	0.010	MCOLN1
positive regulation of lysosome organization	1	601.9×	0.010	MCOLN1
cytochrome metabolic process	1	481.5×	0.010	CYP2U1
glycoside catabolic process	1	401.2×	0.010	GBA2
B cell chemotaxis	1	401.2×	0.010	CYP7B1
sensory perception of bitter taste	1	401.2×	0.010	REEP2
L-proline biosynthetic process	1	401.2×	0.010	ALDH18A1
regulation of membrane lipid distribution	1	401.2×	0.010	GBA2
obsolete organic acid metabolic process	1	343.9×	0.010	CYP2U1
iron ion transmembrane transport	1	343.9×	0.010	MCOLN1
sensory perception of sweet taste	1	343.9×	0.010	REEP2
cholesterol metabolic process	2	56.0×	0.010	CYP7B1, GBA2
cellular response to pH	1	300.9×	0.011	MCOLN1
prostate gland epithelium morphogenesis	1	267.5×	0.011	CYP7B1
response to temperature stimulus	1	218.9×	0.011	ALDH18A1
transferrin transport	1	218.9×	0.011	MCOLN1
glycosphingolipid catabolic process	1	218.9×	0.011	GBA2
omega-hydroxylase P450 pathway	1	218.9×	0.011	CYP2U1
glycolipid biosynthetic process	1	200.6×	0.012	GBA2
phagosome maturation	1	172.0×	0.012	MCOLN1
glutamate metabolic process	1	160.5×	0.012	ALDH18A1
regulation of microtubule polymerization	1	160.5×	0.012	GBA2
negative regulation of intracellular estrogen receptor signaling pathway	1	160.5×	0.012	CYP7B1
endoplasmic reticulum tubular network organization	1	160.5×	0.012	REEP2
bile acid metabolic process	1	141.6×	0.013	GBA2
mitochondrial calcium ion homeostasis	1	141.6×	0.013	C19orf12

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 5 of 7 evidence-associated genes (71%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GBA2	6	4
CYP2U1	1	4
CYP7B1	0	0
MCOLN1	0	0
REEP2	0	0
C19orf12	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
LUCERASTAT	3	GBA2
AFEGOSTAT	2	GBA2
DUVOGLUSTAT	2	GBA2
NIZUBAGLUSTAT	2	GBA2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CYP2U1	183	ADMET:181, Binding:2
GBA2	38	Binding:38
MCOLN1	9	Binding:9
ALDH18A1	3	Binding:3
CYP7B1	2	ADMET:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP7B1	1.14.14.29	25/26-hydroxycholesterol 7alpha-hydroxylase
GBA2	3.2.1.45	glucosylceramidase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CYP2U1	183

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

7 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)
MIGLUSTAT	4	GBA2
MIGALASTAT	4	GBA2
PAZOPANIB	4	CYP2U1
LUCERASTAT	3	GBA2
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)	2	GBA2, CYP2U1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ALDH18A1
D	Druggable family + AlphaFold only, no drug	1	CYP7B1
E	Difficult family or no structure, no drug	3	MCOLN1, REEP2, C19orf12

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CYP7B1	2	—
MCOLN1	9	—
REEP2	0	—
C19orf12	0	—
ALDH18A1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06553976	Not specified	RECRUITING	Spastic Paraplegia - Centers of Excellence Research Network