GBA2

Summary

GBA2 (glucosylceramidase beta 2, HGNC:18986) is a protein-coding gene on chromosome 9p13.3, encoding Non-lysosomal glucosylceramidase (Q9HCG7). 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).

This gene encodes a microsomal beta-glucosidase that catalyzes the hydrolysis of bile acid 3-O-glucosides as endogenous compounds. Studies to determine subcellular localization of this protein in the liver indicated that the enzyme was mainly enriched in the microsomal fraction where it appeared to be confined to the endoplasmic reticulum. This putative transmembrane protein is thought to play a role in carbohydrate transport and metabolism.

Source: NCBI Gene 57704 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex hereditary spastic paraplegia (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 410 total — 28 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 67
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_020944

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18986
Approved symbol	GBA2
Name	glucosylceramidase beta 2
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1605, AD035, DKFZp762K054
Ensembl gene	ENSG00000070610
Ensembl biotype	protein_coding
OMIM	609471
Entrez	57704

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000378088, ENST00000378094, ENST00000378103, ENST00000467252, ENST00000485259, ENST00000486797, ENST00000488292, ENST00000489025, ENST00000880891, ENST00000880892, ENST00000880893, ENST00000880894, ENST00000931073, ENST00000964990

RefSeq mRNA: 2 — MANE Select: NM_020944 NM_001330660, NM_020944

CCDS: CCDS6589, CCDS83363

Canonical transcript exons

ENST00000378103 — 17 exons

Exon	Start	End
ENSE00000699216	35737748	35737939
ENSE00000833033	35741672	35741890
ENSE00001476258	35736866	35737447
ENSE00001476340	35748346	35749228
ENSE00003462546	35744615	35744706
ENSE00003473124	35740526	35740628
ENSE00003474872	35739002	35739109
ENSE00003492724	35738232	35738374
ENSE00003498857	35744297	35744412
ENSE00003538411	35739998	35740123
ENSE00003538501	35738037	35738152
ENSE00003563317	35738526	35738632
ENSE00003572249	35739628	35739800
ENSE00003603892	35739315	35739419
ENSE00003636981	35740209	35740362
ENSE00003640152	35738752	35738903
ENSE00003689735	35740825	35741064

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 98.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.8405 / max 177.7095, expressed in 1804 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100651	20.5407	1796
100650	3.0185	1308
100648	0.8232	334
100649	0.4462	208
100647	0.0120	3

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
metanephros cortex	UBERON:0010533	98.67	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.55	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.53	gold quality
transverse colon	UBERON:0001157	98.45	gold quality
cerebellar hemisphere	UBERON:0002245	98.38	gold quality
cerebellar cortex	UBERON:0002129	98.37	gold quality
mucosa of transverse colon	UBERON:0004991	98.29	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.12	gold quality
right lobe of thyroid gland	UBERON:0001119	98.07	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.02	gold quality
lower esophagus	UBERON:0013473	98.01	gold quality
rectum	UBERON:0001052	98.00	gold quality
apex of heart	UBERON:0002098	97.99	gold quality
left lobe of thyroid gland	UBERON:0001120	97.98	gold quality
adenohypophysis	UBERON:0002196	97.94	gold quality
body of stomach	UBERON:0001161	97.89	gold quality
cerebellum	UBERON:0002037	97.85	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.85	gold quality
small intestine	UBERON:0002108	97.73	gold quality
mucosa of stomach	UBERON:0001199	97.59	gold quality
right frontal lobe	UBERON:0002810	97.56	gold quality
body of uterus	UBERON:0009853	97.41	gold quality
right atrium auricular region	UBERON:0006631	97.37	gold quality
right lung	UBERON:0002167	97.36	gold quality
right coronary artery	UBERON:0001625	97.30	gold quality
body of pancreas	UBERON:0001150	97.26	gold quality
minor salivary gland	UBERON:0001830	97.21	gold quality
left uterine tube	UBERON:0001303	97.19	gold quality
popliteal artery	UBERON:0002250	97.19	gold quality
tibial artery	UBERON:0007610	97.19	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.95

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KMT2A, NR0B2, NR5A2

miRNA regulators (miRDB)

38 targeting GBA2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-7851-3P	98.72	64.88	980
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-193A-3P	98.59	66.36	769
HSA-MIR-193B-3P	98.59	66.62	748
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-6882-3P	98.23	67.01	1119
HSA-MIR-6773-3P	98.17	65.51	1213
HSA-MIR-1262	98.17	66.52	757

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 29)

• the non-lysosomal glucosylceramidase is identical to the earlier described bile acid beta-glucosidase, being beta-glucosidase 2 (PMID:17105727)
• This study suggested that glucosidase-beta variants have a limited role in susceptibility to Lewy body disease in North America. (PMID:18829375)
• Action Myoclonus-Renal Failure Syndrome-causing mutations within LIMP-2 affect the binding to beta-glucocerebrosidase. (PMID:19933215)
• Beta-glycosidase from Sulfolobus solfataricus shows distant similarity to the non-lysosomal bile acid beta-glucosidase GBA2 in humans. (PMID:20427274)
• SPG46 maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum (PMID:20593214)
• The structure of the N370S acid-beta-glucosidase mutant that causes Gaucher disease was studied. (PMID:21724649)
• Results describe the association between the MTX1 and beta-glucocerebrosidase genes and its possible effect on Parkinson disease. (PMID:21837367)
• GBA1 and GBA2 activities had characteristic differences between the studied fibroblast, liver and brain samples. (PMID:22659419)
• GBA2 is down-regulated in melanoma; inducible expression of GBA2 affects endogenous sphingolipid metabolism by promoting glucosylceramide degradation (decrease by 78%) and ceramide generation. (PMID:23073830)
• GBA2 is localized at the ER and Golgi, which puts GBA2 in a key position for a lysosome-independent route of glucosylceramide-dependent signaling. (PMID:23250757)
• GBA2 loss of function led to abnormal motor behavior and axonal shortening/branching of motoneurons. (PMID:23332916)
• This study suggests GBA2 mutations are a cause of recessive spastic ataxia and responsible for a form of glucosylceramide storage disease in humans. (PMID:23332917)
• redefine GBA2 activity as the beta-glucosidase that is sensitive to inhibition by N-butyldeoxygalactonojirimycin. (PMID:23880767)
• observations make GBA2 a likely candidate to be involved in Gaucher disease etiology. (PMID:24070122)
• We hereby report a novel GBA2 mutation associated with spastic ataxia and suggest that GBA2 mutations may be a relatively frequent cause of autosomal recessive cerebellar ataxias. (PMID:24252062)
• Whole-exome and targeted sequencing have defined the genetic basis of dizziness including new genes causing ataxia: GBA2, TGM6, ANO10 and SYT14 (PMID:24275721)
• The GBA2 gene shows a low mutation frequency in a general population of complicated hereditary spastic paraparesis (PMID:24337409)
• Spastic paraplegia/cerebellar ataxia patients have a severe deficit in GBA2 activity, because the GBA2 mutants are intrinsically inactive and/or reduced in amount. (PMID:26220345)
• Our protocol showed high specificity and sensitivity for homozygosity detection and facilitated the identification of novel mutations in GAN, GBA2, and ZFYVE26 in four families affected by hereditary spastic paraplegia or Charcot-Marie-Tooth disease (PMID:26492578)
• Mutagenic analysis of TxGH116 and structural modeling of GBA2 provide a detailed structural and functional rationale for pathogenic missense mutations of GBA2 (PMID:27115290)
• GBA mutations as risk factors for PD and point to lysosomal dysfunction as a mechanism contributing to PD etiology. (PMID:27255555)
• The results suggested that SPG46 and SPG56 are rare causes of hereditary spastic paraplegia in China. (PMID:27553021)
• GBA2 mutations causing a Marinesco-Sjogren-like syndrome in two Norwegian families, are reported. (PMID:28052128)
• sphingosine, the cytotoxic metabolite accumulating in Gaucher cells through the action of GBA2, directly binds to GBA2 and inhibits its activity. (PMID:28258214)
• Demonstrate that GBA2 plays a role in the proinflammatory state characterizing cystic fibrosis cells. Report for the first time that Pseudomonas aeruginosa infection causes a recruitment of plasma membrane-associated glycosphingolipid hydrolases into lipid rafts of CuFi-1-infected cells. (PMID:29333001)
• We conclude that the c.1780G>C mutation results in NLGase loss of function with abolishment of the enzymatic activity and accumulation of GlcCer accompanied by a compensatory increase in GCase. (PMID:30308956)
• results shed light on the molecular mechanism underlying the pathogenesis of GBA2-related hereditary spastic paraplegia (HSP), autosomal-recessive cerebellar ataxia (ARCA) and reveal species-specific differences in GBA2 function in vivo (PMID:30662006)
• Truncated mutants of beta-glucosidase 2 (GBA2) are localized in the mitochondrial matrix and cause mitochondrial fragmentation. (PMID:32492073)
• Dystonia as initial presentation of compound heterozygous GBA2 mutations: Expanding the phenotypic spectrum of SPG46. (PMID:32590105)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	gba2	ENSDARG00000061472
mus_musculus	Gba2	ENSMUSG00000028467
rattus_norvegicus	Gba2	ENSRNOG00000016364
drosophila_melanogaster	CG33090	FBGN0028916
caenorhabditis_elegans	hpo-13	WBGENE00013670
caenorhabditis_elegans		WBGENE00019965

Protein

Protein identifiers

Non-lysosomal glucosylceramidase — Q9HCG7 (reviewed: Q9HCG7)

Alternative names: Beta-glucocerebrosidase 2, Bile acid beta-glucosidase GBA2, Bile acid glucosyl transferase GBA2, Cholesterol glucosyltransferase GBA2, Cholesteryl-beta-glucosidase GBA2, Glucosylceramidase 2, Non-lysosomal cholesterol glycosyltransferase, Non-lysosomal galactosylceramidase, Non-lysosomal glycosylceramidase

All UniProt accessions (2): Q9HCG7, A0A0A0MRV1

UniProt curated annotations — full annotation on UniProt →

Function. 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). GlcCers are membrane glycosphingolipids that have a wide intracellular distribution. They are the main precursors of more complex glycosphingolipids that play a role in cellular growth, differentiation, adhesion, signaling, cytoskeletal dynamics and membrane properties. Involved in the transglucosylation of cholesterol, transfers glucose from GlcCer to cholesterol, thereby modifying its water solubility and biological properties. Under specific conditions, may catalyze the reverse reaction, transferring glucose from cholesteryl-3-beta-D-glucoside to ceramide (such as N-acylsphing-4-enine). May play a role in the metabolism of bile acids. Able to hydrolyze bile acid 3-O-glucosides as well as to produce bile acid-glucose conjugates thanks to a bile acid glucosyl transferase activity. Catalyzes the hydrolysis of galactosylceramides/GalCers (such as beta-D-galactosyl-(1<->1’)-N-acylsphing-4-enine), as well as the galactosyl transfer between GalCers and cholesterol in vitro with lower activity compared with their activity against GlcCers.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane.

Tissue specificity. Widely expressed. Mainly expressed in brain, heart, skeletal muscle, kidney and placenta and expressed at lower levels in liver, spleen, small intestine and lung. Detectable in colon, thymus and peripheral blood leukocytes.

Disease relevance. Spastic paraplegia 46, autosomal recessive (SPG46) [MIM:614409] A neurodegenerative disorder characterized by onset in childhood of slowly progressive spastic paraplegia and cerebellar signs. Some patients have cognitive impairment, cataracts, and cerebral, cerebellar, and corpus callosum atrophy on brain imaging. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by AMP-DMN/N -((5-adamantane-1-yl-methoxy)pentyl)-deoxynojirimycin. Activated by Mn(2+), Co(2+) and Mg(2+) and inhibited by Zn(2+). Enzymatic activity is dependent on membrane association and requires the presence of lipids. The membrane-associated enzyme is not inhibited by condutiriol B epoxide and bromocondutiriol B epoxide.

Pathway. Lipid metabolism; sphingolipid metabolism. Steroid metabolism; cholesterol metabolism.

Similarity. Belongs to the non-lysosomal glucosylceramidase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9HCG7-1	1	yes
Q9HCG7-2	2
Q9HCG7-3	3

RefSeq proteins (2): NP_001317589, NP_065995* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006775	GH116_catalytic	Domain
IPR008928	6-hairpin_glycosidase_sf	Homologous_superfamily
IPR012341	6hp_glycosidase-like_sf	Homologous_superfamily
IPR014551	B_Glucosidase_GBA2-typ	Family
IPR024462	GH116_N	Domain
IPR052566	Non-lysos_glucosylceramidase	Family

Pfam: PF04685, PF12215

Enzyme classification (BRENDA):

• EC 3.2.1.45 — glucosylceramidase (BRENDA: 14 organisms, 148 substrates, 370 inhibitors, 77 Km, 31 kcat entries)

Substrate kinetics (BRENDA)

38 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
4-METHYLUMBELLIFERYL-BETA-D-GLUCOPYRANOSIDE	0.0493–24	13
GLUCOSYLCERAMIDE	0.015–0.247	7
4-NITROPHENYL BETA-D-GLUCOSIDE	0.18–110	6
4-NITROPHENYL BETA-D-GLUCOPYRANOSIDE	2.331–12.6	5
2,4-DINITROPHENYL BETA-D-GLUCOPYRANOSIDE	0.0003–0.16	3
4-METHYLUMBELLIFERYL BETA-D-GLUCOPYRANOSIDE	1.06–1.127	3
4-NONYLUMBELLIFERYL-BETA-D-GLUCOPYRANOSIDE	0.026–0.17	3
BETA-D-GLUCOCEREBROSIDE	0.03–0.65	3
P-NITROPHENYL BETA-D-GLUCOPYRANOSIDE	0.018–0.33	3
P-NITROPHENYL-BETA-GLUCOPYRANOSIDE	0.593–1.35	2
(6-[N-(7-NITROBENZ-2-OXA-1,3 DIAZOL-4-YL)AMINO]H	0.002	1
(6-[N-(7-NITROBENZ-2-OXA-1,3 DIAZOL-4-YL)AMINO]H	0.0046	1
12(N-METHYL-N-(7-NITROBENZ-2-OXA-1,3-DIAZOL-4-YL	0.05	1
4-METHYLUMBELLIFERYL-BETA-D-GALACTOPYRANOSIDE	0.1445	1
4-NITROPHENYL BETA-D-GALACTOSIDE	16.3	1

Catalyzed reactions (Rhea), 11 shown:

• cholesteryl 3-beta-D-glucoside + H2O = cholesterol + D-glucose (RHEA:11956)
• a beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine + H2O = an N-acylsphing-4-enine + D-glucose (RHEA:13269)
• a beta-D-galactosyl-(1<->1’)-N-acylsphing-4-enine + H2O = an N-acylsphing-4-enine + D-galactose (RHEA:14297)
• a beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine + cholesterol = cholesteryl 3-beta-D-glucoside + an N-acylsphing-4-enine (RHEA:58264)
• beta-D-glucosyl-N-(9Z-octadecenoyl)-sphing-4E-enine + cholesterol = N-(9Z-octadecenoyl)-sphing-4-enine + cholesteryl 3-beta-D-glucoside (RHEA:58324)
• beta-D-glucosyl-(1->3)-O-chenodeoxycholate + H2O = chenodeoxycholate + D-glucose (RHEA:58340)
• beta-D-glucosyl-(1->3)-O-lithocholate + H2O = lithocholate + D-glucose (RHEA:58344)
• a di-trans,poly-cis-dolichyl beta-D-glucosyl phosphate + chenodeoxycholate = beta-D-glucosyl-(1->3)-O-chenodeoxycholate + a di-trans,poly-cis-dolichyl phosphate + H(+) (RHEA:59104)
• octyl beta-D-glucose + chenodeoxycholate = beta-D-glucosyl-(1->3)-O-chenodeoxycholate + octan-1-ol (RHEA:59108)
• a beta-D-galactosyl-(1<->1’)-N-acylsphing-4-enine + cholesterol = cholesteryl 3-beta-D-galactoside + an N-acylsphing-4-enine (RHEA:70235)
• 1-(beta-D-galactosyl)-N-dodecanoylsphing-4-enine + cholesterol = cholesteryl 3-beta-D-galactoside + N-dodecanoylsphing-4-enine (RHEA:70255)

UniProt features (16 total): sequence variant 7, sequence conflict 3, splice variant 2, chain 1, region of interest 1, mutagenesis site 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCG7-F1	89.77	0.84

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (1):

Position	Phenotype
419	loss of glucosylceramide catabolic process.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9840310	Glycosphingolipid catabolism

MSigDB gene sets: 303 (showing top): GOBP_CERAMIDE_CATABOLIC_PROCESS, GCM_MAP4K4, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, LFA1_Q6, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_MEMBRANE_LIPID_CATABOLIC_PROCESS, GOBP_REGULATION_OF_MEMBRANE_LIPID_DISTRIBUTION, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, NFKB_Q6, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS

GO Biological Process (17): carbohydrate metabolic process (GO:0005975), glucosylceramide catabolic process (GO:0006680), central nervous system development (GO:0007417), cholesterol metabolic process (GO:0008203), bile acid metabolic process (GO:0008206), glycolipid biosynthetic process (GO:0009247), glycoside catabolic process (GO:0016139), central nervous system neuron development (GO:0021954), regulation of actin filament polymerization (GO:0030833), regulation of microtubule polymerization (GO:0031113), glycosphingolipid catabolic process (GO:0046479), regulation of membrane lipid distribution (GO:0097035), lipid metabolic process (GO:0006629), sphingolipid metabolic process (GO:0006665), steroid metabolic process (GO:0008202), obsolete lipid glycosylation (GO:0030259), small molecule metabolic process (GO:0044281)

GO Molecular Function (10): galactosylceramidase activity (GO:0004336), glucosylceramidase activity (GO:0004348), beta-glucosidase activity (GO:0008422), glucosyltransferase activity (GO:0046527), steryl-beta-glucosidase activity (GO:0050295), hydrolase activity, hydrolyzing O-glycosyl compounds (GO:0004553), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (8): Golgi membrane (GO:0000139), endoplasmic reticulum membrane (GO:0005789), smooth endoplasmic reticulum (GO:0005790), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glycosphingolipid metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
primary metabolic process	2
regulation of protein polymerization	2
lipid metabolic process	2
glycosylceramidase activity	2
catalytic activity	2
cellular anatomical structure	2
endomembrane system	2
intracellular membrane-bounded organelle	2
glucosylceramide metabolic process	1
glycosylceramide catabolic process	1
nervous system development	1
system development	1
sterol metabolic process	1
secondary alcohol metabolic process	1
steroid metabolic process	1
monocarboxylic acid metabolic process	1
glycolipid metabolic process	1
lipid biosynthetic process	1
carbohydrate derivative biosynthetic process	1
glycoside metabolic process	1
glycosyl compound catabolic process	1
central nervous system neuron differentiation	1
neuron development	1
regulation of actin polymerization or depolymerization	1
actin filament polymerization	1
regulation of microtubule polymerization or depolymerization	1
microtubule polymerization	1
regulation of supramolecular fiber organization	1
glycosphingolipid metabolic process	1
glycolipid catabolic process	1
sphingolipid catabolic process	1
membrane organization	1
regulation of biological quality	1
metabolic process	1
glucosidase activity	1
hexosyltransferase activity	1
beta-glucosidase activity	1
hydrolase activity, acting on glycosyl bonds	1
transferase activity	1

Protein interactions and networks

STRING

1634 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GBA2	MSMP	Q1L6U9	952
GBA2	GBA1	P04062	910
GBA2	UGCG	Q16739	763
GBA2	ASAH1	Q13510	676
GBA2	FA2H	Q7L5A8	653
GBA2	SPG11	Q96JI7	628
GBA2	DDHD2	O94830	621
GBA2	DDHD1	Q8NEL9	619
GBA2	AP5Z1	O43299	611
GBA2	SPG7	Q9UQ90	605
GBA2	PNPLA6	Q8IY17	603
GBA2	ZFYVE26	Q68DK2	586
GBA2	C19orf12	Q9NSK7	581
GBA2	CYP2U1	Q7Z449	571
GBA2	SPTLC1	O15269	568

IntAct

25 interactions, top by confidence:

A	B	Type	Score
GBA2	ILVBL	psi-mi:“MI:0914”(association)	0.640
ILVBL	COG7	psi-mi:“MI:0914”(association)	0.640
DPEP1	ILVBL	psi-mi:“MI:0914”(association)	0.530
ILVBL	SLC33A1	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
PCNA	GBA2	psi-mi:“MI:0915”(physical association)	0.370
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350
MFSD3	NME4	psi-mi:“MI:0914”(association)	0.350
NIPAL3	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC10A4	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC30A7	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC35F2	EI24	psi-mi:“MI:0914”(association)	0.350
SLC38A8	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC39A4	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC39A8	CEBPZOS	psi-mi:“MI:0914”(association)	0.350
SLC6A11	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC7A1	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC7A3	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC7A8	SPTLC1	psi-mi:“MI:0914”(association)	0.350
TMEM216	GPR89A	psi-mi:“MI:2364”(proximity)	0.270
GBA2	MTNR1A	psi-mi:“MI:0915”(physical association)	0.000
mtlA	GBA2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (50): GBA2 (Proximity Label-MS), SRP68 (Affinity Capture-MS), PPFIA1 (Affinity Capture-MS), BAG5 (Affinity Capture-MS), LAMTOR5 (Affinity Capture-MS), AFG3L2 (Affinity Capture-MS), ILVBL (Affinity Capture-MS), MRPS22 (Affinity Capture-MS), MRPL44 (Affinity Capture-MS), GBA2 (Affinity Capture-MS), GBA2 (Two-hybrid), GBA2 (Proximity Label-MS), GBA2 (Proximity Label-MS), GBA2 (Proximity Label-MS), GBA2 (Proximity Label-MS)

ESM2 similar proteins: A0JMP0, A7MBI7, D3YWP0, F1NZI4, G5E872, O09175, O88587, O97583, P04062, P17405, P21139, P21964, P22734, P25409, P52850, P55345, P58242, Q0V8G3, Q0VD19, Q14CH1, Q2KHZ8, Q2TBI8, Q32M88, Q5H879, Q5M868, Q5R6K5, Q5R8E3, Q69ZF3, Q6P9U1, Q6YGZ1, Q70KH2, Q71RP1, Q8BNV1, Q8BP56, Q8IZ69, Q8N371, Q8QZR5, Q8VCT3, Q91W89, Q920N2

Diamond homologs: Q5M868, Q69ZF3, Q7KT91, Q9HCG7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SLC-mediated transmembrane transport	5	16.4×	7e-04
Transport of small molecules	5	7.0×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
amino acid transport	5	65.0×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

410 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	28
Likely pathogenic	17
Uncertain significance	174
Likely benign	119
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1451525	NM_020944.3(GBA2):c.2036G>A (p.Trp679Ter)	Pathogenic
1452029	NM_020944.3(GBA2):c.651G>A (p.Trp217Ter)	Pathogenic
2019783	NM_020944.3(GBA2):c.1651_1654del (p.Trp551fs)	Pathogenic
2093512	NM_020944.3(GBA2):c.1528_1529del (p.Met510fs)	Pathogenic
2126684	NM_020944.3(GBA2):c.2274G>A (p.Trp758Ter)	Pathogenic
2501909	NM_020944.3(GBA2):c.1195C>T (p.Arg399Ter)	Pathogenic
2572509	NM_020944.3(GBA2):c.1602C>A (p.Tyr534Ter)	Pathogenic
2712536	NM_020944.3(GBA2):c.2635C>T (p.Arg879Trp)	Pathogenic
2730218	NM_020944.3(GBA2):c.1111C>T (p.Gln371Ter)	Pathogenic
2833690	NM_020944.3(GBA2):c.1680T>G (p.Tyr560Ter)	Pathogenic
3068747	NM_020944.3(GBA2):c.1720C>T (p.Arg574Ter)	Pathogenic
3148838	NM_020944.3(GBA2):c.1351C>T (p.Arg451Ter)	Pathogenic
3337137	NM_020944.3(GBA2):c.2192G>A (p.Trp731Ter)	Pathogenic
3775633	NM_020944.3(GBA2):c.2025del (p.Tyr676fs)	Pathogenic
41486	NM_020944.3(GBA2):c.700C>T (p.Arg234Ter)	Pathogenic
41488	NM_020944.3(GBA2):c.1471_1474dup (p.Thr492fs)	Pathogenic
41489	NM_020944.3(GBA2):c.1018C>T (p.Arg340Ter)	Pathogenic
4526006	NM_020944.3(GBA2):c.323_327del (p.Leu108fs)	Pathogenic
567447	NM_020944.3(GBA2):c.2202del (p.Tyr735fs)	Pathogenic
596782	NM_020944.3(GBA2):c.1153G>T (p.Gly385Ter)	Pathogenic
620390	NM_020944.3(GBA2):c.2413C>T (p.Gln805Ter)	Pathogenic
638293	NM_020944.3(GBA2):c.363C>A (p.Tyr121Ter)	Pathogenic
638294	NM_020944.3(GBA2):c.518G>A (p.Trp173Ter)	Pathogenic
652834	NM_020944.3(GBA2):c.2101C>T (p.Gln701Ter)	Pathogenic
933437	NM_020944.3(GBA2):c.1532_1533del (p.Cys511fs)	Pathogenic
964742	NM_020944.3(GBA2):c.145G>T (p.Glu49Ter)	Pathogenic
989141	NM_020944.3(GBA2):c.2166_2176del (p.Gly722_Gln723insTer)	Pathogenic
989142	NM_020944.3(GBA2):c.2248_2249del (p.Met750fs)	Pathogenic
1066152	NM_020944.3(GBA2):c.1129+1G>C	Likely pathogenic
1802259	NM_020944.3(GBA2):c.2506-2A>G	Likely pathogenic

SpliceAI

3169 predictions. Top by Δscore:

Variant	Effect	Δscore
9:35738031:TCTCA:T	donor_loss	1.0000
9:35738032:CTCAC:C	donor_loss	1.0000
9:35738033:TCA:T	donor_loss	1.0000
9:35738034:CA:C	donor_loss	1.0000
9:35738035:A:AG	donor_loss	1.0000
9:35738036:C:CA	donor_loss	1.0000
9:35738152:CCT:C	acceptor_loss	1.0000
9:35738153:C:CC	acceptor_gain	1.0000
9:35738153:C:CG	acceptor_loss	1.0000
9:35738154:T:A	acceptor_loss	1.0000
9:35738160:C:CT	acceptor_gain	1.0000
9:35738569:AG:A	donor_gain	1.0000
9:35738629:CAGC:C	acceptor_gain	1.0000
9:35738632:CCT:C	acceptor_loss	1.0000
9:35738633:C:CA	acceptor_loss	1.0000
9:35738633:C:CC	acceptor_gain	1.0000
9:35738634:T:C	acceptor_loss	1.0000
9:35738714:ACC:A	donor_gain	1.0000
9:35738715:CCC:C	donor_gain	1.0000
9:35738745:C:A	donor_gain	1.0000
9:35738750:A:AC	donor_gain	1.0000
9:35738751:C:CC	donor_gain	1.0000
9:35738751:CTAGA:C	donor_gain	1.0000
9:35738752:TAGA:T	donor_gain	1.0000
9:35738771:T:TA	donor_gain	1.0000
9:35738829:A:AC	donor_gain	1.0000
9:35738830:C:CC	donor_gain	1.0000
9:35738832:T:TA	donor_gain	1.0000
9:35738899:ATCAT:A	acceptor_gain	1.0000
9:35738900:TCAT:T	acceptor_gain	1.0000

AlphaMissense

6070 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:35737792:A:G	W821R	0.999
9:35737792:A:T	W821R	0.999
9:35738545:A:G	W679R	0.999
9:35738545:A:T	W679R	0.999
9:35738850:A:G	W617R	0.999
9:35738850:A:T	W617R	0.999
9:35739389:T:A	D538V	0.999
9:35738374:A:C	S685R	0.998
9:35738374:A:T	S685R	0.998
9:35738527:T:G	S685R	0.998
9:35738810:C:G	R630P	0.998
9:35739389:T:G	D538A	0.998
9:35737303:A:G	W884R	0.997
9:35737303:A:T	W884R	0.997
9:35737305:A:T	I883K	0.997
9:35737361:C:A	E864D	0.997
9:35737361:C:G	E864D	0.997
9:35737847:A:C	N802K	0.997
9:35737847:A:T	N802K	0.997
9:35738843:T:G	D619A	0.997
9:35738844:C:G	D619H	0.997
9:35739020:G:C	H593D	0.997
9:35739374:G:T	A543D	0.997
9:35739386:A:T	V539D	0.997
9:35739388:A:C	D538E	0.997
9:35739388:A:T	D538E	0.997
9:35739389:T:C	D538G	0.997
9:35739411:A:G	Y531H	0.997
9:35739628:C:G	G528R	0.997
9:35739629:C:A	E527D	0.997

dbSNP variants (sampled 300 via entrez): RS1000278137 (9:35743880 G>T), RS1000532303 (9:35740911 G>A), RS1000690639 (9:35747607 A>C), RS1001000455 (9:35747863 GAAGA>G), RS1001269338 (9:35742306 C>T), RS1001297356 (9:35749019 C>G), RS1001897660 (9:35747630 T>G), RS1002342233 (9:35740467 T>C), RS1002411792 (9:35748227 G>T), RS1002844291 (9:35747471 G>A,C,T), RS1002859146 (9:35747927 G>T), RS1003010507 (9:35737102 A>AG), RS1003346257 (9:35738695 C>T), RS1003354762 (9:35738921 A>T), RS1003424714 (9:35746711 G>A)

Disease associations

OMIM: gene MIM:609471 | disease phenotypes: MIM:303350, MIM:614409, MIM:270800

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 46	Definitive	Autosomal recessive
autosomal recessive cerebellar ataxia with late-onset spasticity	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex hereditary spastic paraplegia	Definitive	AR

Mondo (10): hereditary spastic paraplegia (MONDO:0019064), hereditary spastic paraplegia 46 (MONDO:0013737), CEP290-related ciliopathy (MONDO:0100451), neurodevelopmental disorder (MONDO:0700092), hereditary spastic paraplegia 5A (MONDO:0010047), intellectual disability (MONDO:0001071), polyneuropathy (MONDO:0001824), dilated cardiomyopathy (MONDO:0005021), cerebellar ataxia (MONDO:0000437), autosomal recessive cerebellar ataxia with late-onset spasticity (MONDO:0018129)

Orphanet (6): Hereditary spastic paraplegia (Orphanet:685), Autosomal recessive spastic paraplegia type 46 (Orphanet:320391), Autosomal recessive spastic paraplegia type 5A (Orphanet:100986), Dilated cardiomyopathy (Orphanet:217604), Rare ataxia (Orphanet:102002), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

67 total (30 of 67 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000518	Cataract
HP:0000570	Abnormal saccadic eye movements
HP:0000639	Nystagmus
HP:0000726	Dementia
HP:0000789	Infertility
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0001761	Pes cavus
HP:0002015	Dysphagia
HP:0002059	Cerebral atrophy
HP:0002061	Lower limb spasticity
HP:0002064	Spastic gait
HP:0002066	Gait ataxia
HP:0002073	Progressive cerebellar ataxia
HP:0002078	Truncal ataxia
HP:0002079	Hypoplasia of the corpus callosum
HP:0002120	Cerebral cortical atrophy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010703_52	Brain morphology (MOSTest)	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D011115	Polyneuropathies	C10.668.829.800
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3761 (SINGLE PROTEIN), CHEMBL4106172 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 10,354 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1029	MIGLUSTAT	4	4,770
CHEMBL110458	MIGALASTAT	4	430
CHEMBL1086997	LUCERASTAT	3	74
CHEMBL206468	AFEGOSTAT	2	334
CHEMBL307429	DUVOGLUSTAT	2	4,739
CHEMBL3354637	NIZUBAGLUSTAT	2	7

PharmGKB: 1 entry (VIP=true, CPIC=false)

Binding affinities (BindingDB)

3 measured of 5 human assays (5 total across all organisms); most potent 3 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL4559665	IC50	4 nM
CHEMBL4435506	IC50	65 nM
CHEMBL2011603	IC50	30000 nM

ChEMBL bioactivities

149 potent at pChembl≥5 of 167 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.10	IC50	0.08	nM	CHEMBL3354624
10.10	IC50	0.08	nM	CHEMBL3354625
10.10	IC50	0.08	nM	CHEMBL3354627
10.00	IC50	0.1	nM	CHEMBL3354634
10.00	IC50	0.1	nM	CHEMBL3354635
9.92	IC50	0.12	nM	CHEMBL3354626
9.52	IC50	0.3	nM	CHEMBL574645
9.40	IC50	0.4	nM	CHEMBL3354636
9.40	IC50	0.4	nM	CHEMBL1651630
9.30	IC50	0.5	nM	CHEMBL3354041
9.22	IC50	0.6	nM	NIZUBAGLUSTAT
9.00	IC50	1	nM	CHEMBL574645
9.00	IC50	1	nM	CHEMBL1086996
9.00	IC50	1	nM	CHEMBL3354019
9.00	IC50	1	nM	CHEMBL3354021
9.00	IC50	1	nM	CHEMBL3354022
9.00	IC50	1	nM	CHEMBL3354035
9.00	IC50	1	nM	CHEMBL3354037
9.00	IC50	1	nM	CHEMBL3354048
9.00	IC50	1	nM	CHEMBL3354049
9.00	IC50	1	nM	CHEMBL3354621
9.00	IC50	1	nM	CHEMBL3354629
9.00	IC50	1	nM	CHEMBL1088158
9.00	IC50	1	nM	CHEMBL4459011
8.70	IC50	2	nM	CHEMBL574645
8.70	IC50	2	nM	CHEMBL3354016
8.70	IC50	2	nM	CHEMBL3354025
8.70	IC50	2	nM	CHEMBL3354032
8.70	IC50	2	nM	CHEMBL3354040
8.70	IC50	2	nM	CHEMBL3354046
8.70	IC50	2	nM	CHEMBL3354050
8.70	IC50	2	nM	CHEMBL3354051
8.70	IC50	2	nM	CHEMBL3354054
8.70	IC50	2	nM	CHEMBL3354063
8.70	IC50	2	nM	CHEMBL3354628
8.70	IC50	2	nM	CHEMBL3354631
8.70	IC50	2	nM	CHEMBL3354632
8.70	IC50	2	nM	CHEMBL3354633
8.70	IC50	2	nM	CHEMBL3354638
8.70	IC50	2	nM	CHEMBL450985
8.60	IC50	2.5	nM	CHEMBL3354029
8.52	IC50	3	nM	CHEMBL3354024
8.52	IC50	3	nM	CHEMBL3354034
8.52	IC50	3	nM	CHEMBL3354038
8.52	IC50	3	nM	CHEMBL3354039
8.52	IC50	3	nM	CHEMBL3354044
8.52	IC50	3	nM	CHEMBL3354045
8.52	IC50	3	nM	CHEMBL3354062
8.52	IC50	3	nM	CHEMBL3354064
8.52	IC50	3	nM	CHEMBL3354622

PubChem BioAssay actives

150 with measured affinity, of 246 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[[4-phenyl-3-(trifluoromethyl)phenyl]methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0001	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[[4-phenyl-2-(trifluoromethyl)phenyl]methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0001	uM
(2R,3R,4R,5S)-1-[5-[(2-fluoro-4-phenylphenyl)methoxy]pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0001	uM
(2R,3R,4R,5S)-1-[5-[(3-fluoro-4-phenylphenyl)methoxy]pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0001	uM
(2S,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[[4-phenyl-2-(trifluoromethyl)phenyl]methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0001	uM
(2S,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[[4-phenyl-3-(trifluoromethyl)phenyl]methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0001	uM
(2R,3R,4R,5S)-1-[5-(1-adamantylmethoxy)pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	700851: Inhibition of non-lysosomal glucosylceramidase in cultured melanoma cells	ic50	0.0003	uM
(2S,3R,4R,5S)-1-[5-[(2-fluoro-4-phenylphenyl)methoxy]pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0004	uM
(2R,3R,4R,5S)-1-(5-hexoxypentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol	1596605: Inhibition of NLGase in human SH-SY5Y cells using MUG-Gluc as fluorogenic substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs in presence of AMP-DNM by fluorescence based assay	ic50	0.0004	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[[4-(2-methylphenyl)phenyl]methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0005	uM
(2S,3R,4R,5S)-1-[5-[(3-fluoro-4-phenylphenyl)methoxy]pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0006	uM
(2R,3R,4R,5S)-1-[4,4-difluoro-5-[(4-phenylphenyl)methoxy]pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0010	uM
(2S,3R,4R,5S)-1-[5-(1-adamantylmethoxy)pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0010	uM
(2R,3R,4R,5S)-1-[5-(2-adamantylmethoxy)pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0010	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-(5-phenylmethoxypentyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0010	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-(naphthalen-2-ylmethoxy)pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0010	uM
(2S,3R,4R,5S)-2-(hydroxymethyl)-1-[5-(naphthalen-2-ylmethoxy)pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0010	uM
(2S,3R,4R,5S)-2-(hydroxymethyl)-1-[5-(pyren-1-ylmethoxy)pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0010	uM
(2R,3R,4R,5S)-1-[5-[[4-(4-fluorophenyl)phenyl]methoxy]pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0010	uM
(2R,3R,4R,5S)-1-[5-[[4-(3-fluorophenyl)phenyl]methoxy]pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0010	uM
(2S,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[(1R)-1-(4-phenylphenyl)ethoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0010	uM
(2R,3S,4R,5S)-1-[5-(1-adamantylmethoxy)pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0010	uM
1-(5-hexoxypentyl)-2-(hydroxymethyl)piperidine-3,4,5-triol	1596605: Inhibition of NLGase in human SH-SY5Y cells using MUG-Gluc as fluorogenic substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs in presence of AMP-DNM by fluorescence based assay	ic50	0.0010	uM
(2R,3S,4R,5S)-2-(hydroxymethyl)-1-[5-[(4-phenylphenyl)methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0020	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[(4-phenylphenyl)methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0020	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[[4-(3-methylphenyl)phenyl]methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0020	uM
(2R,3R,4R,5S)-1-[6-(1-adamantylmethoxy)hexyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0020	uM
(2S,3R,4R,5S)-1-[5-(2-adamantylmethoxy)pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0020	uM
3-[4-[5-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl]pentoxymethyl]phenyl]benzonitrile	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0020	uM
(2R,3R,4R,5S)-1-[5-[[4-(2-fluorophenyl)phenyl]methoxy]pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0020	uM
(2R,3R,4R,5S)-1-[5-[[4-(4-chlorophenyl)phenyl]methoxy]pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0020	uM
(2R,3R,4R,5S)-1-[5-[[4-(1,3-benzodioxol-5-yl)phenyl]methoxy]pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0020	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[(3-phenylphenyl)methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0020	uM
(2S,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[(1S)-1-(4-phenylphenyl)ethoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0020	uM
(2S,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[(3-phenylphenyl)methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0020	uM
(2S,3R,4R,5S)-1-[2,2-difluoro-5-[(4-phenylphenyl)methoxy]pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0020	uM
(2S,3R,4R,5S)-1-[4,4-difluoro-5-[(4-phenylphenyl)methoxy]pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0020	uM
(2R,3R,4R,5S)-1-dodecyl-2-(hydroxymethyl)piperidine-3,4,5-triol	386398: Inhibition of bile acid beta-glucosidase activity of human liver GBA2	ic50	0.0020	uM
(2S,3R,4R,5S)-1-[6-(1-adamantylmethoxy)hexyl]-2-(hydroxymethyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0025	uM
(2S,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[(4-phenylphenyl)methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0030	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[(2-phenylphenyl)methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0030	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[(5-phenyl-2-pyridinyl)methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0030	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[[4-(2-methoxyphenyl)phenyl]methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0030	uM
(2S,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[(2-phenylphenyl)methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0030	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-(pyren-1-ylmethoxy)pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0030	uM
(2S,3R,4R,5S)-2-(hydroxymethyl)-1-(5-phenylmethoxypentyl)piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0030	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[[4-(4-methylphenyl)phenyl]methoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0030	uM
4-[4-[5-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl]pentoxymethyl]phenyl]benzonitrile	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0030	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[(1S)-1-(4-phenylphenyl)ethoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0030	uM
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-[5-[(1R)-1-(4-phenylphenyl)ethoxy]pentyl]piperidine-3,4,5-triol	1166039: Inhibition of GBA2 (unknown origin)	ic50	0.0030	uM

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol F	decreases expression, affects cotreatment	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Diazinon	increases methylation	1
Indomethacin	affects cotreatment, decreases expression	1
Nickel	decreases expression	1
Ozone	affects cotreatment, decreases expression, increases abundance	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	decreases methylation	1
Urethane	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Aflatoxin B1	decreases methylation	1
Lactic Acid	decreases expression	1
Acrylamide	decreases expression	1
Particulate Matter	increases expression	1
Volatile Organic Compounds	affects cotreatment, decreases expression	1

ChEMBL screening assays

38 unique, capped per target: 38 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1040323	Binding	Inhibition of human GBA2	Synthesis and evaluation of D-gluco-pyranocyclopropyl amines as potential glucosidase inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7QJ	Ubigene A-549 GBA2 KO	Cancer cell line	Male
CVCL_SP68	HAP1 GBA2 (-) 1	Cancer cell line	Male
CVCL_SP69	HAP1 GBA2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

260 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT06891443	PHASE3	RECRUITING	Study to Evaluate Sepofarsen in Subjects With Leber Congenital Amaurosis (LCA) Type 10 (HYPERION)
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
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)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
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)
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
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
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
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
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
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
NCT04912609	Not specified	COMPLETED	Trehalose Administration in Subjects With Spastic Paraplegia 11 (3AL-SPG11)