SCARB2

Summary

SCARB2 (scavenger receptor class B member 2, HGNC:1665) is a protein-coding gene on chromosome 4q21.1, encoding Lysosome membrane protein 2 (Q14108). Acts as a lysosomal receptor for glucosylceramidase (GBA1) targeting.

The protein encoded by this gene is a type III glycoprotein that is located primarily in limiting membranes of lysosomes and endosomes. Earlier studies in mice and rat suggested that this protein may participate in membrane transportation and the reorganization of endosomal/lysosomal compartment. The protein deficiency in mice was reported to impair cell membrane transport processes and cause pelvic junction obstruction, deafness, and peripheral neuropathy. Further studies in human showed that this protein is a ubiquitously expressed protein and that it is involved in the pathogenesis of HFMD (hand, foot, and mouth disease) caused by enterovirus-71 and possibly by coxsackievirus A16. Mutations in this gene caused an autosomal recessive progressive myoclonic epilepsy-4 (EPM4), also known as action myoclonus-renal failure syndrome (AMRF). Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 950 — RefSeq curated summary.

At a glance

• Gene–disease (curated): progressive myoclonus epilepsy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 556 total — 22 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 82
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005506

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1665
Approved symbol	SCARB2
Name	scavenger receptor class B member 2
Location	4q21.1
Locus type	gene with protein product
Status	Approved
Aliases	HLGP85, LIMPII, SR-BII, LIMP-2
Ensembl gene	ENSG00000138760
Ensembl biotype	protein_coding
OMIM	602257
Entrez	950

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 15 protein_coding, 11 retained_intron, 5 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000264896, ENST00000452464, ENST00000502908, ENST00000509994, ENST00000511129, ENST00000638175, ENST00000638295, ENST00000638372, ENST00000638409, ENST00000638567, ENST00000638603, ENST00000638663, ENST00000638680, ENST00000638843, ENST00000639145, ENST00000639300, ENST00000639324, ENST00000639715, ENST00000639738, ENST00000640076, ENST00000640341, ENST00000640634, ENST00000640640, ENST00000640880, ENST00000640900, ENST00000640916, ENST00000640957, ENST00000682785, ENST00000862442, ENST00000862443, ENST00000862444, ENST00000862445, ENST00000921155

RefSeq mRNA: 2 — MANE Select: NM_005506 NM_001204255, NM_005506

CCDS: CCDS3577, CCDS56335

Canonical transcript exons

ENST00000264896 — 12 exons

Exon	Start	End
ENSE00000725188	76179517	76179705
ENSE00000725195	76180954	76181101
ENSE00000725202	76195707	76195864
ENSE00000800847	76174144	76174313
ENSE00000800848	76169867	76169985
ENSE00000800849	76168403	76168476
ENSE00000800850	76166250	76166301
ENSE00000800851	76163225	76163383
ENSE00001077893	76176437	76176528
ENSE00001077894	76175791	76175910
ENSE00001278458	76158737	76161751
ENSE00003803172	76213427	76213824

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 99.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 96.4160 / max 554.2903, expressed in 1818 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52653	44.6128	1813
52648	23.1673	1749
52655	17.7450	1757
52647	5.7308	1465
52649	1.8545	1074
52654	1.3197	867
52650	0.8589	329
52651	0.6372	246
52657	0.4401	221
203248	0.0497	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior vagus X ganglion	UBERON:0005363	99.61	gold quality
subthalamic nucleus	UBERON:0001906	99.53	gold quality
germinal epithelium of ovary	UBERON:0001304	99.42	gold quality
superior vestibular nucleus	UBERON:0007227	99.42	gold quality
lateral globus pallidus	UBERON:0002476	99.41	gold quality
pons	UBERON:0000988	99.37	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.37	gold quality
substantia nigra pars compacta	UBERON:0001965	99.30	gold quality
mammary duct	UBERON:0001765	99.28	gold quality
trigeminal ganglion	UBERON:0001675	99.27	gold quality
middle temporal gyrus	UBERON:0002771	99.26	gold quality
corpus callosum	UBERON:0002336	99.25	gold quality
endothelial cell	CL:0000115	99.23	gold quality
stromal cell of endometrium	CL:0002255	99.06	gold quality
cardia of stomach	UBERON:0001162	99.03	gold quality
urethra	UBERON:0000057	99.00	gold quality
ventral tegmental area	UBERON:0002691	98.99	gold quality
lower lobe of lung	UBERON:0008949	98.97	gold quality
pylorus	UBERON:0001166	98.83	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.83	gold quality
corpus epididymis	UBERON:0004359	98.83	gold quality
pericardium	UBERON:0002407	98.78	gold quality
islet of Langerhans	UBERON:0000006	98.74	gold quality
renal medulla	UBERON:0000362	98.74	gold quality
cortical plate	UBERON:0005343	98.69	gold quality
visceral pleura	UBERON:0002401	98.66	gold quality
parotid gland	UBERON:0001831	98.61	gold quality
synovial joint	UBERON:0002217	98.56	gold quality
skin of hip	UBERON:0001554	98.53	gold quality
parietal lobe	UBERON:0001872	98.43	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-13	yes	13.28
E-CURD-112	no	3.15
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARD, SPI1, STAT2

miRNA regulators (miRDB)

109 targeting SCARB2, 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-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4307	99.82	70.45	3374

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Functional analysis of the mouse homolog (PMID:12620969)
• Several putative signalling motifs identified in the C-terminus of human SR-BII, which are absent from SR-BI, interact with signalling molecules to mobilize stored cholesteryl esters and/or promote the efflux of intracellular free cholesterol. (PMID:14570588)
• High density lipoprotein endocytosis by scavenger receptor SR-BII is clathrin-dependent and requires a carboxyl-terminal dileucine motif. (PMID:16368683)
• Residues favoring AP3 binding introduced into a protein that is transported via the PM such as the invariant chain can re-route such protein into direct sorting to late endosomal/lysosomal structures. (PMID:16542748)
• Scavenger receptors SR-BI and SR-BII localized mainly to the ganglion cell layer and photoreceptor outer segments; in the latter they appear to be associated with microtubules. (PMID:17110915)
• HCV soluble E2 can interact with human SR-BI and SR-BII (PMID:17215280)
• Regulation of alternative splicing of liver scavenger receptor class B gene by estrogen. (PMID:17673517)
• SCARB2/Limp2 has pleiotropic effects that may be relevant to understanding the pathogenesis of other forms of glomerulosclerosis or collapse and myoclonic epilepsies. (PMID:18308289)
• Scavenger receptor B2 is a cellular receptor for enterovirus 71. (PMID:19543282)
• Study of SCARB2 mutations finds unsolved cases of progressive myoclonus epilepsy without renal impairment, especially those resembling Unverricht-Lundborg disease. (PMID:19847901)
• Action Myoclonus-Renal Failure Syndrome-causing mutations within LIMP-2 affect the binding to beta-glucocerebrosidase. (PMID:19933215)
• smooth muscle cells and macrophages expressing scavenger receptor BI/II in different stages of atherosclerosis (PMID:20032583)
• L929 cells expressing chimeras that carried amino acids 142 to 204 from the human sequence were susceptible to enterovirus 71, while chimeras that carried the mouse sequence in this region were not. (PMID:21389126)
• Two sisters are described with action myoclonus-renal failure (AMRF) syndrome resulting from a mutation in the SCARB2 gene. (PMID:21782476)
• Sequencing of SCARB2 genomic and cDNA identified a heterozygous, maternally inherited novel mutation (SCARB2 ) (PMID:21796727)
• We showed that just four genes, G3BP2, SCARB2, CSNK1A1 and SPRR2B, can classify patients as presence of lymph node metastasis negative or positive, with 80.0% accuracy. (PMID:21985131)
• in rare cases heterozygous SCARB2 mutations may be associated with demyelinating polyneuropathy features. (PMID:22032306)
• This study demonistrated that patients with SCARB2 mutations showed the clinical and neurophysiologic phenotype of progressive myoclonus epilepsy , extending the spectrum reported in the typical action myoclonus renal failure syndrome. (PMID:22050460)
• The residues between 144 and 151 are critical for SCARB2 binding to VP1 of EV71 and seven residues from the human receptor could convert murine SCARB2, an otherwise inefficient receptor, to an efficient receptor for EV71 viral infection. (PMID:22219187)
• This study supported a genetic contribution of the SCARB2 locus to PD; future studies in larger cohorts are necessary to verify this finding. (PMID:22223122)
• Results show that EV71 binds to SCARB2 and triggers a clathrin- and dynamin-dependent endocytosis for its entry. (PMID:22272359)
• Coxsackievirus A infection is via celluar virus receptor SCARB2. (PMID:22438546)
• Our data do not support the association of SNP rs6812193 with PD in Han Chinese of mainland China. (PMID:22465138)
• H171 residue in LIMP-2 is necessary for LIMP-2 and beta-glucocerebrosidase binding (PMID:22537104)
• Lysosomal storage disorders are associated with deficiencies of alternative lysosomal receptors LIMPII and sortilin and/or of their cargos. (Review) (PMID:22884962)
• These results indicated that SCARB2 is capable of viral binding, viral internalization, and viral uncoating and that the low infection efficiency of L-PSGL1 cells is due to the inability of PSGL1 to induce viral uncoating. (PMID:23302872)
• study of two Japanese siblings with late-onset progressive myoclonus epilepsy without renal failure having a novel homozygous SCARB2 mutation (PMID:23325613)
• identified no novel exonic variants in SCARB2 but confirmed the association between SNP rs6812193 and Parkinson’s disease. (PMID:23408458)
• Human SCARB2-transgenic mice are a useful model for assessing anti-EV71 medications. (PMID:23451246)
• SCARB2 is implicated in the lysosomal pathway recently associated with Parkinson disease (PD) pathogenesis. The rs6812193 polymorphism doesn’t increase susceptibility to PD in the Greek population. (PMID:23473716)
• Results suggest that this hSCARB2 transgenic mouse could represent a useful animal model for the study of enterovirus 71 (EV71) infection. (PMID:23959904)
• Mutations in LIMP-2, the specific receptor for glucocerebrosidase that is missing in Gaucher disease patients, substantially contribute to the pathology and heterogeneity of the disease. (Review) (PMID:24389070)
• A novel SCARB2 mutation was indicated by reduced Beta-glucocerebrosidase activity in progressive myoclonus epilepsy. (PMID:24485911)
• a novel mutation in SCARB2 as a cause of progressive myoclonus epilepsy in China (PMID:24620919)
• SNCA and SCARB2 loci are also associated with dementia with Lewy bodies, after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in Parkinson’s. (PMID:24973356)
• Data indicate that scavenger receptor SCARB2 triggers uncoating of human enterovirus 71 (EV71) under low pH conditions. (PMID:24986489)
• SCARB2 and PSGL-1 in human gastrointestinal tract, lung, and brain tissues correlated with the distribution of pathological changes seen in EV71 infection. (PMID:24997419)
• The LIMP-2/SCARB2 binding sequences for enterovirus 71 and GCase are not similar, indicating that LIMP-2/SCARB2 may have multiple or overlapping binding sites with differing specificities. (PMID:25202012)
• In LIMP-2-deficient brains a significant reduction in GC activity led to lipid storage, disturbed autophagic/lysosomal function, and alpha-synuclein accumulation. (PMID:25316793)
• Disease-causing cathepsin-F mutants fail to cleave LIMP-2. Our findings provide evidence that LIMP-2 represents an in vivo substrate of cathepsin-F with relevance for understanding the pathophysiology of type-B-Kufs-disease. (PMID:25576872)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	scarb2c	ENSDARG00000089844
mus_musculus	Scarb2	ENSMUSG00000029426
rattus_norvegicus	Scarb2	ENSRNOG00000002225
caenorhabditis_elegans		WBGENE00013039
caenorhabditis_elegans		WBGENE00013578
caenorhabditis_elegans		WBGENE00015389

Paralogs (2): SCARB1 (ENSG00000073060), CD36 (ENSG00000135218)

Protein

Protein identifiers

Lysosome membrane protein 2 — Q14108 (reviewed: Q14108)

Alternative names: 85 kDa lysosomal membrane sialoglycoprotein, CD36 antigen-like 2, Lysosome membrane protein II, Scavenger receptor class B member 2

All UniProt accessions (14): Q14108, A0A1W2PNX7, A0A1W2PPU6, A0A1W2PPX5, A0A1W2PPX6, A0A1W2PQB7, A0A1W2PQL5, A0A1W2PQR6, A0A1W2PRF6, A0A1W2PRS1, A0A1W2PS43, A0A1W2PS70, A0A1W2PSE4, D6RDG0

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a lysosomal receptor for glucosylceramidase (GBA1) targeting. (Microbial infection) Acts as a receptor for enterovirus 71.

Subunit / interactions. Interacts with GBA1. (Microbial infection) Interacts with enterovirus 71 capsid proteins VP1 and VP2.

Subcellular location. Lysosome membrane.

Disease relevance. Epilepsy, progressive myoclonic 4, with or without renal failure (EPM4) [MIM:254900] A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. EPM4 is an autosomal recessive form associated with renal failure in some cases. Cognitive function is preserved. The disease is caused by variants affecting the gene represented in this entry. Genetic variants in SCARB2 can act as modifier of the phenotypic expression and severity of Gaucher disease.

Similarity. Belongs to the CD36 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14108-1	1	yes
Q14108-2	2

RefSeq proteins (2): NP_001191184, NP_005497* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002159	CD36_fam	Family
IPR005429	LimpII	Family

Pfam: PF01130

UniProt features (75 total): strand 21, helix 17, glycosylation site 10, mutagenesis site 7, turn 7, topological domain 3, disulfide bond 2, transmembrane region 2, sequence variant 2, chain 1, splice variant 1, sequence conflict 1, region of interest 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
4Q4F	X-RAY DIFFRACTION	2.8
4Q4B	X-RAY DIFFRACTION	2.82
4TW2	X-RAY DIFFRACTION	2.89
4F7B	X-RAY DIFFRACTION	3
5UPH	X-RAY DIFFRACTION	3
4TVZ	X-RAY DIFFRACTION	3.01
6I2K	ELECTRON MICROSCOPY	3.4
5XBM	X-RAY DIFFRACTION	3.5
4TW0	X-RAY DIFFRACTION	3.65
9FJF	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14108-F1	93.01	0.82

Antibody-complex structures (SAbDab): 2 — 5XBM, 9FJF

Functional residue map

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

Disulfide bonds (2): 274–329, 312–318

Glycosylation sites (10): 206, 224, 249, 304, 325, 412, 430, 45, 68, 105

Mutagenesis-validated functional residues (7):

Position	Phenotype
475	prevents the targeting of the protein to lysosomes.
475	some loss in the efficiency of targeting of the protein to lysosomes.
476	does not prevent the targeting of the protein to lysosomes completely.
476	prevents the targeting of the protein to lysosomes.
476	normal targeting of the protein to lysosomes.
477	normal targeting of the protein to lysosomes.
478	normal targeting of the protein to lysosomes.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-199991	Membrane Trafficking
R-HSA-5653656	Vesicle-mediated transport

MSigDB gene sets: 512 (showing top): GOBP_CERAMIDE_CATABOLIC_PROCESS, GOBP_LYSOSOMAL_TRANSPORT, GCM_PTPRD, GOBP_ENDOSOME_ORGANIZATION, GOBP_VACUOLE_ORGANIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, GCM_ZNF198, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_DN, GOBP_PROTEIN_TARGETING, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_VACUOLAR_TRANSPORT, KEGG_LYSOSOME

GO Biological Process (13): protein targeting to lysosome (GO:0006622), receptor-mediated endocytosis (GO:0006898), autophagy (GO:0006914), sensory perception of sound (GO:0007605), positive regulation of neuron projection development (GO:0010976), aminophospholipid transport (GO:0015917), regulation of carbohydrate catabolic process (GO:0043470), endosome to plasma membrane protein transport (GO:0099638), regulation of endosome organization (GO:1904978), regulation of lysosome organization (GO:1905671), regulation of glucosylceramide catabolic process (GO:2000752), vesicle-mediated transport (GO:0016192), symbiont entry into host cell (GO:0046718)

GO Molecular Function (11): virus receptor activity (GO:0001618), phosphatidylserine binding (GO:0001786), transmembrane signaling receptor activity (GO:0004888), scavenger receptor activity (GO:0005044), cholesterol binding (GO:0015485), enzyme binding (GO:0019899), phosphatidylcholine binding (GO:0031210), cargo receptor activity (GO:0038024), protein homodimerization activity (GO:0042803), protein-folding chaperone binding (GO:0051087), protein binding (GO:0005515)

GO Cellular Component (13): Golgi membrane (GO:0000139), lysosomal membrane (GO:0005765), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), focal adhesion (GO:0005925), endosome membrane (GO:0010008), membrane (GO:0016020), endocytic vesicle membrane (GO:0030666), clathrin-coated endocytic vesicle membrane (GO:0030669), late endosome membrane (GO:0031902), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), lysosome (GO:0005764)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
Vesicle-mediated transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
bounding membrane of organelle	3
phospholipid binding	2
protein binding	2
lysosome	2
cytoplasmic vesicle membrane	2
protein targeting to vacuole	1
lysosomal transport	1
protein localization to lysosome	1
endocytosis	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
sensory perception of mechanical stimulus	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
phospholipid transport	1
nitrogen compound transport	1
regulation of carbohydrate metabolic process	1
regulation of catabolic process	1
carbohydrate catabolic process	1
intracellular protein transport	1
endocytic recycling	1
establishment of protein localization to plasma membrane	1
protein localization to plasma membrane	1
endosome organization	1
regulation of organelle organization	1
lysosome organization	1
regulation of vacuole organization	1
glucosylceramide catabolic process	1
regulation of lipid catabolic process	1
transport	1
cellular process	1
viral life cycle	1
symbiont entry into host	1
symbiont entry into host cell	1
exogenous protein binding	1
anion binding	1
modified amino acid binding	1
signaling receptor activity	1

Protein interactions and networks

STRING

5112 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SCARB2	TLR2	O60603	996
SCARB2	THBS1	P07996	996
SCARB2	TLR4	O00206	996
SCARB2	CD47	Q08722	994
SCARB2	TLR6	Q9Y2C9	993
SCARB2	LYN	P07948	973
SCARB2	GBA1	P04062	970
SCARB2	THBS2	P35442	953
SCARB2	CAV1	Q03135	944
SCARB2	FYN	P06241	942
SCARB2	TLR1	Q15399	931
SCARB2	APOB	P04114	929
SCARB2	FCGR3B	O75015	916
SCARB2	FCGR3A	P08637	916
SCARB2	PPARA	Q07869	908

IntAct

71 interactions, top by confidence:

A	B	Type	Score
RHCG	SCARB2	psi-mi:“MI:0915”(physical association)	0.590
CLDN19	SCARB2	psi-mi:“MI:0915”(physical association)	0.560
SCARB2	LAPTM4B	psi-mi:“MI:0915”(physical association)	0.560
GPR37L1	SCARB2	psi-mi:“MI:0915”(physical association)	0.560
SCARB2	CLDN19	psi-mi:“MI:0915”(physical association)	0.560
HIBADH	SCARB2	psi-mi:“MI:0915”(physical association)	0.560
SCARB2	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
SCARB2	GPX8	psi-mi:“MI:0915”(physical association)	0.560
SCGB1D1	FAM234B	psi-mi:“MI:0914”(association)	0.530
SCARB2	CLGN	psi-mi:“MI:0914”(association)	0.530
RAB27B	GBA1	psi-mi:“MI:0914”(association)	0.530
SCARB2	Gba1	psi-mi:“MI:0407”(direct interaction)	0.440
SMC6	IFT88	psi-mi:“MI:0914”(association)	0.350
SCARB2	EIF2AK2	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
SCARB2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
PTPRK	MANBA	psi-mi:“MI:0914”(association)	0.350
SCARB2	SPAG9	psi-mi:“MI:0914”(association)	0.350
RAB27B	GBA1	psi-mi:“MI:0914”(association)	0.350
TEX101	PSMD12	psi-mi:“MI:0914”(association)	0.350
TEX101	NDUFA4	psi-mi:“MI:0914”(association)	0.350
CTBP1	TAF15	psi-mi:“MI:0914”(association)	0.350
	VPS37C	psi-mi:“MI:0914”(association)	0.350

BioGRID (222): SCARB2 (Affinity Capture-MS), SCARB2 (Affinity Capture-MS), SCARB2 (Affinity Capture-MS), SCARB2 (Affinity Capture-MS), SCARB2 (Affinity Capture-MS), SCARB2 (Affinity Capture-MS), SCARB2 (Affinity Capture-MS), EIF2AK2 (Affinity Capture-MS), PRPF8 (Affinity Capture-MS), PNKD (Affinity Capture-MS), MYOF (Affinity Capture-MS), SCARB2 (Affinity Capture-MS), VAMP3 (Affinity Capture-MS), SPAG9 (Affinity Capture-MS), GLMN (Affinity Capture-MS)

ESM2 similar proteins: B0X4H5, B2LT48, B2RFN2, B3MTS2, B3P048, B4GMC9, B4IKJ4, B4JG39, B4KB36, B4LYC5, B4NK88, B4PQC2, B4R136, B7Z031, C3U0S3, D2A0H5, E0W3E3, E1JI63, E2IHA6, E5EZW6, E5EZW7, E5EZW9, E5EZX0, O02351, O35114, P26201, P27615, P70110, P86905, Q07969, Q08857, Q09606, Q11124, Q14108, Q17A88, Q19127, Q24046, Q27367, Q295A8, Q7Q6R1

Diamond homologs: O18824, O35114, P16671, P26201, P27615, P70110, P97943, Q07969, Q08857, Q14108, Q27367, Q60417, Q61009, Q8SQC1, Q8WTV0, Q11124, Q55FQ9, Q9BKJ9, Q9XYS8, E1JI63, C3U0S3, P86905, B2RFN2, Q7Q6R1, B7Z031

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	12
Uncertain significance	223
Likely benign	193
Benign	54

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1323553	NM_005506.4(SCARB2):c.1240_1241delAG (p.Ser414fs)	Pathogenic
1441270	NM_005506.4(SCARB2):c.850del (p.Tyr284fs)	Pathogenic
1457299	NC_000004.12:g.76163382CT[1]	Pathogenic
1457513	NM_005506.4(SCARB2):c.638_639del (p.Tyr213fs)	Pathogenic
2005737	NM_005506.4(SCARB2):c.1260_1261dup (p.Thr421fs)	Pathogenic
206723	NM_005506.4(SCARB2):c.1337del (p.Gly446fs)	Pathogenic
268138	NM_005506.4(SCARB2):c.666_670del (p.Tyr222_Asn224delinsTer)	Pathogenic
268139	NM_005506.4(SCARB2):c.704+1G>A	Pathogenic
268142	NM_005506.4(SCARB2):c.1016dup (p.His341fs)	Pathogenic
268146	NM_005506.4(SCARB2):c.1270C>T (p.Arg424Ter)	Pathogenic
2781498	NM_005506.4(SCARB2):c.226del (p.Leu76fs)	Pathogenic
2846431	NM_005506.4(SCARB2):c.1030C>T (p.Gln344Ter)	Pathogenic
30257	NM_005506.4(SCARB2):c.1114-2A>C	Pathogenic
30258	NM_005506.4(SCARB2):c.1258del (p.Glu420fs)	Pathogenic
4292546	NM_005506.4(SCARB2):c.994+1G>T	Pathogenic
453288	NM_005506.4(SCARB2):c.367dup (p.Gln123fs)	Pathogenic
7376	NM_005506.4(SCARB2):c.1239+1G>T	Pathogenic
7377	NM_005506.4(SCARB2):c.434_435dup (p.Trp146fs)	Pathogenic
7378	NM_005506.4(SCARB2):c.862C>T (p.Gln288Ter)	Pathogenic
7379	NM_005506.4(SCARB2):c.533G>A (p.Trp178Ter)	Pathogenic
807488	NM_005506.4(SCARB2):c.134del (p.Asn45fs)	Pathogenic
971806	NM_005506.4(SCARB2):c.956del (p.Leu319fs)	Pathogenic
1179028	NM_005506.4(SCARB2):c.994+2T>C	Likely pathogenic
1494940	NM_005506.4(SCARB2):c.1113+1G>T	Likely pathogenic
2433153	NM_005506.4(SCARB2):c.1114-2A>G	Likely pathogenic
2744535	NM_005506.4(SCARB2):c.1240-2A>G	Likely pathogenic
2763410	NM_005506.4(SCARB2):c.995-16_1062delinsG	Likely pathogenic
3590843	NM_005506.4(SCARB2):c.1353_1357del (p.Leu451fs)	Likely pathogenic
3590860	NM_005506.4(SCARB2):c.117+2T>C	Likely pathogenic
3713540	NM_005506.4(SCARB2):c.1187+1G>A	Likely pathogenic

SpliceAI

1740 predictions. Top by Δscore:

Variant	Effect	Δscore
4:76161747:GTTCC:G	acceptor_gain	1.0000
4:76161748:TTCC:T	acceptor_gain	1.0000
4:76161749:TCC:T	acceptor_gain	1.0000
4:76161750:CC:C	acceptor_gain	1.0000
4:76161750:CCC:C	acceptor_gain	1.0000
4:76161751:CC:C	acceptor_gain	1.0000
4:76161752:C:CC	acceptor_gain	1.0000
4:76161752:C:T	acceptor_gain	1.0000
4:76161753:T:A	acceptor_loss	1.0000
4:76161758:C:CT	acceptor_gain	1.0000
4:76161760:C:CT	acceptor_gain	1.0000
4:76161761:A:T	acceptor_gain	1.0000
4:76163380:CACT:C	acceptor_gain	1.0000
4:76163382:CT:C	acceptor_gain	1.0000
4:76166297:TTTCA:T	acceptor_gain	1.0000
4:76166299:TCA:T	acceptor_gain	1.0000
4:76166300:CA:C	acceptor_gain	1.0000
4:76166300:CAC:C	acceptor_gain	1.0000
4:76166302:C:CC	acceptor_gain	1.0000
4:76168401:A:AC	donor_gain	1.0000
4:76168402:C:CC	donor_gain	1.0000
4:76168477:C:CC	acceptor_gain	1.0000
4:76169860:TAC:T	donor_loss	1.0000
4:76169861:ACTC:A	donor_loss	1.0000
4:76169862:CTCA:C	donor_loss	1.0000
4:76169863:TCACA:T	donor_loss	1.0000
4:76169865:A:AC	donor_gain	1.0000
4:76169865:ACAG:A	donor_loss	1.0000
4:76169866:C:A	donor_loss	1.0000
4:76169866:C:CA	donor_gain	1.0000

AlphaMissense

3168 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:76213484:G:C	S20R	0.997
4:76213484:G:T	S20R	0.997
4:76213486:T:G	S20R	0.997
4:76168432:G:C	N386K	0.996
4:76168432:G:T	N386K	0.996
4:76174152:C:G	C329S	0.994
4:76174153:A:T	C329S	0.994
4:76174205:G:C	F311L	0.994
4:76174205:G:T	F311L	0.994
4:76174207:A:G	F311L	0.994
4:76195823:C:A	W53C	0.994
4:76195823:C:G	W53C	0.994
4:76169967:G:A	S338F	0.992
4:76175895:C:A	W240C	0.992
4:76175895:C:G	W240C	0.992
4:76169968:A:G	S338P	0.991
4:76174152:C:T	C329Y	0.991
4:76174153:A:G	C329R	0.991
4:76174203:C:G	C312S	0.991
4:76174204:A:T	C312S	0.991
4:76175809:A:C	F269C	0.991
4:76195722:C:T	G87E	0.991
4:76175794:C:T	C274Y	0.989
4:76175897:A:G	W240R	0.989
4:76175897:A:T	W240R	0.989
4:76179595:C:A	W178C	0.989
4:76179595:C:G	W178C	0.989
4:76175793:G:C	C274W	0.988
4:76175866:C:A	G250V	0.988
4:76175866:C:T	G250E	0.988

dbSNP variants (sampled 300 via entrez): RS1000024148 (4:76202945 T>A), RS1000032192 (4:76172010 ATATATAC>A), RS1000064284 (4:76199719 C>T), RS1000074005 (4:76199961 C>T), RS1000121654 (4:76220875 C>T), RS1000221904 (4:76206462 T>C), RS1000231661 (4:76196647 C>G), RS1000266755 (4:76162209 G>T), RS1000280416 (4:76202587 C>T), RS1000344242 (4:76211742 T>C), RS1000360045 (4:76158763 T>C), RS1000377773 (4:76214037 C>T), RS1000393486 (4:76169829 A>G), RS1000399657 (4:76212009 A>T), RS10004032 (4:76177741 G>A)

Disease associations

OMIM: gene MIM:602257 | disease phenotypes: MIM:254800, MIM:254900, MIM:117100

GenCC curated gene-disease

Disease	Classification	Inheritance
action myoclonus-renal failure syndrome	Definitive	Autosomal recessive
progressive myoclonus epilepsy	Strong	Autosomal recessive
Unverricht-Lundborg syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
progressive myoclonus epilepsy	Definitive	AR

Mondo (5): progressive myoclonus epilepsy (MONDO:0020074), action myoclonus-renal failure syndrome (MONDO:0009699), focal segmental glomerulosclerosis (MONDO:0100313), self-limited epilepsy with centrotemporal spikes (MONDO:0007295), Unverricht-Lundborg syndrome (MONDO:0009698)

Orphanet (4): Progressive myoclonic epilepsy type 1 (Orphanet:308), Progressive myoclonic epilepsy (Orphanet:98261), Action myoclonus-renal failure syndrome (Orphanet:163696), Self-limited epilepsy with centrotemporal spikes (Orphanet:1945)

HPO phenotypes

82 total (30 of 82 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000097	Focal segmental glomerulosclerosis
HP:0000100	Nephrotic syndrome
HP:0000112	Nephropathy
HP:0000225	Gingival bleeding
HP:0000716	Depression
HP:0000726	Dementia
HP:0000790	Hematuria
HP:0000823	Delayed puberty
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000969	Edema
HP:0000978	Bruising susceptibility
HP:0000992	Cutaneous photosensitivity
HP:0001081	Cholelithiasis
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001300	Parkinsonism
HP:0001336	Myoclonus
HP:0001394	Cirrhosis
HP:0001399	Hepatic failure
HP:0001409	Portal hypertension
HP:0001433	Hepatosplenomegaly
HP:0001510	Growth delay
HP:0001541	Ascites

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001126_1	Parkinson’s disease	8.000000e-10
GCST002544_18	Parkinson’s disease	3.000000e-11
GCST002783_28	Body mass index	2.000000e-06
GCST002783_293	Body mass index	5.000000e-09
GCST002783_549	Body mass index	8.000000e-09
GCST004495_97	BMI (adjusted for smoking behaviour)	2.000000e-07
GCST004497_39	Body mass index (joint analysis main effects and smoking interaction)	2.000000e-06
GCST007009_4	Hippocampal volume	3.000000e-07
GCST007876_84	Estimated glomerular filtration rate	2.000000e-72
GCST009325_26	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	1.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004318	smoking behavior
EFO:0005035	hippocampal volume

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D020191	Myoclonic Epilepsies, Progressive	C10.228.140.490.375.130.650; C10.228.140.490.493.063.650
D020194	Unverricht-Lundborg Syndrome	C10.228.140.490.375.130.650.900; C10.228.140.490.493.063.650.900; C10.574.500.875; C16.320.400.940

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

65 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
Valproic Acid	decreases methylation, increases expression	3
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	2
Cisplatin	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
2,4,6-tribromophenol	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
decabromobiphenyl ether	increases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
yessotoxin	increases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects expression, affects reaction	1
CGP 52608	affects binding, increases reaction	1
U 0126	affects expression, affects reaction	1
corosolic acid	increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 1 transformed cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A5HZ	293-SCARB2	Transformed cell line	Female
CVCL_A5IA	RD-SCARB2	Cancer cell line	Female
CVCL_A5IB	Vero-SCARB2	Spontaneously immortalized cell line	Female
CVCL_B9BE	Abcam MCF-7 SCARB2 KO	Cancer cell line	Female
CVCL_D1U9	Abcam U-87MG SCARB2 KO	Cancer cell line	Male
CVCL_D5FI	HeLa::TMEM192-3xHA SCARB2 partial KO	Cancer cell line	Female
CVCL_E0N7	Ubigene HeLa SCARB2 KO	Cancer cell line	Female
CVCL_E0ZN	Ubigene NCI-H1299 SCARB2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01129557	PHASE4	TERMINATED	Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
NCT02399462	PHASE4	WITHDRAWN	Acthar for Treatment of Post-transplant FSGS
NCT02585804	PHASE4	COMPLETED	Treating to Reduce Albuminuria and Normalize Hemodynamic Function in Focal ScLerosis With dApagliflozin Trial Effects
NCT02633046	PHASE4	COMPLETED	Acthar for Treatment-Resistant or Treatment-Intolerant Proteinuria
NCT07219121	PHASE4	RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT03490487	PHASE4	UNKNOWN	Electroclinical Effect of Steroid in Patients With Benign Childhood Epilepsy With Centrotemporal Spikes
NCT04610879	PHASE4	TERMINATED	Changing Agendas on Sleep, Treatment and Learning in Epilepsy
NCT00357669	PHASE3	COMPLETED	Brivaracetam as add-on Treatment of Unverricht-Lundborg Disease in Adolescents and Adults
NCT00368251	PHASE3	COMPLETED	Brivaracetam as add-on Treatment of Unverricht-Lundborg Disease (ULD) in Adolescents and Adults
NCT03351569	PHASE3	UNKNOWN	Intravenous Immunoglobulin for Unverricht-Lundborg Disease.
NCT01164098	PHASE3	TERMINATED	Rituximab to Prevent Recurrence of Proteinuria
NCT02683889	PHASE3	COMPLETED	Use of Acthar in Patients With FSGS That Will be Undergoing Renal Transplantation
NCT03298698	PHASE3	UNKNOWN	Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome
NCT03493685	PHASE3	COMPLETED	Study of Sparsentan in Patients With Primary Focal Segmental Glomerulosclerosis (FSGS)
NCT05183646	PHASE3	RECRUITING	A Study of the Efficacy and Safety of DMX-200 in Patients With FSGS Who Are Receiving an ARB
NCT07220083	PHASE3	RECRUITING	A Study to Find Out if BI 764198 Helps Adults and Adolescents With a Kidney Condition Called Focal Segmental Glomerulosclerosis (FSGS)
NCT00639119	PHASE2	UNKNOWN	Effect of Ropinirole Hydrochloride in Progressive Myoclonic Epilepsy of Unverricht-Lundborg Type
NCT00550342	PHASE2	WITHDRAWN	Rituximab Treatment of Focal Segmental Glomerulosclerosis
NCT00814255	PHASE2	COMPLETED	Novel Therapies for Resistant FSGS (FONTII): Phase II Clinical Trial
NCT01613118	PHASE2	COMPLETED	Randomized, Double-Blind, Safety and Efficacy Study of RE-021 (Sparsentan) in Focal Segmental Glomerulosclerosis
NCT02592798	PHASE2	COMPLETED	Pilot Study to Evaluate the Safety and Efficacy of Abatacept in Adults and Children 6 Years and Older With Excessive Loss of Protein in the Urine Due to Either Focal Segmental Glomerulosclerosis (FSGS) or Minimal Change Disease (MCD)
NCT03366337	PHASE2	COMPLETED	A Phase 2 Trial of the Safety and Efficacy of Bardoxolone Methyl in Patients With Rare Chronic Kidney Diseases - PHOENIX
NCT03448692	PHASE2	TERMINATED	A Study to Evaluate PF-06730512 in Adults With Focal Segmental Glomerulosclerosis (FSGS)
NCT03536754	PHASE2	COMPLETED	A Study of CCX140-B in Subjects With FSGS
NCT03598036	PHASE2	TERMINATED	Dose-Exploration Evaluating the Efficacy and Safety of Voclosporin in Subjects With Focal Segmental Glomerulosclerosis
NCT03649152	PHASE2	COMPLETED	Safety and Effectiveness of Propagermanium in Focal Segmental Glomerulosclerosis Participants Receiving Irbesartan
NCT03703908	PHASE2	TERMINATED	A Study of CCX140-B in Subjects With Primary FSGS and Nephrotic Syndrome
NCT04009668	PHASE2	COMPLETED	Tumor Necrosis Factor Inhibition in Focal Segmental Glomerulosclerosis and Treatment Resistant Minimal Change Disease
NCT04573920	PHASE2	ACTIVE_NOT_RECRUITING	Atrasentan in Patients With Proteinuric Glomerular Diseases
NCT05003986	PHASE2	RECRUITING	Study of Sparsentan Treatment in Pediatrics With Proteinuric Glomerular Diseases
NCT05267262	PHASE2	COMPLETED	Study to Evaluate R3R01 in Patients With Alport Syndrome and Patients With Focal Segmental Glomerulosclerosis
NCT05441826	PHASE2	TERMINATED	Efficacy and Safety of VB119 in Subjects With Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS)
NCT06500702	PHASE2	RECRUITING	A Study to Evaluate the Efficacy and Safety of Frexalimab, Brivekimig, or Rilzabrutinib in Participants Aged 16 to 75 Years With Primary Focal Segmental Glomerulosclerosis or Minimal Change Disease
NCT06664814	PHASE2	RECRUITING	An Open-Label Phase 2 Study of N-Acetyl-D-Mannosamine (ManNAc) in Subjects With Primary Focal Segmental Glomerulosclerosis
NCT06983028	PHASE2	RECRUITING	Atacicept in Multiple Glomerular Diseases
NCT07268638	PHASE2	RECRUITING	A Study of Praliciguat in Participants With Focal Segmental Glomerulosclerosis (FSGS)
NCT07614477	PHASE2	RECRUITING	Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of EVER001 in Participants With Selected Proteinuric Glomerular Diseases
NCT00464321	PHASE1	COMPLETED	Safety Study of GC1008 in Patients With Focal Segmental Glomerulosclerosis (FSGS) of Single Doses of GC1008 in Patients With Treatment Resistant Idiopathic FSGS
NCT00782561	PHASE1	TERMINATED	Safety and Pharmacokinetics of FG-3019 in Adolescents and Adults With Focal Segmental Glomerulosclerosis (FSGS)
NCT00816478	PHASE1	TERMINATED	Effect of Oral Galactose on Focal Segmental Glomerulosclerosis (FSGS) Permeability Factor