SCAP

Summary

SCAP (SREBF chaperone, HGNC:30634) is a protein-coding gene on chromosome 3p21.31, encoding Sterol regulatory element-binding protein cleavage-activating protein (Q12770). Escort protein required for cholesterol as well as lipid homeostasis. It is a selective cancer dependency (DepMap: 69.3% of cell lines).

This gene encodes a protein with a sterol sensing domain (SSD) and seven WD domains. In the presence of cholesterol, this protein binds to sterol regulatory element binding proteins (SREBPs) and mediates their transport from the ER to the Golgi. The SREBPs are then proteolytically cleaved and regulate sterol biosynthesis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 22937 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 240 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 69.3% of screened cell lines
• MANE Select transcript: NM_012235

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30634
Approved symbol	SCAP
Name	SREBF chaperone
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0199
Ensembl gene	ENSG00000114650
Ensembl biotype	protein_coding
OMIM	601510
Entrez	22937

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 34 protein_coding, 5 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000265565, ENST00000320017, ENST00000416208, ENST00000416847, ENST00000420588, ENST00000441517, ENST00000448217, ENST00000465628, ENST00000468965, ENST00000485967, ENST00000487942, ENST00000494938, ENST00000495603, ENST00000648151, ENST00000886153, ENST00000886154, ENST00000886155, ENST00000886156, ENST00000886157, ENST00000886158, ENST00000886159, ENST00000886160, ENST00000886161, ENST00000886162, ENST00000886163, ENST00000886164, ENST00000886165, ENST00000886166, ENST00000886167, ENST00000886168, ENST00000886169, ENST00000886170, ENST00000886171, ENST00000886172, ENST00000886173, ENST00000886174, ENST00000886175, ENST00000935102, ENST00000935103, ENST00000960390, ENST00000960391, ENST00000960392, ENST00000960393

RefSeq mRNA: 2 — MANE Select: NM_012235 NM_001320044, NM_012235

CCDS: CCDS2755

Canonical transcript exons

ENST00000265565 — 23 exons

Exon	Start	End
ENSE00001633865	47427157	47427262
ENSE00001634707	47417304	47417826
ENSE00001696298	47427447	47427667
ENSE00001887062	47475799	47475941
ENSE00003462257	47425997	47426169
ENSE00003473582	47418321	47418522
ENSE00003491996	47417122	47417207
ENSE00003506769	47419328	47419704
ENSE00003533680	47423933	47424045
ENSE00003540986	47435008	47435137
ENSE00003549323	47420554	47420772
ENSE00003569263	47418134	47418249
ENSE00003580814	47422442	47422536
ENSE00003586965	47418655	47418843
ENSE00003591941	47414572	47414652
ENSE00003592831	47414827	47414993
ENSE00003633812	47414180	47414386
ENSE00003635055	47413681	47414099
ENSE00003637416	47420931	47421029
ENSE00003643100	47415098	47415180
ENSE00003716561	47425485	47425611
ENSE00003728083	47442872	47443091
ENSE00003788657	47428513	47428670

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 98.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.2872 / max 155.2170, expressed in 1790 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42044	19.1469	1790
42043	0.1403	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	98.97	gold quality
right adrenal gland cortex	UBERON:0035827	97.83	gold quality
right adrenal gland	UBERON:0001233	97.72	gold quality
adrenal cortex	UBERON:0001235	97.51	gold quality
left adrenal gland cortex	UBERON:0035825	97.43	gold quality
left adrenal gland	UBERON:0001234	97.38	gold quality
adrenal gland	UBERON:0002369	97.29	gold quality
mucosa of transverse colon	UBERON:0004991	95.50	gold quality
right lobe of liver	UBERON:0001114	95.36	gold quality
skin of abdomen	UBERON:0001416	95.28	gold quality
skin of leg	UBERON:0001511	95.19	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.78	gold quality
transverse colon	UBERON:0001157	94.35	gold quality
cerebellar hemisphere	UBERON:0002245	94.35	gold quality
cerebellar cortex	UBERON:0002129	94.27	gold quality
right ovary	UBERON:0002118	94.22	gold quality
left ovary	UBERON:0002119	94.17	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.11	gold quality
right testis	UBERON:0004534	93.97	gold quality
right lobe of thyroid gland	UBERON:0001119	93.85	gold quality
zone of skin	UBERON:0000014	93.80	gold quality
adenohypophysis	UBERON:0002196	93.80	gold quality
left testis	UBERON:0004533	93.77	gold quality
body of stomach	UBERON:0001161	93.72	gold quality
stromal cell of endometrium	CL:0002255	93.70	gold quality
apex of heart	UBERON:0002098	93.64	gold quality
metanephros cortex	UBERON:0010533	93.62	gold quality
body of uterus	UBERON:0009853	93.60	gold quality
lower esophagus mucosa	UBERON:0035834	93.59	gold quality
mucosa of stomach	UBERON:0001199	93.47	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.66
E-MTAB-6142	no	201.02

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, CNBP

miRNA regulators (miRDB)

16 targeting SCAP, 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-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-1271-3P	97.56	64.85	865
HSA-MIR-550A-3-5P	97.56	65.35	823
HSA-MIR-550A-5P	97.56	65.35	823

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 69.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 31)

• Required for sterol-regulated transport of SREBPs from ER to Golgi. (PMID:12842885)
• A possible gene-gene interaction between the genes encoding SREBP-2 and SCAP that modulate plasma lipids in a strictly gender-specific fashion. (PMID:16466730)
• SCAP polymorphism appeared to modify the associations of SREBF-2 genotype with myocardial infarction risk among men. (PMID:17383658)
• TNF alpha upregulates the expression of SCAP and promotes the synthesis of triglyceride in cultured steatotic hepatocytes. (PMID:17963605)
• TRC8 is a novel sterol-sensing endoplasmic reticulum membrane protein that hinders SREBP-2 processing through interaction with SREBP-2 and SCAP, regulating its own turnover rate by means of its E3 ubiquitin ligase activity (PMID:19706601)
• could not identify any association between SREBF-2 1784G > C or SCAP 2386A > G SNPs and premature coronary artery disease or extent of coronary lesions in a Chinese population. (PMID:20111910)
• the SCAP/SREBP signaling axis has a role in protecting cancer cells from lipotoxicity (PMID:23440422)
• Data indicate that SREBP-2 and Scap are regulated by factors driving prostate growth, and suggest exploring this observation further could shed light on prostate carcinogenesis. (PMID:23454642)
• A point mutation in Scap Loop 7 prevents interaction with Loop 1 and abolishes endoplasmic reticulum exit. (PMID:23564452)
• Enhanced SCAP glycosylation by inflammation induces macrophage foam cell formation. (PMID:24146768)
• SCAP gene polymorphisms decrease the risk of nonalcoholic fatty liver disease in females with metabolic syndrome. (PMID:24371177)
• SREBP cleavage regulates Golgi-to-endoplasmic reticulum recycling of SREBP cleavage-activating protein (SCAP) (PMID:24478315)
• identified interaction of three genes in INSIG-SCAP-SREBP pathway on risk of obesity, revealing that these genes affect obesity more likely through a complex interaction pattern than single gene effect. (PMID:25028659)
• Data indicate that glucose-mediated glycosylation promotes SREBP cleavage-activating protein (SCAP) trafficking to the Golgi Leading to sterol regulatory element binding protein 1 (SREBP-1) activation. (PMID:26555173)
• The genetic polymorphisms of SREBF1 could play a role in the mechanism for interindividual variation of atypical antipsychotics-induced metabolic syndrome (MetS). SCAP polymorphisms with drug-induced MetS were negative in this study. (PMID:26982812)
• this study uncovered a novel function of SCAP of counteracting the inhibitory action of Dengue Virus NS2B3 protease on STING signaling, suggesting that modulation of SCAP levels may have therapeutic implications. (PMID:28228593)
• These insights suggest a new structural model for cholesterol-mediated regulation of Scap activity. (PMID:28377508)
• Polymorphism in SCAP gene is associated with high blood pressure. (PMID:28542467)
• GP73 is indispensable for SREBPs activation and lipogenesis. Notably, GP73 overexpression enhanced SCAP-SREBP1 binding and its Golgi trafficking even under cholesterol sufficiency. (PMID:29097707)
• Our study reveals that, in addition to controlling cholesterol biosynthesis, SCAP-SREBP2 also serves as a signaling hub integrating cholesterol metabolism with inflammation in macrophages. (PMID:30366764)
• cholesterol inhibited the progression of HCC through restraining SCAP-mediated fatty acid de novo synthesis. (PMID:30638930)
• Interaction between lifestyle behaviors and genetic polymorphism in SCAP gene on blood pressure among Chinese children. (PMID:31003232)
• Ring finger protein 5 activates sterol regulatory element-binding protein 2 (SREBP2) to promote cholesterol biosynthesis via inducing polyubiquitination of SREBP chaperone SCAP. (PMID:32054686)
• Discovery of a potent SCAP degrader that ameliorates HFD-induced obesity, hyperlipidemia and insulin resistance via an autophagy-independent lysosomal pathway. (PMID:32432943)
• The ER cholesterol sensor SCAP promotes CARTS biogenesis at ER-Golgi membrane contact sites. (PMID:33156328)
• A structure of human Scap bound to Insig-2 suggests how their interaction is regulated by sterols. (PMID:33446483)
• Structural basis for sterol sensing by Scap and Insig. (PMID:34192549)
• PKM2-TMEM33 axis regulates lipid homeostasis in cancer cells by controlling SCAP stability. (PMID:34487377)
• Deficiency of SCAP inhibits HBV pathogenesis via activation of the interferon signaling pathway. (PMID:37437369)
• SARS-CoV-2 nucleocapsid protein promotes TMAO-induced NLRP3 inflammasome activation by SCAP-SREBP signaling pathway. (PMID:37979395)
• The Role of SCAP/SREBP as Central Regulators of Lipid Metabolism in Hepatic Steatosis. (PMID:38256181)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	scap	ENSDARG00000018096
mus_musculus	Scap	ENSMUSG00000032485
rattus_norvegicus	Scap	ENSRNOG00000020853
drosophila_melanogaster	SCAP	FBGN0033052

Paralogs (10): NPC1L1 (ENSG00000015520), PTCH2 (ENSG00000117425), DISP2 (ENSG00000140323), NPC1 (ENSG00000141458), DISP1 (ENSG00000154309), PTCHD1 (ENSG00000165186), PTCHD3 (ENSG00000182077), PTCH1 (ENSG00000185920), DISP3 (ENSG00000204624), PTCHD4 (ENSG00000244694)

Protein

Protein identifiers

Sterol regulatory element-binding protein cleavage-activating protein — Q12770 (reviewed: Q12770)

All UniProt accessions (7): C9JFY0, C9JQ35, Q12770, D6RA39, F8W921, F8W9W7, F8WDP3

UniProt curated annotations — full annotation on UniProt →

Function. Escort protein required for cholesterol as well as lipid homeostasis. Regulates export of the SCAP-SREBP complex from the endoplasmic reticulum to the Golgi upon low cholesterol, thereby regulating the processing of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2. At high sterol concentrations, formation of a ternary complex with INSIG (INSIG1 or INSIG2) leads to mask the ER export signal in SCAP, promoting retention of the complex in the endoplasmic reticulum. Low sterol concentrations trigger release of INSIG, a conformational change in the SSD domain of SCAP, unmasking of the ER export signal, promoting recruitment into COPII-coated vesicles and transport of the SCAP-SREBP to the Golgi: in the Golgi, SREBPs are then processed, releasing the transcription factor fragment of SREBPs from the membrane, its import into the nucleus and up-regulation of LDLR, INSIG1 and the mevalonate pathway. Binds cholesterol via its SSD domain.

Subunit / interactions. Membrane region forms a homotetramer. Component of the SCAP-SREBP complex (composed of SCAP and SREBF1/SREBP1 or SREBF2/SREBP2); interacts with SREBF1/SREBP1 or SREBF2/SREBP2 through its C-terminal cytoplasmic domain. Forms a ternary complex with INSIG1 or INSIG2 through its transmembrane domains at high sterol concentrations. Interacts with PAQR3; the interaction anchors the SCAP-SREBP complex to the Golgi apparatus in low cholesterol conditions. Interacts with the SEC23-SEC24 complex in a SAR1-GTP-dependent manner through an ER export signal in its third cytoplasmic loop. Interacts with RNF139; the interaction inhibits the interaction of SCAP with SEC24B and hampering the ER to Golgi transport of the SCAP-SREBP complex. Interacts with SPRING1.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane. Cytoplasmic vesicle. COPII-coated vesicle membrane.

Post-translational modifications. Ubiquitinated at Lys-454 and Lys-466. RNF145 triggers ubiquitination of SCAP, likely inhibiting SCAP-SREBP complex transport to the Golgi apparatus and the subsequent processing/maturation of SREBF2/SREBP2.

Domain organisation. Loop-1 binds to loop-7, enabling interaction with COPII-coated vesicles. When levels of cholesterol in the endoplasmic reticulum increase, Loop-1 binds to cholesterol instead, thereby disrupting direct binding between the two loops and preventing the SCAP-SREBP complex from exiting the endoplasmic reticulum. Cholesterol bound to SSD domain of SCAP or oxysterol bound to INSIG (INSIG1 or INSIG2) leads to masking of an ER export signal (also named MELADL motif) on SCAP possibly by moving the signal further away from the ER membrane.

Induction. By androgen-bound AR and glucocorticoid-bound NR3C1 in a prostate cancer cell line (LNCaP).

Similarity. Belongs to the WD repeat SCAP family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q12770-1	1	yes
Q12770-2	2
Q12770-3	3
Q12770-4	4

RefSeq proteins (2): NP_001306973, NP_036367* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000731	SSD	Domain
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR030225	SCAP	Family
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR053958	HMGCR/SNAP/NPC1-like_SSD	Domain
IPR057041	SCAP_N	Domain
IPR057042	Beta-prop_SCAP	Domain

Pfam: PF12349, PF24006, PF24017

UniProt features (61 total): topological domain 9, sequence conflict 9, transmembrane region 8, region of interest 8, repeat 7, modified residue 6, splice variant 4, glycosylation site 3, cross-link 2, chain 1, domain 1, short sequence motif 1, compositionally biased region 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6M49	ELECTRON MICROSCOPY	3.7
7ETW	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12770-F1	65.89	0.09

Functional residue map

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

Post-translational modifications (8): 822, 838, 851, 907, 937, 1051, 454, 466

Glycosylation sites (3): 263, 590, 641

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1655829	Regulation of cholesterol biosynthesis by SREBP (SREBF)
R-HSA-9918432	Maturation of DENV proteins
R-HSA-1430728	Metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-8957322	Metabolism of steroids

MSigDB gene sets: 192 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_VESICLE_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_STEROID_METABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_ALCOHOL_BIOSYNTHETIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_ALCOHOL_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_REGULATION_OF_FATTY_ACID_METABOLIC_PROCESS

GO Biological Process (14): response to hypoxia (GO:0001666), immune response (GO:0006955), cholesterol metabolic process (GO:0008203), response to insulin (GO:0032868), SREBP signaling pathway (GO:0032933), response to vitamin B3 (GO:0033552), regulation of fatty acid biosynthetic process (GO:0042304), regulation of cholesterol biosynthetic process (GO:0045540), negative regulation of cholesterol biosynthetic process (GO:0045541), positive regulation of cholesterol biosynthetic process (GO:0045542), COPII-coated vesicle cargo loading (GO:0090110), lipid metabolic process (GO:0006629), steroid metabolic process (GO:0008202), regulation of fatty acid metabolic process (GO:0019217)

GO Molecular Function (5): sterol binding (GO:0032934), protein-containing complex binding (GO:0044877), obsolete unfolded protein binding (GO:0051082), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (10): Golgi membrane (GO:0000139), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), ER to Golgi transport vesicle membrane (GO:0012507), membrane (GO:0016020), SREBP-SCAP complex (GO:0032936), endomembrane system (GO:0012505), cytoplasmic vesicle (GO:0031410), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Metabolism of steroids	1
Dengue Virus Genome Translation and Replication	1
Metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cholesterol biosynthetic process	3
binding	3
cytoplasm	3
regulation of cholesterol biosynthetic process	2
endomembrane system	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
response to stress	1
response to decreased oxygen levels	1
immune system process	1
response to stimulus	1
sterol metabolic process	1
secondary alcohol metabolic process	1
response to peptide hormone	1
ER-nucleus signaling pathway	1
cellular response to sterol depletion	1
response to vitamin	1
fatty acid biosynthetic process	1
regulation of fatty acid metabolic process	1
regulation of lipid biosynthetic process	1
regulation of cholesterol metabolic process	1
regulation of sterol biosynthetic process	1
regulation of alcohol biosynthetic process	1
negative regulation of cholesterol metabolic process	1
negative regulation of sterol biosynthetic process	1
negative regulation of alcohol biosynthetic process	1
positive regulation of cholesterol metabolic process	1
positive regulation of sterol biosynthetic process	1
positive regulation of alcohol biosynthetic process	1
vesicle cargo loading	1
intracellular transport	1
COPII-coated vesicle budding	1
primary metabolic process	1
lipid metabolic process	1
fatty acid metabolic process	1
regulation of ketone metabolic process	1
regulation of lipid metabolic process	1
regulation of small molecule metabolic process	1
steroid binding	1
Golgi apparatus	1

Protein interactions and networks

STRING

1404 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SCAP	INSIG1	O15503	997
SCAP	SREBF2	Q12772	996
SCAP	INSIG2	Q9Y5U4	992
SCAP	SREBF1	P36956	963
SCAP	MBTPS2	O43462	918
SCAP	MBTPS1	Q14703	907
SCAP	ATF6	P18850	743
SCAP	NPC2	P61916	704
SCAP	OSBP	P22059	647
SCAP	HMGA1	P10910	641
SCAP	RNF139	Q8WU17	629
SCAP	ATF6B	Q99941	623
SCAP	HSPA5	P11021	606
SCAP	HMGCR	P04035	600
SCAP	FASN	P49327	589

IntAct

79 interactions, top by confidence:

A	B	Type	Score
	DDR1	psi-mi:“MI:2364”(proximity)	0.670
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
MCOLN3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
	UBXN8	psi-mi:“MI:0914”(association)	0.530
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
B4GAT1	ADCY6	psi-mi:“MI:0914”(association)	0.530
EVA1C	STK25	psi-mi:“MI:0914”(association)	0.530
SLC30A2	ESYT2	psi-mi:“MI:0914”(association)	0.530
GALNTL5	SCAP	psi-mi:“MI:0915”(physical association)	0.400
NUDC	SCAP	psi-mi:“MI:0915”(physical association)	0.400
B4GAT1	ADCY6	psi-mi:“MI:0914”(association)	0.350
	ZFC3H1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
RYBP	FAM186A	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
TTMP	TMEM223	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
CMTM5	TMEM120B	psi-mi:“MI:0914”(association)	0.350
TNFSF18	TMEM120B	psi-mi:“MI:0914”(association)	0.350
ZDHHC12	NBAS	psi-mi:“MI:0914”(association)	0.350
GPRC5D	FAM234B	psi-mi:“MI:0914”(association)	0.350

BioGRID (189): SCAP (Affinity Capture-RNA), SCAP (Affinity Capture-RNA), SCAP (Affinity Capture-MS), SCAP (Affinity Capture-MS), SCAP (Affinity Capture-MS), SCAP (Affinity Capture-MS), SCAP (Affinity Capture-MS), SCAP (Affinity Capture-MS), SCAP (Affinity Capture-MS), RPTOR (Co-fractionation), INSIG1 (Affinity Capture-Western), SCAP (Affinity Capture-MS), SCAP (Affinity Capture-MS), SCAP (Affinity Capture-MS), SCAP (Affinity Capture-MS)

ESM2 similar proteins: A0JPH4, A3KFU9, A6H7H1, A7UA95, B9U3F2, D3ZWZ9, D4A6L0, E1BBQ2, F1M8G0, O15040, O54828, O75129, O88974, P49805, P97260, Q00M95, Q12770, Q13370, Q14432, Q15047, Q3B7M3, Q3B7T1, Q4ZIN3, Q5MNU5, Q5R9R1, Q5T848, Q5VW38, Q5ZKN3, Q61409, Q62865, Q63085, Q6A0A9, Q6F6B3, Q6GQV7, Q6L8S8, Q6P6V6, Q6PJF5, Q80WQ6, Q80Z10, Q86XL3

Diamond homologs: A0JPH4, A2RRU4, A6QM06, P07834, P0CS44, P0CS45, P16393, P49026, P93340, P97260, Q12770, Q5MNU5, Q5ZKU8, Q6GQT6, Q6TNS2, Q758R7, Q7S8R5, Q9XWL9, A4RJV3, O43043, Q6CJ50, A1C7E4, A1CBP8, A1D7I5, A1DDL6, A1DHW6, A2QCU8, A2QEV8, A2R3Z3, A4R3M4, A5DGL8, A6ZMK5, A6ZQL5, A6ZZZ8, A7ETB3, A7TMF9, A7TNS8, A8PTE4, B0XTS1, B0XYC8

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
INSIG2	“down-regulates activity”	SCAP	binding
SCAP	“up-regulates activity”	SREBF1	binding
INSIG1	“down-regulates activity”	SCAP	binding
SCAP	“up-regulates activity”	SREBF1	relocalization
SCAP	“up-regulates activity”	SREBF2	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	189
Likely benign	11
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

4476 predictions. Top by Δscore:

Variant	Effect	Δscore
3:47414176:CTAC:C	donor_loss	1.0000
3:47414178:ACCT:A	donor_loss	1.0000
3:47414179:CCTG:C	donor_gain	1.0000
3:47414382:ATGGT:A	acceptor_gain	1.0000
3:47414383:TGGT:T	acceptor_gain	1.0000
3:47414384:GGT:G	acceptor_gain	1.0000
3:47414384:GGTC:G	acceptor_loss	1.0000
3:47414385:GT:G	acceptor_gain	1.0000
3:47414385:GTCTG:G	acceptor_loss	1.0000
3:47414386:TCTG:T	acceptor_loss	1.0000
3:47414387:C:CC	acceptor_gain	1.0000
3:47414387:C:T	acceptor_loss	1.0000
3:47414569:TA:T	donor_loss	1.0000
3:47414571:C:CT	donor_loss	1.0000
3:47414994:C:CC	acceptor_gain	1.0000
3:47414995:T:G	acceptor_loss	1.0000
3:47418132:AC:A	donor_gain	1.0000
3:47418133:CC:C	donor_gain	1.0000
3:47418315:GCTCA:G	donor_loss	1.0000
3:47418316:CTCA:C	donor_loss	1.0000
3:47418317:TCACC:T	donor_loss	1.0000
3:47418318:CAC:C	donor_loss	1.0000
3:47418319:ACCAT:A	donor_loss	1.0000
3:47418320:C:T	donor_loss	1.0000
3:47418518:CCACC:C	acceptor_gain	1.0000
3:47418519:CACC:C	acceptor_gain	1.0000
3:47418519:CACCC:C	acceptor_gain	1.0000
3:47418520:ACC:A	acceptor_gain	1.0000
3:47418521:CC:C	acceptor_gain	1.0000
3:47418521:CCC:C	acceptor_gain	1.0000

AlphaMissense

8221 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:47414021:A:G	W1225R	1.000
3:47414021:A:T	W1225R	1.000
3:47414029:A:T	V1222D	1.000
3:47414249:G:C	S1175R	1.000
3:47414249:G:T	S1175R	1.000
3:47414251:T:G	S1175R	1.000
3:47414341:A:G	W1145R	1.000
3:47414341:A:T	W1145R	1.000
3:47414369:A:C	S1135R	1.000
3:47414369:A:T	S1135R	1.000
3:47414371:T:G	S1135R	1.000
3:47418180:A:G	W801R	1.000
3:47418180:A:T	W801R	1.000
3:47418208:G:C	S791R	1.000
3:47418208:G:T	S791R	1.000
3:47418210:T:G	S791R	1.000
3:47420956:A:G	L440P	1.000
3:47421024:G:C	F417L	1.000
3:47421024:G:T	F417L	1.000
3:47421026:A:G	F417L	1.000
3:47423938:G:T	A382D	1.000
3:47424003:A:C	N360K	1.000
3:47424003:A:T	N360K	1.000
3:47425596:A:T	V309D	1.000
3:47413891:A:G	L1268P	0.999
3:47413897:A:G	L1266P	0.999
3:47413918:A:T	V1259D	0.999
3:47414019:C:A	W1225C	0.999
3:47414019:C:G	W1225C	0.999
3:47414053:A:G	L1214P	0.999

dbSNP variants (sampled 300 via entrez): RS1000012543 (3:47448947 T>G), RS1000078940 (3:47448515 T>G), RS1000162307 (3:47421444 A>G), RS1000179428 (3:47427652 G>A), RS1000220495 (3:47455466 G>A,T), RS1000250366 (3:47477169 A>G), RS1000259209 (3:47474794 C>T), RS1000259967 (3:47441461 A>C,G), RS1000310670 (3:47474203 T>A,G), RS1000365642 (3:47416062 C>A), RS1000398199 (3:47434781 G>A), RS1000411504 (3:47441843 C>T), RS1000473933 (3:47471545 T>A,C), RS1000502268 (3:47456780 G>A,C), RS1000534482 (3:47476391 G>A,T)

Disease associations

OMIM: gene MIM:601510 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010002_422	Refractive error	4.000000e-14
GCST010244_190	Triglyceride levels	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879458 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs12487736	Efficacy	3	simvastatin	Hypercholesterolemia
rs12487736	Other	4	atorvastatin

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12487736	SCAP	3	1.75	2	atorvastatin;simvastatin

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
fatostatin	decreases expression, increases reaction, increases response to substance	3
sodium arsenite	affects methylation, decreases expression	2
Arsenic	decreases expression, increases abundance, affects methylation	2
Valproic Acid	affects cotreatment, increases expression	2
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
arsenic trichloride	decreases expression, increases abundance	1
ICG 001	increases expression	1
bisphenol S	increases methylation	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Caffeine	increases phosphorylation	1
Doxorubicin	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Lipopolysaccharides	increases expression, decreases reaction	1
Ozone	affects expression, increases abundance	1
Dihydrotestosterone	increases expression	1
Tetrachlorodibenzodioxin	decreases expression, increases expression	1
Thiram	decreases expression	1
Asbestos, Crocidolite	affects expression	1
Copper Sulfate	decreases expression	1
Simvastatin	affects response to substance	1
Acrylamide	decreases expression	1
Vitamin K 3	affects expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4824186	Binding	Inhibition of FLAG-tagged SCAP (unknown origin) expressed in CHO-K1 cells assessed as reduction in SCAP protein level at 5 uM after 24 hrs by Western blotting analysis	Discovery of a Vitamin D Receptor-Silent Vitamin D Derivative That Impairs Sterol Regulatory Element-Binding Protein In Vivo. — J Med Chem

Clinical trials (associated diseases)

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