SCUBE3

Summary

SCUBE3 (signal peptide, CUB domain and EGF like domain containing 3, HGNC:13655) is a protein-coding gene on chromosome 6p21.3, encoding Signal peptide, CUB and EGF-like domain-containing protein 3 (Q8IX30). Is a positive regulator of the BMP signaling pathway, required for proper chondrogenesis, osteogenesis and skeletal development.

This gene encodes a member of the signal peptide, complement subcomponents C1r/C1s, Uegf, bone morphogenetic protein-1 and epidermal growth factor-like domain containing protein family. Overexpression of this gene in human embryonic kidney cells results in secretion of a glycosylated form of the protein that forms oligomers and tethers to the cell surface. This gene is upregulated in lung cancer tumor tissue compared to healthy tissue and is associated with loss of the epithelial marker E-cadherin and with increased expression of vimentin, a mesenchymal marker. In addition, the protein encoded by this gene is a transforming growth factor beta receptor ligand, and when secreted by cancer cells, it can be cleaved in vitro to release the N-terminal epidermal growth factor-like repeat domain and the C-terminal complement subcomponents C1r/C1s domain. Both the full length protein and C-terminal fragment can bind to the transforming growth factor beta type II receptor to promote the epithelial-mesenchymal transition and tumor angiogenesis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 222663 — RefSeq curated summary.

At a glance

• Gene–disease (curated): short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 (Strong, GenCC)
• GWAS associations: 12
• Clinical variants (ClinVar): 155 total — 7 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 41
• MANE Select transcript: NM_152753

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13655
Approved symbol	SCUBE3
Name	signal peptide, CUB domain and EGF like domain containing 3
Location	6p21.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ34743
Ensembl gene	ENSG00000146197
Ensembl biotype	protein_coding
OMIM	614708
Entrez	222663

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 12 protein_coding

ENST00000274938, ENST00000889524, ENST00000889525, ENST00000889526, ENST00000889527, ENST00000889528, ENST00000926754, ENST00000926755, ENST00000940913, ENST00000940914, ENST00000940915, ENST00000940916

RefSeq mRNA: 2 — MANE Select: NM_152753 NM_001303136, NM_152753

CCDS: CCDS4800

Canonical transcript exons

ENST00000274938 — 22 exons

Exon	Start	End
ENSE00000974359	35239752	35239874
ENSE00000974361	35241141	35241266
ENSE00000974363	35228614	35228739
ENSE00000974435	35245228	35245425
ENSE00001032115	35246206	35246285
ENSE00001032137	35245944	35246096
ENSE00001085010	35233185	35233301
ENSE00001085021	35237902	35238018
ENSE00001173426	35243021	35243236
ENSE00001173431	35242622	35242780
ENSE00001173477	35232850	35232975
ENSE00001173490	35227580	35227702
ENSE00001193754	35243963	35244130
ENSE00001193758	35243594	35243755
ENSE00001246285	35242204	35242320
ENSE00001246290	35241806	35241910
ENSE00001246297	35241543	35241659
ENSE00001339092	35231725	35231859
ENSE00001870277	35248556	35253079
ENSE00001933656	35213956	35214503
ENSE00002486365	35244650	35244811
ENSE00002493221	35240374	35240490

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 96.69.

FANTOM5 (CAGE): breadth broad, TPM avg 10.2704 / max 318.2078, expressed in 863 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67397	3.2682	698
67398	2.9848	506
67395	1.4398	272
67416	0.6093	222
67401	0.4701	208
67402	0.3760	186
67399	0.2640	145
67404	0.2263	127
67405	0.1253	65
67403	0.0986	54

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	96.69	gold quality
descending thoracic aorta	UBERON:0002345	94.78	gold quality
saphenous vein	UBERON:0007318	92.78	gold quality
thoracic aorta	UBERON:0001515	91.59	gold quality
ascending aorta	UBERON:0001496	91.23	gold quality
aorta	UBERON:0000947	89.60	gold quality
epithelial cell of pancreas	CL:0000083	89.08	gold quality
left lobe of thyroid gland	UBERON:0001120	88.67	gold quality
tibia	UBERON:0000979	88.62	gold quality
right lobe of thyroid gland	UBERON:0001119	88.58	gold quality
thyroid gland	UBERON:0002046	88.25	gold quality
popliteal artery	UBERON:0002250	88.12	gold quality
tibial artery	UBERON:0007610	88.09	gold quality
kidney epithelium	UBERON:0004819	88.08	gold quality
superficial temporal artery	UBERON:0001614	87.85	gold quality
artery	UBERON:0001637	86.33	gold quality
cardiac muscle of right atrium	UBERON:0003379	85.78	gold quality
mucosa of paranasal sinus	UBERON:0005030	83.75	gold quality
stromal cell of endometrium	CL:0002255	81.08	gold quality
pigmented layer of retina	UBERON:0001782	81.07	gold quality
cauda epididymis	UBERON:0004360	79.52	gold quality
right coronary artery	UBERON:0001625	77.76	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.40	gold quality
sperm	CL:0000019	77.12	gold quality
nipple	UBERON:0002030	76.70	gold quality
heart right ventricle	UBERON:0002080	76.58	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	75.19	gold quality
apex of heart	UBERON:0002098	74.87	gold quality
upper arm skin	UBERON:0004263	74.81	gold quality
quadriceps femoris	UBERON:0001377	74.38	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7052	yes	267.82
E-HCAD-10	yes	22.77
E-ANND-3	no	5.87

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

221 targeting SCUBE3, 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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-185-3P	99.95	67.01	1743
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-6809-3P	99.91	71.45	3814

Literature-anchored findings (GeneRIF, showing 15)

• may act locally and/or distantly through a proteolytic mechanism, and may play an important role in bone cell biology (PMID:15234972)
• in lung cancer cells, SCUBE3 could serve as an endogenous autocrine and paracrine ligand of TGF-beta type II receptor, which could regulate TGF-beta receptor signaling and modulate EMT and cancer progression (PMID:21441952)
• results show that SCUBE3 knockdown was associated with lower vascular permeability in the tumor and effectively inhibited the metastatic potential of non-small-cell lung carcinoma (PMID:23420440)
• Scube3 facilitates both TGFbeta and Hh signalling within an overall role of facillating inflammatory angiogenesis. (PMID:24084593)
• Results indicated that SCUBE3 might be involved in regulating the epithelial-mesenchymal transition (EMT) and malignant progression in NSCLC. (PMID:24390364)
• Elevated expression of SCUBE3 in osteosarcoma tissues correlated with poor prognosis of the osteosarcoma patients. (PMID:27259322)
• The results of this pioneering study indicate that SCUBE protein family appears to have a probable role in the pathogenesis and angiogenesis development in psoriasis and SCUBE 1 and 3 may be novel markers of angiogenesis in psoriasis. (PMID:28238185)
• Activation of TGF-beta1 Pathway by SCUBE3 Regulates TWIST1 Expression and Promotes Breast Cancer Progression. (PMID:31742430)
• The relationship of serum SCUBE-1, -2 and -3 levels with clinical findings and ultrasonographic skin thickness in systemic sclerosis patients. (PMID:31991528)
• SCUBE3 Is Likely a Susceptibility Gene for Systemic Lupus Erythematosus for Chinese Populations. (PMID:33274247)
• SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling. (PMID:33308444)
• DEPDC1B Promotes Melanoma Angiogenesis and Metastasis through Sequestration of Ubiquitin Ligase CDC16 to Stabilize Secreted SCUBE3. (PMID:35088579)
• Epithelium-derived SCUBE3 promotes polarized odontoblastic differentiation of dental mesenchymal stem cells and pulp regeneration. (PMID:37189178)
• CircSCUBE3 promoted ferroptosis to inhibit lung adenocarcinoma progression. (PMID:38430026)
• Biochemical study of ZNF76 rs10947540 and SCUBE3 rs1888822 single nucleotide polymorphisms in the Egyptian patients with systemic lupus Erythematosus. (PMID:38982741)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	scube3	ENSDARG00000011490
mus_musculus	Scube3	ENSMUSG00000038677
rattus_norvegicus	Scube3	ENSRNOG00000000500

Paralogs (2): SCUBE1 (ENSG00000159307), SCUBE2 (ENSG00000175356)

Protein

Protein identifiers

Signal peptide, CUB and EGF-like domain-containing protein 3 — Q8IX30 (reviewed: Q8IX30)

All UniProt accessions (1): Q8IX30

UniProt curated annotations — full annotation on UniProt →

Function. Is a positive regulator of the BMP signaling pathway, required for proper chondrogenesis, osteogenesis and skeletal development. It acts as a coreceptor for BMP ligands, particularly BMP2 and BMP4, facilitating their interactions with BMP type I receptors. It is required for ligand-induced recruitment of BMP receptors to lipid rafts. Binds to TGFBR2 and activates TGFB signaling. In lung cancer cells, could serve as an endogenous autocrine and paracrine ligand of TGFBR2, which could regulate TGFBR2 signaling and hence modulate epithelial-mesenchymal transition and cancer progression.

Subunit / interactions. Forms homooligomers. Forms heterooligomers with SCUBE1 and SCUBE2. Interacts with TGFBR2 through the CUB domain; this interaction does not affect TGFB1-binding to TGFBR2. Interacts with BMP2, BMP4 and BMP7; the interaction is mediated by the CUB domain. Interacts with BMPR1A, BMPR1B and BMPR2; the interaction with BMPR1A and BMPR1B is BMP2- and BMP4-dependent.

Subcellular location. Secreted. Cell surface.

Tissue specificity. Highly expressed in osteoblasts. In normal lung, mainly expressed in bronchial epithelial cells. Tends to be up-regulated in lung cancer cells.

Post-translational modifications. N-glycosylated. Proteolytic cleavage produces a CUB-containing C-terminal fragment that retains the ability to bind to TGFBR2. This reaction is catalyzed in vitro by MMP2 and, to a lesser extent, by MMP9.

Disease relevance. Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 (SSFSC2) [MIM:619184] An autosomal recessive disorder characterized by reduced growth, skeletal abnormalities, a distinctive craniofacial appearance, and dental anomalies. Cardiac anomalies have been reported in some patients. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IX30-1	1	yes
Q8IX30-2	2

RefSeq proteins (2): NP_001290065, NP_689966* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR000859	CUB_dom	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011641	Tyr-kin_ephrin_A/B_rcpt-like	Domain
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR024731	NELL2-like_EGF	Domain
IPR026823	cEGF	Domain
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily
IPR049883	NOTCH1_EGF-like	Domain
IPR052071	SCUB_EGF-like_domain	Family

Pfam: PF00431, PF07645, PF07699, PF12662, PF12947, PF14670

UniProt features (57 total): disulfide bond 28, domain 10, sequence variant 6, glycosylation site 5, sequence conflict 5, signal peptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IX30-F1	77.61	0.24

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 (28): 33–46, 40–55, 57–68, 74–86, 82–95, 97–110, 116–127, 123–136, 161–172, 168–182, 184–197, 201–212, 208–221, 223–236, 240–251, 247–260, 262–275, 281–292, 288–301, 303–316 …

Glycosylation sites (5): 417, 464, 685, 756, 785

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1474244	Extracellular matrix organization

MSigDB gene sets: 321 (showing top): AP1_01, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, FREAC2_01, BENPORATH_ES_WITH_H3K27ME3, WWTAAGGC_UNKNOWN, PAX4_01, CCAWYNNGAAR_UNKNOWN, LFA1_Q6, SP3_Q3, GOCC_CELL_SURFACE, GOBP_OSTEOBLAST_DIFFERENTIATION, TGACCTY_ERR1_Q2, FOXO1_01, CAGCTG_AP4_Q5, FOXD3_01

GO Biological Process (4): signal transduction (GO:0007165), positive regulation of BMP signaling pathway (GO:0030513), positive regulation of osteoblast differentiation (GO:0045669), positive regulation of signal transduction (GO:0009967)

GO Molecular Function (5): calcium ion binding (GO:0005509), BMP binding (GO:0036122), identical protein binding (GO:0042802), BMP receptor binding (GO:0070700), protein binding (GO:0005515)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), cell surface (GO:0009986), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
osteoblast differentiation	1
positive regulation of cell differentiation	1
regulation of osteoblast differentiation	1
signal transduction	1
regulation of signal transduction	1
positive regulation of cell communication	1
positive regulation of signaling	1
positive regulation of response to stimulus	1
metal ion binding	1
cytokine binding	1
protein binding	1
transmembrane receptor protein serine/threonine kinase binding	1
binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1073 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SCUBE3	TGFBR2	P37173	816
SCUBE3	TCP11	Q8WWU5	665
SCUBE3	TAF11	Q15544	568
SCUBE3	ANKS1A	Q92625	543
SCUBE3	BLTP3A	Q6BDS2	511
SCUBE3	KLHL35	Q6PF15	479
SCUBE3	FANCE	Q9HB96	427
SCUBE3	SPADH	A0A494C103	397
SCUBE3	FAM180A	Q6UWF9	386
SCUBE3	SLC25A29	Q8N8R3	370
SCUBE3	ZSCAN18	Q8TBC5	367
SCUBE3	PCDH8	O95206	366
SCUBE3	CORO6	Q6QEF8	363
SCUBE3	PI15	O43692	350
SCUBE3	KRTAP1-5	Q9BYS1	350

IntAct

11 interactions, top by confidence:

A	B	Type	Score
TGFBR2	TGFB1	psi-mi:“MI:0914”(association)	0.890
SCUBE3	TGFBR2	psi-mi:“MI:0915”(physical association)	0.630
TGFBR2	SCUBE3	psi-mi:“MI:0915”(physical association)	0.630
SCUBE3	TGFBR2	psi-mi:“MI:0407”(direct interaction)	0.630
SCUBE3	MMP2	psi-mi:“MI:0570”(protein cleavage)	0.440
MMP9	SCUBE3	psi-mi:“MI:0570”(protein cleavage)	0.440
MMP2	SCUBE3	psi-mi:“MI:0570”(protein cleavage)	0.440
SCUBE3	MMP9	psi-mi:“MI:0570”(protein cleavage)	0.440

BioGRID (4): SCUBE3 (Affinity Capture-RNA), SCUBE3 (Negative Genetic), SCUBE3 (Affinity Capture-MS), SCUBE3 (Affinity Capture-MS)

ESM2 similar proteins: A0A096LNW5, B8JI71, D3ZHH1, G3I6Z6, O00548, O35516, O57409, P0DPK3, P0DPK4, P35442, P46531, P78504, P97677, Q01705, Q04721, Q05793, Q07008, Q08E66, Q2QI47, Q5G872, Q5ZQU0, Q61483, Q63722, Q66PY1, Q6DI48, Q6NZL8, Q70E20, Q7TQN3, Q7Z3S9, Q8IWY4, Q8IX30, Q8JZM4, Q8K3K1, Q8NFT8, Q8TER0, Q8TEU8, Q8UWJ4, Q8VHS2, Q90Y54, Q90Y57

Diamond homologs: A0A1D5NSM8, A2AVA0, D3YXF5, O02839, O19124, O35764, O43405, O62685, O62837, O70340, O76536, O95502, O96530, P00751, P04003, P04186, P06205, P06206, P06207, P06681, P07629, P08174, P08607, P0C6B8, P13944, P14151, P14650, P15529, P17690, P18337, P26022, P32018, P33703, P35419, P42201, P47970, P47971, P47972, P48199, P48759

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	3
Uncertain significance	124
Likely benign	1
Benign	4

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
981655	NM_152753.4(SCUBE3):c.291C>G (p.Cys97Trp)	Pathogenic
981656	NM_152753.4(SCUBE3):c.611G>A (p.Gly204Asp)	Pathogenic
981659	NM_152753.4(SCUBE3):c.2239+1G>A	Pathogenic
981661	NM_152753.4(SCUBE3):c.2599+2T>C	Pathogenic
981662	NM_152753.4(SCUBE3):c.2785C>T (p.Arg929Ter)	Pathogenic
996761	NG_050574.1:g.29310_309865delins27802_27890inv	Pathogenic
996779	NM_152753.4(SCUBE3):c.1557C>A (p.Cys519Ter)	Pathogenic
3731373	NM_152753.4(SCUBE3):c.2419G>T (p.Glu807Ter)	Likely pathogenic
3780585	NM_152753.4(SCUBE3):c.1909+1G>A	Likely pathogenic
4292575	NM_152753.4(SCUBE3):c.222C>A (p.Cys74Ter)	Likely pathogenic

SpliceAI

4356 predictions. Top by Δscore:

Variant	Effect	Δscore
6:35214501:AAGG:A	donor_loss	1.0000
6:35214502:AGGTA:A	donor_loss	1.0000
6:35214504:GTAA:G	donor_loss	1.0000
6:35227579:GAT:G	acceptor_gain	1.0000
6:35228609:CACA:C	acceptor_loss	1.0000
6:35228610:ACAGA:A	acceptor_loss	1.0000
6:35228611:CA:C	acceptor_loss	1.0000
6:35228612:A:AG	acceptor_gain	1.0000
6:35228612:AG:A	acceptor_loss	1.0000
6:35228612:AGAC:A	acceptor_gain	1.0000
6:35228613:G:GA	acceptor_gain	1.0000
6:35228613:G:T	acceptor_loss	1.0000
6:35228613:GAC:G	acceptor_gain	1.0000
6:35228613:GACG:G	acceptor_gain	1.0000
6:35228613:GACGT:G	acceptor_gain	1.0000
6:35228736:CTGGG:C	donor_loss	1.0000
6:35228737:TGGG:T	donor_loss	1.0000
6:35228738:GG:G	donor_gain	1.0000
6:35228739:GG:G	donor_gain	1.0000
6:35228739:GGT:G	donor_loss	1.0000
6:35228740:G:GG	donor_gain	1.0000
6:35228741:T:A	donor_loss	1.0000
6:35231720:CACA:C	acceptor_loss	1.0000
6:35231722:CA:C	acceptor_loss	1.0000
6:35231723:A:AC	acceptor_loss	1.0000
6:35231723:A:AG	acceptor_gain	1.0000
6:35231724:G:GA	acceptor_gain	1.0000
6:35231724:G:GC	acceptor_loss	1.0000
6:35231856:GAAG:G	donor_gain	1.0000
6:35231857:AAG:A	donor_loss	1.0000

AlphaMissense

6591 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:35227591:T:A	C33S	1.000
6:35227592:G:C	C33S	1.000
6:35227612:T:A	C40S	1.000
6:35227612:T:C	C40R	1.000
6:35227613:G:C	C40S	1.000
6:35227614:C:G	C40W	1.000
6:35227624:G:C	A44P	1.000
6:35227630:T:A	C46S	1.000
6:35227630:T:C	C46R	1.000
6:35227631:G:A	C46Y	1.000
6:35227631:G:C	C46S	1.000
6:35227632:C:G	C46W	1.000
6:35227657:T:A	C55S	1.000
6:35227657:T:C	C55R	1.000
6:35227658:G:C	C55S	1.000
6:35227663:T:A	C57S	1.000
6:35227663:T:C	C57R	1.000
6:35227664:G:A	C57Y	1.000
6:35227664:G:C	C57S	1.000
6:35227665:C:G	C57W	1.000
6:35227696:T:A	C68S	1.000
6:35227696:T:C	C68R	1.000
6:35227697:G:A	C68Y	1.000
6:35227697:G:C	C68S	1.000
6:35227698:C:G	C68W	1.000
6:35228649:T:A	C82S	1.000
6:35228649:T:C	C82R	1.000
6:35228650:G:A	C82Y	1.000
6:35228650:G:C	C82S	1.000
6:35228651:T:G	C82W	1.000

dbSNP variants (sampled 300 via entrez): RS1000014997 (6:35228146 C>G), RS1000066808 (6:35214368 C>G,T), RS1000107771 (6:35248083 A>G), RS1000140749 (6:35235941 GT>G), RS1000193646 (6:35236242 G>C), RS1000269328 (6:35231059 C>A), RS1000421240 (6:35243510 TGGC>T), RS1000656223 (6:35232432 T>C), RS1000713079 (6:35246740 C>T), RS1000772808 (6:35245032 C>G), RS1000808479 (6:35239232 T>A,C), RS1001005515 (6:35232654 C>G), RS1001063996 (6:35225774 G>A,T), RS1001072557 (6:35230581 A>C), RS1001228136 (6:35215302 C>A)

Disease associations

OMIM: gene MIM:614708 | disease phenotypes: MIM:619184

GenCC curated gene-disease

Disease	Classification	Inheritance
short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2	Strong	Autosomal recessive

Mondo (2): prostate cancer (MONDO:0008315), short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 (MONDO:0030953)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000175	Cleft palate
HP:0000201	Pierre-Robin sequence
HP:0000252	Microcephaly
HP:0000276	Long face
HP:0000307	Pointed chin
HP:0000325	Triangular face
HP:0000331	Short chin
HP:0000348	High forehead
HP:0000426	Prominent nasal bridge
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000639	Nystagmus
HP:0000668	Hypodontia
HP:0000677	Oligodontia
HP:0000678	Dental crowding
HP:0000878	11 pairs of ribs
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001382	Joint hypermobility
HP:0001387	Joint stiffness
HP:0001511	Intrauterine growth retardation
HP:0001631	Atrial septal defect
HP:0001655	Patent foramen ovale
HP:0002299	Brittle hair
HP:0002650	Scoliosis
HP:0002786	Tracheobronchomalacia

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST000175_47	Height	4.000000e-08
GCST005752_31	Systemic lupus erythematosus	7.000000e-08
GCST007798_49	Asthma	8.000000e-09
GCST007800_85	Asthma (childhood onset)	1.000000e-07
GCST008839_501	Height	8.000000e-16
GCST010042_74	Asthma	7.000000e-10
GCST012226_476	Waist circumference adjusted for body mass index	1.000000e-08
GCST012227_969	Hip circumference adjusted for BMI	4.000000e-11
GCST90020027_1142	Waist-hip index	4.000000e-09
GCST90020027_1144	Waist-hip index	3.000000e-08
GCST90020028_685	Hip circumference adjusted for BMI	1.000000e-10
GCST90020029_1546	Waist circumference adjusted for body mass index	5.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	6
triphenyl phosphate	affects expression, increases expression	2
trichostatin A	decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Nickel	decreases expression	2
methylmercuric chloride	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
trimellitic anhydride	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
diallyl trisulfide	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
incobotulinumtoxinA	increases expression	1
2,6-dichloro-(1,4)benzoquinone	increases expression	1
Sunitinib	decreases expression	1
Vorinostat	affects cotreatment, decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Bleomycin	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Diazinon	increases methylation	1
Indomethacin	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0UV	Ubigene Hep G2 SCUBE3 KO	Cancer cell line	Male
CVCL_E0VY	Ubigene Huh-7 SCUBE3 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer