SERPINB4

Summary

SERPINB4 (serpin family B member 4, HGNC:10570) is a protein-coding gene on chromosome 18q21.33, encoding Serpin B4 (P48594). May act as a protease inhibitor to modulate the host immune response against tumor cells.

The protein encoded by this gene is a member of the serpin family of serine protease inhibitors. The encoded protein is highly expressed in many tumor cells and can inactivate granzyme M, an enzyme that kills tumor cells. This protein, along with serpin B3, can be processed into smaller fragments that aggregate to form an autoantigen in psoriasis, probably by causing chronic inflammation.

Source: NCBI Gene 6318 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 70 total — 1 pathogenic
• MANE Select transcript: NM_002974

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10570
Approved symbol	SERPINB4
Name	serpin family B member 4
Location	18q21.33
Locus type	gene with protein product
Status	Approved
Aliases	PI11, LEUPIN, SCCA-2, SCCA1
Ensembl gene	ENSG00000206073
Ensembl biotype	protein_coding
OMIM	600518
Entrez	6318

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000341074, ENST00000413673, ENST00000436264, ENST00000498496

RefSeq mRNA: 2 — MANE Select: NM_002974 NM_002974, NM_175041

CCDS: CCDS11986

Canonical transcript exons

ENST00000341074 — 8 exons

Exon	Start	End
ENSE00001602600	63643161	63643217
ENSE00001678003	63641760	63641888
ENSE00001715507	63639185	63639340
ENSE00001742851	63640874	63640991
ENSE00001777198	63644209	63644256
ENSE00001799299	63639634	63639776
ENSE00001858647	63637259	63638123
ENSE00003657228	63643413	63643603

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 99.34.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2153 / max 111.8187, expressed in 45 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172287	0.2153	45

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nasal cavity epithelium	UBERON:0005384	99.34	gold quality
mammalian vulva	UBERON:0000997	99.19	gold quality
cervix squamous epithelium	UBERON:0006922	99.11	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.75	gold quality
cervix epithelium	UBERON:0004801	98.71	gold quality
penis	UBERON:0000989	98.45	gold quality
nasal cavity mucosa	UBERON:0001826	98.12	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.36	gold quality
epithelium of bronchus	UBERON:0002031	97.04	gold quality
esophagus squamous epithelium	UBERON:0006920	97.02	gold quality
bronchus	UBERON:0002185	96.72	gold quality
squamous epithelium	UBERON:0006914	96.60	gold quality
bronchial epithelial cell	CL:0002328	96.56	gold quality
epithelium of esophagus	UBERON:0001976	96.54	gold quality
gingiva	UBERON:0001828	96.40	gold quality
gingival epithelium	UBERON:0001949	95.51	gold quality
tongue squamous epithelium	UBERON:0006919	93.04	gold quality
oral cavity	UBERON:0000167	92.58	gold quality
esophagus mucosa	UBERON:0002469	92.58	gold quality
epithelium of nasopharynx	UBERON:0001951	86.38	gold quality
vagina	UBERON:0000996	83.53	gold quality
lower esophagus mucosa	UBERON:0035834	82.87	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.39	silver quality
upper leg skin	UBERON:0004262	81.79	gold quality
trachea	UBERON:0003126	80.02	gold quality
pancreatic ductal cell	CL:0002079	79.49	silver quality
periodontal ligament	UBERON:0008266	79.23	gold quality
body of tongue	UBERON:0011876	78.35	gold quality
buccal mucosa cell	CL:0002336	76.36	gold quality
pharyngeal mucosa	UBERON:0000355	75.31	silver quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-7	yes	3506.96
E-CURD-114	yes	2972.86
E-HCAD-1	yes	2508.73
E-MTAB-8530	yes	1165.01
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT1, STAT6

miRNA regulators (miRDB)

30 targeting SERPINB4, 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-4533	100.00	69.48	2758
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-8054	99.48	70.81	2084
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-299-3P	97.73	66.67	773
HSA-MIR-6807-5P	97.51	64.25	1046
HSA-MIR-1202	97.19	66.43	827
HSA-MIR-3972	97.19	66.46	808
HSA-MIR-27A-5P	97.01	65.63	528
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-4265	96.18	64.68	557
HSA-MIR-4322	96.18	64.85	539
HSA-MIR-4462	95.10	66.27	172
HSA-MIR-10A-3P	93.57	64.43	451

Literature-anchored findings (GeneRIF, showing 40)

• expression in various normal tissue types and in tumor cell lines, increase in expression induced by TNF-alpha, and role in protecting tumor cells against TNF-alpha induced apoptsis (PMID:12437110)
• SCCA2-like serpins mediate genetic predisposition to skin cancer in a mouse model and in humans. (PMID:12702576)
• SCCA2 acts as a cross-class serpin targeting an extrinsic cysteine proteinase from mites and may have a protective role against biological reactions caused by mites (PMID:14630915)
• SCCA variants are overexpressed in hepatocellular carcinoma independently of tumour etiology (PMID:14970861)
• Uteroglobin suppresses SCCA gene expression associated with airway inflammation in asthma (PMID:15677460)
• SCCAs can alter invasive phenotype of cervical squamous cell carcinoma cells, probably by stimulating proMMP-9 production, and intact conformational structure of SCCAs is required for its stimulatory activity on proMMP-9 production (PMID:16211231)
• Up-regulation of squamous cell carcinoma antigen-1 (SCCA1) suppresses c-Jun NH2-terminal kinase-1 (JNK1) and thus blocks UV-induced keratinocyte apoptosis. (PMID:16549498)
• These results, in transgenic mice, suggest that SCAA1 might serve as an hepatitis B virus receptor or co-receptor and play an important role in mediating HBV entry into hepatocytes. (PMID:16820864)
• SCCA2 regulates cell migration and invasion via E-cadherin expression, suggesting that SCCA2 may be involved in cancer behavior such as invasion or metastasis. (PMID:17016656)
• SCCA2 may be involved in cancer behavior such as metastasis, and as such can be a useful marker in predicting lymph node metastasis. (PMID:18097581)
• Activated STAT3 is a required part of the continuous activation of B3/B4 genes, which protects tumor cells from dying. (PMID:19070595)
• fatty acid-binding protein-5, squamous cell carcinoma antigens 2, alpha-enolase, annexin II, apolipoprotein A-I and albumin were detected at a high level in Atopic dermatitis skin lesions, but scarcely in the normal controls (PMID:19339807)
• Transgenic mice expressing human SCCA1 showed higher liver regenerative potential compared to wild-type mice, supporting the dual role of this serpin as an anti-apoptotic and pro-proliferative stimulus for liver cells in vivo. (PMID:19956912)
• Data show that show that SCCA-1 (B3) and SCCA-2 (B4) can bind heparin as demonstrated by affinity chromatography, native PAGE gel shifts, and intrinsic fluorescence quenching. (PMID:19959474)
• carbonyl reductase binds to SCCA1 and SCCA2 and they are co-located in the same layer of the squamous epithelium (PMID:20428762)
• Elevated serum SCCA1 is associated with squamous cell carcinoma in cervical cancer. (PMID:21338226)
• Data suggest that SCCA1 inhibits cell death induced by lysosomal injury while, on the other hand, it sensitizes cells to ER stress by activating caspase-8 independently of the death receptor apoptotic pathway. (PMID:21576355)
• Results indicate that cellular overexpression of SERPINB4 inhibits recombinant GrM-induced as well as NK cell-mediated cell death. (PMID:21857942)
• Serpin B4 isoform overexpression is associated with aberrant epithelial proliferation and lung cancer in idiopathic pulmonary fibrosis. (PMID:22406480)
• Toxoplasma gondii induces SERPIN B3/B4 expression via STAT6 activation to inhibit the apoptosis of infected cells for survival of the parasites. (PMID:22451727)
• High serum SCCA1 levels are associated with lymph node metastasis, advanced tumor stage and tumor recurrence in oral cavity squamous cell carcinoma. (PMID:22576068)
• IgM-linked SCCA isoforms circulate in patients with chronic liver disease, compared to total SCCA-IgM levels. (PMID:22808225)
• both HPV status and the SCCA2/SCCA1 mRNA ratio are independently associated with prognosis in HNSCC (PMID:22937809)
• The serum level of SCCA is effective for detecting inverted papilloma (IP), including recurrent IP. In contrast, the SCCA2/SCCA1 ratio is useful for detecting squamous cell carcinoma among other sinonasal diseases. (PMID:23168150)
• The results show that SCCA1 has diverse effects on many of the cellular events that characterize asthma and its role extends beyond protease inhibition. (PMID:23199842)
• demonstrate the generation of Pso p27 from SCCA1 with extracts from psoriatic scale and even more remarkably, the generation of Pso p27 from SCCA1 in the presence of mast cell associated chymase (PMID:24560885)
• It is a promising serological marker for hepatocellular carcinoma. (PMID:24635038)
• we identified four proteins with different expression in paclitaxel resistant cells, i.e., serpin B3, serpin B4, heat shock protein 27 (all three upregulated) and cytokeratin 18 (downregulated). (PMID:24898082)
• Silencing of SERPINB3/B4 in human keratinocytes decreased S100A8 expression, supporting a role for SERPINB3/B4 in the initiation of the acute inflammatory response. (PMID:25111616)
• our findings established that SCCA1 contributes to tumorigenesis by promoting EMT and a UPR-dependent induction of NF-kappaB and IL6 autocrine signaling that promotes a protumorigenic inflammation. (PMID:25213322)
• Pediatric CNS-PNETs evade immune recognition by downregulating cell surface MHC-I and CD1d expression. Intriguingly, expression of SERPINB9, SERPINB1, and SERPINB4 is acquired during tumorigenesis in 29%, 29%, and 57% of the tumors (PMID:26963506)
• Data show that oropharyngeal squamous cell carcinomas (OPSCCs) express granzyme inhibitors SERPINB1, SERPINB4 and SERPINB9 for cytotoxicity and the expression was not different between human papillomavirus (HPV)-positive and HPV-negative tumors. (PMID:26993499)
• role of SERPINB3/B4 mutations in immunotherapy response (PMID:27668655)
• Serum SCCA2 levels reflected disease severity and clinical type of atopic dermatitis. Serum SCCA2 may thus be a relevant biomarker for atopic dermatitis. (PMID:28734739)
• While novel diagnostic tumour markers are urgently needed, the examined potential tumour markers, with the exception of PIVKAII seem to be inadequate for diagnosing HCC in ALC (PMID:28766361)
• this study shows that SERPINB4 contributes to survival of allergenic TH2 cells (PMID:29106998)
• Results provide the first evidence that failure of serum SCCA to fall into the normal range by the fourth week of definitive radiotherapy is associated with significantly increased risk of recurrence and death. (PMID:29112685)
• Both periostin and SCCA may play a role in the pathogenesis of acute bronchitis due to respiratory syncytial virus (PMID:29122495)
• SCCA2 is a reliable biomarker. (PMID:29421276)
• Findings point to potential interest of squamous cell carcinoma antigen SERPINB3/B4 for the stratification of head and neck squamous cell carcinoma (HNSCC) patients in the therapeutic context. (PMID:29491058)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Serpinb3a	ENSMUSG00000044594
mus_musculus	Serpinb3d	ENSMUSG00000058017
mus_musculus	Serpinb3c	ENSMUSG00000073601
mus_musculus	Serpinb3b	ENSMUSG00000073602
rattus_norvegicus	Serpinb3a	ENSRNOG00000066913
rattus_norvegicus	Serpinb3	ENSRNOG00000070387

Paralogs (36): SERPINB1 (ENSG00000021355), SERPINB3 (ENSG00000057149), SERPIND1 (ENSG00000099937), SERPINA4 (ENSG00000100665), SERPINE1 (ENSG00000106366), SERPINI2 (ENSG00000114204), SERPINC1 (ENSG00000117601), SERPINA7 (ENSG00000123561), SERPINB6 (ENSG00000124570), SERPINF1 (ENSG00000132386), AGT (ENSG00000135744), SERPINE2 (ENSG00000135919), SERPINA10 (ENSG00000140093), SERPING1 (ENSG00000149131), SERPINH1 (ENSG00000149257), SERPINI1 (ENSG00000163536), SERPINA12 (ENSG00000165953), SERPINB7 (ENSG00000166396), SERPINB8 (ENSG00000166401), SERPINB12 (ENSG00000166634), SERPINF2 (ENSG00000167711), SERPINA9 (ENSG00000170054), SERPINA6 (ENSG00000170099), SERPINB9 (ENSG00000170542), SERPINA11 (ENSG00000186910), SERPINA5 (ENSG00000188488), SERPINA3 (ENSG00000196136), SERPINA1 (ENSG00000197249), SERPINB2 (ENSG00000197632), SERPINB13 (ENSG00000197641), SERPINB11 (ENSG00000206072), SERPINB5 (ENSG00000206075), HMSD (ENSG00000221887), SERPINB10 (ENSG00000242550), SERPINE3 (ENSG00000253309), SERPINA2 (ENSG00000258597)

Protein

Protein identifiers

Serpin B4 — P48594 (reviewed: P48594)

Alternative names: Leupin, Peptidase inhibitor 11, Squamous cell carcinoma antigen 2

All UniProt accessions (3): P48594, C9JZ65, H0Y5H9

UniProt curated annotations — full annotation on UniProt →

Function. May act as a protease inhibitor to modulate the host immune response against tumor cells.

Subcellular location. Cytoplasm.

Tissue specificity. Squamous cells.

Similarity. Belongs to the serpin family. Ov-serpin subfamily.

RefSeq proteins (2): NP_002965, NP_778206 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000215	Serpin_fam	Family
IPR023795	Serpin_CS	Conserved_site
IPR023796	Serpin_dom	Domain
IPR036186	Serpin_sf	Homologous_superfamily
IPR042178	Serpin_sf_1	Homologous_superfamily
IPR042185	Serpin_sf_2	Homologous_superfamily

Pfam: PF00079

UniProt features (4 total): chain 1, site 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48594-F1	89.67	0.80

Functional residue map

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

Catalytic / active sites (1): 354–355 (reactive bond)

Post-translational modifications (1): 1

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 125 (showing top): RNGTGGGC_UNKNOWN, JAEGER_METASTASIS_DN, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, GOBP_NEGATIVE_REGULATION_OF_NATURAL_KILLER_CELL_MEDIATED_IMMUNITY, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY

GO Biological Process (3): regulation of proteolysis (GO:0030162), protection from natural killer cell mediated cytotoxicity (GO:0042270), negative regulation of peptidase activity (GO:0010466)

GO Molecular Function (6): protease binding (GO:0002020), serine-type endopeptidase inhibitor activity (GO:0004867), enzyme binding (GO:0019899), endopeptidase inhibitor activity (GO:0004866), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), cytosol (GO:0005829), plasma membrane (GO:0005886), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidase activity	2
cellular anatomical structure	2
proteolysis	1
regulation of protein metabolic process	1
negative regulation of natural killer cell mediated cytotoxicity	1
negative regulation of proteolysis	1
negative regulation of hydrolase activity	1
regulation of peptidase activity	1
enzyme binding	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
protein binding	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
binding	1
enzyme inhibitor activity	1
peptidase regulator activity	1
cytoplasm	1
membrane	1
cell periphery	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1064 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SERPINB4	CTRL	P40313	781
SERPINB4	CMA1	P23946	691
SERPINB4	PLG	P00747	674
SERPINB4	CTSG	P08311	651
SERPINB4	CSTA	P01040	606
SERPINB4	CTSS	P25774	553
SERPINB4	GALR1	P47211	513
SERPINB4	S100A7	P31151	506
SERPINB4	PI15	O43692	471
SERPINB4	KRT6B	P04259	456
SERPINB4	ING1	Q9UK53	454
SERPINB4	BPIFB1	Q8TDL5	449
SERPINB4	S100A7A	Q86SG5	446
SERPINB4	KLK6	Q92876	444
SERPINB4	PI16	Q6UXB8	432

IntAct

211 interactions, top by confidence:

A	B	Type	Score
MAPK6	HERC2	psi-mi:“MI:0914”(association)	0.840
MED24	MED19	psi-mi:“MI:0914”(association)	0.730
SINHCAF	TNRC18	psi-mi:“MI:0914”(association)	0.640
CCNC	MED19	psi-mi:“MI:0914”(association)	0.640
SERPINB3	SERPINB4	psi-mi:“MI:0914”(association)	0.620
MAP2K6	MAP2K3	psi-mi:“MI:0914”(association)	0.610
HOXD10	SERPINB4	psi-mi:“MI:0915”(physical association)	0.590
IL18	SERPINB4	psi-mi:“MI:0915”(physical association)	0.590
NPPA	A2ML1	psi-mi:“MI:0914”(association)	0.530
FTH1	A2ML1	psi-mi:“MI:0914”(association)	0.530
ZFAND4	A2ML1	psi-mi:“MI:0914”(association)	0.530
FRMD1	A2ML1	psi-mi:“MI:0914”(association)	0.530
UGT1A10	A2ML1	psi-mi:“MI:0914”(association)	0.530
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
CCDC92	PSMD11	psi-mi:“MI:0914”(association)	0.530
ZNF354C	IPO8	psi-mi:“MI:0914”(association)	0.530
KIR3DS1	PPL	psi-mi:“MI:0914”(association)	0.530
MMRN1	CTSV	psi-mi:“MI:0914”(association)	0.530
MRPL38	DUSP14	psi-mi:“MI:0914”(association)	0.530
UCP2	CST4	psi-mi:“MI:0914”(association)	0.530
CYP3A5	IGHG1	psi-mi:“MI:0914”(association)	0.530
UPRT	SERPINB4	psi-mi:“MI:0914”(association)	0.530
STK35	HSP90AA1	psi-mi:“MI:0914”(association)	0.530
PINK1	CLUH	psi-mi:“MI:0914”(association)	0.530
HLA-DPA1	TYW5	psi-mi:“MI:0914”(association)	0.530

BioGRID (249): SERPINB4 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), METTL13 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS)

ESM2 similar proteins: A0A090BX51, A2I7M9, A2I7N0, A2I7N2, A5PJK0, A9RA96, B0CMB0, B1MTB7, B1MTC3, B2KI30, B3RFC3, B4USX2, E2RVI8, O08800, O73790, O73860, O75635, P01012, P01013, P01014, P05120, P05544, P09006, P12388, P19104, P29508, P29524, P36952, P48594, P48595, P70124, P70458, P70564, Q03044, Q52L45, Q5I0S8, Q5M8J5, Q5SV42, Q6GLQ1, Q6V115

Diamond homologs: A0A090BX51, A0A0K8RCY5, A0A0K8RJ89, A0A0K8RJV9, A5PJK0, A9RA96, B0CMB0, B1MTB7, B1MTC3, B2KI30, B3RFC3, B4USX2, E2RVI8, O02739, O08800, O35684, O54757, O54758, O54759, O54760, O73790, O73860, O75635, O75830, P01008, P01011, P01012, P01014, P05120, P05619, P12388, P17475, P19104, P22323, P22325, P22922, P23035, P29508, P29524, P30740

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	59
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4682936	GRCh37/hg19 18q21.2-22.2(chr18:52640210-68070259)x4	Pathogenic

SpliceAI

758 predictions. Top by Δscore:

Variant	Effect	Δscore
18:63638120:CAAG:C	acceptor_gain	1.0000
18:63638122:AG:A	acceptor_gain	1.0000
18:63638122:AGC:A	acceptor_loss	1.0000
18:63638122:AGCT:A	acceptor_gain	1.0000
18:63638123:GC:G	acceptor_loss	1.0000
18:63638123:GCTAT:G	acceptor_gain	1.0000
18:63638124:C:CC	acceptor_gain	1.0000
18:63638126:A:AC	acceptor_gain	1.0000
18:63638126:A:C	acceptor_gain	1.0000
18:63639179:TCTTA:T	donor_loss	1.0000
18:63639180:CTTA:C	donor_loss	1.0000
18:63639181:TTA:T	donor_loss	1.0000
18:63639182:TAC:T	donor_loss	1.0000
18:63639183:A:C	donor_loss	1.0000
18:63639184:C:CT	donor_loss	1.0000
18:63639184:CCTT:C	donor_gain	1.0000
18:63639282:A:T	acceptor_gain	1.0000
18:63639352:CAA:C	acceptor_gain	1.0000
18:63639371:CACG:C	acceptor_gain	1.0000
18:63639374:G:C	acceptor_gain	1.0000
18:63639628:CAATA:C	donor_loss	1.0000
18:63639629:AATAC:A	donor_loss	1.0000
18:63639630:ATACC:A	donor_loss	1.0000
18:63639631:TA:T	donor_loss	1.0000
18:63639632:ACC:A	donor_loss	1.0000
18:63639772:TTTTT:T	acceptor_gain	1.0000
18:63639773:TTTT:T	acceptor_gain	1.0000
18:63639774:TTT:T	acceptor_gain	1.0000
18:63639777:C:CC	acceptor_gain	1.0000
18:63640869:CCTAC:C	donor_loss	1.0000

AlphaMissense

2620 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:63639690:A:G	W186R	0.990
18:63639690:A:T	W186R	0.990
18:63643479:G:C	S33R	0.988
18:63643479:G:T	S33R	0.988
18:63643481:T:G	S33R	0.988
18:63637785:G:C	F369L	0.987
18:63637785:G:T	F369L	0.987
18:63637787:A:G	F369L	0.987
18:63639646:A:C	F200L	0.987
18:63639646:A:T	F200L	0.987
18:63639648:A:G	F200L	0.987
18:63639676:A:C	F190L	0.984
18:63639676:A:T	F190L	0.984
18:63639678:A:G	F190L	0.984
18:63639688:C:A	W186C	0.983
18:63639688:C:G	W186C	0.983
18:63643445:C:G	A45P	0.974
18:63643534:A:G	L15P	0.973
18:63637968:G:C	F308L	0.969
18:63637968:G:T	F308L	0.969
18:63637970:A:G	F308L	0.969
18:63640935:A:C	F136L	0.969
18:63640935:A:T	F136L	0.969
18:63640937:A:G	F136L	0.969
18:63637803:G:C	F363L	0.965
18:63637803:G:T	F363L	0.965
18:63637805:A:G	F363L	0.965
18:63639647:A:G	F200S	0.965
18:63637738:C:T	G385D	0.964
18:63637743:G:C	F383L	0.964

dbSNP variants (sampled 300 via entrez): RS1000251482 (18:63640185 G>C), RS1000308317 (18:63644790 A>G), RS1000360039 (18:63644466 A>G), RS1000643908 (18:63643526 G>A), RS1002190206 (18:63641525 A>G), RS1002419126 (18:63636903 T>C), RS1003093573 (18:63638711 A>T), RS1003145621 (18:63638551 A>C), RS1003708743 (18:63642106 A>G), RS1003866110 (18:63642063 T>C), RS1004044939 (18:63637675 C>A,G,T), RS1004692411 (18:63645410 A>G), RS1006496454 (18:63643064 C>G,T), RS1006918519 (18:63644934 T>C), RS1007090950 (18:63640253 A>G)

Disease associations

OMIM: gene MIM:600518 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): prostate cancer (MONDO:0008315)

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

HPO phenotypes

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

GWAS associations

0 associations (top):

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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression	5
sodium arsenate	decreases expression, increases abundance	2
Lipopolysaccharides	affects response to substance, affects cotreatment, affects expression, increases expression, affects reaction	2
Tobacco Smoke Pollution	affects expression, increases expression	2
methylmercuric chloride	increases expression	1
propionaldehyde	increases expression	1
lead acetate	decreases expression	1
arsenite	decreases methylation	1
cupric chloride	decreases expression	1
nickel sulfate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
Acetylglucosamine	increases expression	1
Amphotericin B	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Benztropine	increases expression	1
Cannabidiol	increases expression	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Fluorouracil	decreases expression	1
Methotrexate	increases expression	1
Nickel	increases expression	1
Plant Extracts	affects expression, affects reaction	1
Silicon Dioxide	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tretinoin	increases expression	1
Silver Compounds	decreases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases expression	1

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