SERPINA5

Summary

SERPINA5 (serpin family A member 5, HGNC:8723) is a protein-coding gene on chromosome 14q32.13, encoding Plasma serine protease inhibitor (P05154). Heparin-dependent serine protease inhibitor acting in body fluids and secretions.

The protein encoded by this gene is a member of the serpin family of proteins, a group of proteins that inhibit serine proteases. This gene is one in a cluster of serpin genes located on the q arm of chromosome 14. This family member is a glycoprotein that can inhibit several serine proteases, including protein C and various plasminogen activators and kallikreins, and it thus plays diverse roles in hemostasis and thrombosis in multiple organs.

Source: NCBI Gene 5104 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 89 total
• MANE Select transcript: NM_000624

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8723
Approved symbol	SERPINA5
Name	serpin family A member 5
Location	14q32.13
Locus type	gene with protein product
Status	Approved
Aliases	PAI3, PROCI
Ensembl gene	ENSG00000188488
Ensembl biotype	protein_coding
OMIM	601841
Entrez	5104

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 27 protein_coding, 1 retained_intron

ENST00000329597, ENST00000553511, ENST00000553780, ENST00000554220, ENST00000554276, ENST00000554633, ENST00000554866, ENST00000555681, ENST00000556064, ENST00000556730, ENST00000556775, ENST00000557598, ENST00000884744, ENST00000884745, ENST00000884746, ENST00000884747, ENST00000884748, ENST00000884749, ENST00000884750, ENST00000884751, ENST00000884752, ENST00000884753, ENST00000884754, ENST00000884755, ENST00000884756, ENST00000969487, ENST00000969488, ENST00000969489

RefSeq mRNA: 1 — MANE Select: NM_000624 NM_000624

CCDS: CCDS9928

Canonical transcript exons

ENST00000329597 — 6 exons

Exon	Start	End
ENSE00001098000	94590749	94590896
ENSE00001098004	94590041	94590311
ENSE00001376792	94592057	94593118
ENSE00001514145	94581615	94581710
ENSE00003625398	94587346	94587981
ENSE00003742080	94581426	94581490

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 99.54.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0515 / max 324.4416, expressed in 53 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
141248	5.2035	423
141245	1.0515	53
141247	0.5887	187
141244	0.3262	34
141250	0.0392	16
141251	0.0243	9
141252	0.0168	8
141249	0.0124	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	99.54	gold quality
right adrenal gland	UBERON:0001233	99.51	gold quality
right testis	UBERON:0004534	99.51	gold quality
left testis	UBERON:0004533	99.39	gold quality
left adrenal gland cortex	UBERON:0035825	99.31	gold quality
left adrenal gland	UBERON:0001234	99.30	gold quality
adrenal cortex	UBERON:0001235	99.30	gold quality
testis	UBERON:0000473	98.97	gold quality
gall bladder	UBERON:0002110	98.72	gold quality
adrenal gland	UBERON:0002369	98.44	gold quality
adrenal tissue	UBERON:0018303	98.41	gold quality
seminal vesicle	UBERON:0000998	98.08	gold quality
right lobe of liver	UBERON:0001114	98.03	gold quality
adult organism	UBERON:0007023	97.71	gold quality
body of pancreas	UBERON:0001150	97.60	gold quality
liver	UBERON:0002107	97.55	gold quality
adult mammalian kidney	UBERON:0000082	96.57	gold quality
spleen	UBERON:0002106	95.89	gold quality
renal medulla	UBERON:0000362	95.75	gold quality
pancreas	UBERON:0001264	95.31	gold quality
islet of Langerhans	UBERON:0000006	93.82	gold quality
tibia	UBERON:0000979	93.61	gold quality
tendon of biceps brachii	UBERON:0008188	93.58	gold quality
male germ cell	CL:0000015	93.47	gold quality
sperm	CL:0000019	92.89	gold quality
kidney	UBERON:0002113	91.89	gold quality
metanephros cortex	UBERON:0010533	91.27	gold quality
nephron tubule	UBERON:0001231	88.83	gold quality
triceps brachii	UBERON:0001509	88.53	gold quality
dorsal root ganglion	UBERON:0000044	88.29	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	38.44
E-MTAB-5061	yes	28.21
E-GEOD-81547	yes	24.15
E-MTAB-10553	yes	21.31
E-GEOD-83139	yes	11.13
E-HCAD-9	yes	10.15
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, SP1, TFAP2A

miRNA regulators (miRDB)

37 targeting SERPINA5, 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-6748-5P	100.00	65.81	1057
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4658	99.77	64.94	514
HSA-MIR-6790-5P	99.77	65.24	505
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-365A-3P	99.43	70.02	836
HSA-MIR-365B-3P	99.43	70.02	836
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-198	98.70	67.32	920
HSA-MIR-93-3P	98.15	66.65	1309
HSA-MIR-338-3P	98.14	67.38	1137
HSA-MIR-203B-3P	97.82	66.27	979
HSA-MIR-3151-3P	97.80	66.16	479
HSA-MIR-634	97.74	67.11	818
HSA-MIR-376C-3P	97.63	68.88	1263
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-6508-3P	96.73	65.48	576
HSA-MIR-4790-3P	96.63	67.08	806
HSA-MIR-376A-2-5P	96.43	68.06	715

Literature-anchored findings (GeneRIF, showing 36)

• PCI can up regulate TAFI activation by inhibiting the protein C activation. PCI may therefore be an important regulator in the balance between coagulation and fibrinolysis by differentially inhibiting the activation of TAFI and of protein C. (PMID:11686324)
• Role of each Asn-linked glycan in the anticoagulant activity of human protein C inhibitor. (PMID:11864713)
• Protein C inhibitor regulates the invasive potential of renal cell carcinoma by inhibiting urinary plasminogen activator secreted by these cells (PMID:14696115)
• PCI may be involved in regulating key serine proteases involved in metastatic prostate disease (PMID:15878512)
• PAI-3, but not PAI-1 or uPA, may have a role in breast cancer survival by suppression of tumor invasion through protease inhibition in stroma (PMID:17258797)
• exposure of oxidized PE and/or PS may be important for the local regulation of protein C inhibitor activity in vivo (PMID:17332248)
• anti-angiogenic activity of PCI was strong as cleaved antithrombin, and slightly stronger than that of plasminogen activator inhibitor-1 and pigment epithelium-derived factor (PMID:17450526)
• Patients with abdominal aortic aneurysm have increased thrombin generation reflected by an increase in the activated protein C-protein C inhibitor complex, which correlates with aneurysm size. (PMID:18184931)
• In human renal tissues, PCI and urinary plasminogen activator colocalized in the cytoplasm of renal proximal tubular epithelial cells (PMID:18193533)
• A crystallographic structure of the Michaelis complex of PCI, thrombin, and heparin to 1.6 A resolution, was determined. (PMID:18362344)
• The heparin binding site of protein C inhibitor is protease-dependent. (PMID:18974053)
• In men involved in total fertilization failure, a heterozygous adenosine/guanine (A/G) base combination in position 1389 (rs2069990) (exon 6) in the protein C inhibitor gene was significantly more common compared with controls (10.9% vs. 0). (PMID:19765701)
• function for PCI in innate immunity (PMID:20019810)
• APC-PCI complex levels were higher in peripheral arterial disease patients than in controls, but did not predict the clinical outcome. (PMID:20409682)
• This study was undertaken to further understand the structural micro-heterogeneity of PCI. Individuals of two different ethnicities possess a similar PCI pattern, verifying that the micro-heterogeneity is conserved among humans. (PMID:21056543)
• SerpinA5 expression is significantly reduced in advanced-stage serous borderline tumors and serous carcinomas. (PMID:21102419)
• the effects of N-glycans and the NH-terminus on a PCI function (PMID:22205989)
• One of the monomers, 52-kDa PCI, formed a stable complex with activated protein C, urokinase, plasma and tissue kallikrein, but the dimer species and 48-kDa PCI were inactive. (PMID:22206708)
• the SERPINA5 gene, which codes for the protein C inhibitor involved in many biological processes including inflammation, may be a new susceptibility locus for PTC. (PMID:23520464)
• A novel protein C inhibitor gene mutation in pediatric stroke patients after bone marrow transplantation. (PMID:23670045)
• Decreased SERPINA5 expression due to DNA promoter methylation is associated with papillary thyroid carcinoma. (PMID:24222120)
• These findings highlight an important role of SERPINA5 in the regulation of migratory and metastatic potentials of HCC and suggest a potential application of SERPINA5 in cancer treatment. (PMID:24388360)
• These results suggest that HIV resistance in some exposed patients is the result of a balance between downregulation of serine proteinases and upregulation of their inhibitors. (PMID:24928035)
• host protein C inhibitor expressed in mouse has a role in inhibiting tumor growth, but promotes tumor metastasis, which is closely correlated with hypercoagulability (PMID:25887633)
• We confirmed associations with papillary thyroid cancer and SNPs in FOXE1/HEMGN, SERPINA5 (rs2069974), FTO (rs8047395), EVPL (rs2071194), TICAM1 (rs8120) and SCARB1 (rs11057820) genes. We found associations with SNPs in FOXE1, SERPINA5, FTO, TICAM1 and HSPA6 and and follicular thyroid cancer (PMID:27207655)
• the snp rs1955656 in the SERPINA5 were associated with the development of severe acute kidney injury (KDIGO stage 2-3) in critically ill patients with septic shock (PMID:28270177)
• Data show that the methylation degree of five CpG sites significantly correlated with lower SERPINA5 expression levels. (PMID:29187436)
• Genetic association in female stress urinary incontinence based on proteomic findings: a case-control study. (PMID:30715578)
• data suggests that SPA17, ANXA2, and SERPINA5 may potentially serve as non-invasive protein biomarkers associated with the fertilization process of the spermatozoa in unexplained male infertility (PMID:31336797)
• SERPIN A5 may have a potential as a biomarker in reflecting the improvement of semen quality in infertile men who underwent varicocele repair. (PMID:34009669)
• Evaluation the Presence of SERPINA5 (Exon 3) and FTO rs9939609 Polymorphisms in Papillary Thyroid Cancer Patients. (PMID:34837923)
• Proteomic analysis of human articular cartilage unravels the dyscoagulation in osteoarthritis and the potential value of serpinA5 as a biomarker for osteoarthritis. (PMID:34964303)
• SERPINA5 may promote the development of preeclampsia by disruption of the uPA/uPAR pathway. (PMID:35717024)
• SERPINA5 promotes tumour cell proliferation by modulating the PI3K/AKT/mTOR signalling pathway in gastric cancer. (PMID:36000536)
• ANXA2, SP17, SERPINA5, PRDX2 genes, and sperm DNA fragmentation differentially represented in male partners of infertile couples with normal and abnormal sperm parameters. (PMID:36177795)
• The SERPINA5 coding variant E228Q does not contribute to clinicopathologic characteristics in Alzheimer’s disease: A cross-sectional study. (PMID:37327267)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Serpina5	ENSMUSG00000041550
rattus_norvegicus	Serpina5	ENSRNOG00000009855

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), SERPINA3 (ENSG00000196136), SERPINA1 (ENSG00000197249), SERPINB2 (ENSG00000197632), SERPINB13 (ENSG00000197641), SERPINB11 (ENSG00000206072), SERPINB4 (ENSG00000206073), SERPINB5 (ENSG00000206075), HMSD (ENSG00000221887), SERPINB10 (ENSG00000242550), SERPINE3 (ENSG00000253309), SERPINA2 (ENSG00000258597)

Protein

Protein identifiers

Plasma serine protease inhibitor — P05154 (reviewed: P05154)

Alternative names: Acrosomal serine protease inhibitor, Plasminogen activator inhibitor 3, Protein C inhibitor, Serpin A5

All UniProt accessions (8): P05154, G3V264, G3V265, G3V2M1, G3V3F5, G3V3Y3, G3V482, G3V4B4

UniProt curated annotations — full annotation on UniProt →

Function. Heparin-dependent serine protease inhibitor acting in body fluids and secretions. Inactivates serine proteases by binding irreversibly to their serine activation site. Involved in the regulation of intravascular and extravascular proteolytic activities. Plays hemostatic roles in the blood plasma. Acts as a procoagulant and pro-inflammatory factor by inhibiting the anticoagulant activated protein C factor as well as the generation of activated protein C factor by the thrombin/thrombomodulin complex. Acts as an anticoagulant factor by inhibiting blood coagulation factors like prothrombin, factor XI, factor Xa, plasma kallikrein and fibrinolytic enzymes such as tissue- and urinary-type plasminogen activators. In seminal plasma, inactivates several serine proteases implicated in the reproductive system. Inhibits the serpin acrosin; indirectly protects component of the male genital tract from being degraded by excessive released acrosin. Inhibits tissue- and urinary-type plasminogen activator, prostate-specific antigen and kallikrein activities; has a control on the sperm motility and fertilization. Inhibits the activated protein C-catalyzed degradation of SEMG1 and SEMG2; regulates the degradation of semenogelin during the process of transfer of spermatozoa from the male reproductive tract into the female tract. In urine, inhibits urinary-type plasminogen activator and kallikrein activities. Inactivates membrane-anchored serine proteases activities such as MPRSS7 and TMPRSS11E. Inhibits urinary-type plasminogen activator-dependent tumor cell invasion and metastasis. May also play a non-inhibitory role in seminal plasma and urine as a hydrophobic hormone carrier by its binding to retinoic acid.

Subunit / interactions. Forms protease inhibiting heterodimers in extracellular body fluids with serine proteases such as activated protein C/coagulation factor V/F5, acrosin/ACR, chymotrypsinogen B/CTRB1, prothrombin/F2, factor Xa/F10, factor XI/F11, kallikrein/KLKB1, tissue kallikrein, trypsin/PRSS1, prostate specific antigen/KLK3, tissue plasminogen activator/PLAT and urinary plasminogen activator/PLAU. Forms membrane-anchored serine proteases inhibiting heterodimers with TMPRSS7 and TMPRSS11E. Interacts with SEMG2.

Subcellular location. Secreted. Extracellular space.

Tissue specificity. Predominantly expressed in the epithelium of seminal vesicles. Expressed in the proximal tubular epithelium of the kidney. Expressed in the superficial and more differentiated epidermal keratinocytes of the skin. Expressed in megakaryocytes and platelets. Expressed poorly in kidney tumor cells compared to non tumor kidney tissues. Expressed in spermatozoa. Present in very high concentration in seminal plasma. Present in high concentration in plasma, synovial and Graaf follicle fluids. Present in low concentration in breast milk and in amniotic fluids. Present in very low concentration in urine, cerebrospinal fluids, saliva and tears (at protein level). Strongly expressed in liver. Expressed in kidney, spleen, pancreas, skeletal muscle, heart, testes, ovary, interstitial Leydig cells, epididymal glands, seminal vesicles and prostate.

Post-translational modifications. N- and O-glycosylated. N-glycosylation consists of a mixture of sialylated bi- (including sialyl-Lewis X epitopes), tri- and tetra-antennary complex-type chains; affects the maximal heparin- and thrombomodulin-enhanced rates of thrombin inhibition. O-glycosylated with core 1 or possibly core 8 glycans. Further modified with 2 sialic acid residues. Proteolytically cleaved. Inhibition of proteases is accompanied by formation of a stable enzyme-inhibitor complex and by degradation of the serpin to lower molecular weight derivatives. Proteolytically cleaved at the N-terminus; inhibits slightly the heparin- and thrombomodulin-enhanced rates of thrombin inhibition.

Activity regulation. Its inhibitory activity is greatly enhanced in the presence of glycosaminoglycans, heparin, thrombomodulin and phospholipids vesicles.

Domain organisation. The reactive center loop (RCL) extends out from the body of the protein and directs binding to the target protease. The protease cleaves the serpin at the reactive site within the RCL, establishing a covalent linkage between the carboxyl group of the serpin reactive site and the serine hydroxyl of the protease. The resulting inactive serpin-protease complex is highly stable.

Similarity. Belongs to the serpin family.

RefSeq proteins (1): NP_000615* (*=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 (65 total): strand 16, mutagenesis site 14, helix 12, sequence variant 8, sequence conflict 4, glycosylation site 4, turn 3, signal peptide 1, propeptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3DY0	X-RAY DIFFRACTION	1.55
2OL2	X-RAY DIFFRACTION	2
2HI9	X-RAY DIFFRACTION	2.3
1LQ8	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05154-F1	85.39	0.77

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): 373–374 (reactive bond)

Glycosylation sites (4): 39, 249, 262, 338

Mutagenesis-validated functional residues (14):

Position	Phenotype
248	does not change the rate of thrombin or activated protein c/f5 inhibition in the presence or absence of heparin. strongl
253	inhibits strongly thrombomodulin-enhanced rate of thrombin inhibition in presence of heparin.
272	does not inhibit thrombomodulin-enhanced rate of thrombin inhibition in presence of heparin.
274	does not inhibit thrombomodulin-enhanced rate of thrombin inhibition in presence of heparin.
285	does not change the rate of thrombin or activated protein c/f5 inhibition in the presence or absence of heparin. slightl
288	does not change the rate of thrombin or activated protein c/f5 inhibition in the presence or absence of heparin. slightl
289	does not change the rate of thrombin or activated protein c/f5 inhibition in the presence or absence of heparin. slightl
292	does not change the rate of thrombin or activated protein c/f5 inhibition in the presence or absence of heparin. slightl
360	inhibits heterodimer formation with tmprss11e.
371	increases inhibition of activated protein c/f5 and factor xi/f11 activities. decreases inhibition of thrombin activity.
372	increases inhibition of thrombin activity.
373	increases inhibition of thrombin activity. inhibits heterodimer formation with tmprss11e.
376	does not change inhibition of thrombin, activated protein c/f5 and factor xi/f11 activities.
381	does not inhibit thrombomodulin-enhanced rate of thrombin inhibition in presence of heparin.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-9769733	Fibrin formation
R-HSA-9769739	Regulation of clotting cascade
R-HSA-9769743	Amplification and propagation of coagulation cascade
R-HSA-140837
R-HSA-140875
R-HSA-109582	Hemostasis
R-HSA-140877

MSigDB gene sets: 159 (showing top): GOBP_SINGLE_FERTILIZATION, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_BEHAVIOR, MODULE_169, GOCC_SECRETORY_GRANULE, MODULE_545, GOZGIT_ESR1_TARGETS_DN, GOBP_MEMBRANE_FUSION, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOCC_CELL_SURFACE, GOBP_MALE_GAMETE_GENERATION, GOBP_INSEMINATION, BOQUEST_STEM_CELL_CULTURED_VS_FRESH_DN, ROZANOV_MMP14_TARGETS_UP, SMID_BREAST_CANCER_LUMINAL_B_UP

GO Biological Process (5): lipid transport (GO:0006869), spermatogenesis (GO:0007283), fusion of sperm to egg plasma membrane involved in single fertilization (GO:0007342), seminal clot liquefaction (GO:0070684), single fertilization (GO:0007338)

GO Molecular Function (9): retinoic acid binding (GO:0001972), protease binding (GO:0002020), serine-type endopeptidase inhibitor activity (GO:0004867), glycosaminoglycan binding (GO:0005539), heparin binding (GO:0008201), phosphatidylcholine binding (GO:0031210), acrosin binding (GO:0032190), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (20): acrosomal membrane (GO:0002080), extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), external side of plasma membrane (GO:0009897), membrane (GO:0016020), platelet alpha granule (GO:0031091), platelet dense tubular network (GO:0031094), protein-containing complex (GO:0032991), protein C inhibitor-TMPRSS7 complex (GO:0036024), protein C inhibitor-TMPRSS11E complex (GO:0036025), protein C inhibitor-PLAT complex (GO:0036026), protein C inhibitor-PLAU complex (GO:0036027), protein C inhibitor-thrombin complex (GO:0036028), protein C inhibitor-KLK3 complex (GO:0036029), protein C inhibitor-plasma kallikrein complex (GO:0036030), extracellular exosome (GO:0070062), protein C inhibitor-coagulation factor V complex (GO:0097181), protein C inhibitor-coagulation factor Xa complex (GO:0097182), protein C inhibitor-coagulation factor XI complex (GO:0097183), extracellular matrix (GO:0031012)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Coagulation pathway	3

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
serine protease inhibitor complex	10
enzyme binding	2
cellular anatomical structure	2
transport	1
lipid localization	1
developmental process involved in reproduction	1
male gamete generation	1
single fertilization	1
cellular process involved in reproduction in multicellular organism	1
insemination	1
multicellular organismal reproductive process	1
fertilization	1
retinoid binding	1
monocarboxylic acid binding	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
carbohydrate derivative binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
phospholipid binding	1
cation binding	1
quaternary ammonium group binding	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
acrosomal vesicle	1
secretory granule membrane	1
plasma membrane	1
cell surface	1
side of membrane	1
secretory granule	1
intracellular membrane-bounded organelle	1
cellular_component	1
extracellular vesicle	1
external encapsulating structure	1

Protein interactions and networks

STRING

1336 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SERPINA5	KLK3	P07288	881
SERPINA5	KLKB1	P03952	846
SERPINA5	TMPRSS11E	Q9UL52	833
SERPINA5	KLK2	P20151	818
SERPINA5	KLK1	P06870	784
SERPINA5	THBD	P07204	673
SERPINA5	ELANE	P08246	657
SERPINA5	KLK4	Q9Y5K2	631
SERPINA5	CTRB2	Q6GPI1	617
SERPINA5	F3	P13726	606
SERPINA5	SEMG2	Q02383	597
SERPINA5	CTRB1	P17538	588
SERPINA5	TMPRSS11D	O60235	518
SERPINA5	SDHC	Q99643	479
SERPINA5	CTSG	P08311	477

IntAct

30 interactions, top by confidence:

A	B	Type	Score
FN1	SERPINA5	psi-mi:“MI:0915”(physical association)	0.540
FN1	SERPINA5	psi-mi:“MI:0407”(direct interaction)	0.540
SERPINA5	ZZEF1	psi-mi:“MI:0914”(association)	0.530
SERPINA5	F2	psi-mi:“MI:0407”(direct interaction)	0.440
SERPINA5		psi-mi:“MI:0570”(protein cleavage)	0.440
SERPINA5	PGRMC2	psi-mi:“MI:0915”(physical association)	0.400
SERPINA5	SEC22B	psi-mi:“MI:0915”(physical association)	0.400
SERPINA5	BCAP31	psi-mi:“MI:0915”(physical association)	0.400
SERPINA5	BCAP29	psi-mi:“MI:0915”(physical association)	0.400
SERPINA5	H1-5	psi-mi:“MI:0915”(physical association)	0.400
SERPINA5	MSMO1	psi-mi:“MI:0915”(physical association)	0.400
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
CBL	SERPINA5	psi-mi:“MI:0915”(physical association)	0.370
SERPINA5	EPS8	psi-mi:“MI:0915”(physical association)	0.370
RCHY1	SERPINA5	psi-mi:“MI:0915”(physical association)	0.370
SERPINA5	PIAS4	psi-mi:“MI:0915”(physical association)	0.370
SERPINA5	EP300	psi-mi:“MI:0915”(physical association)	0.370
RIDA	SERPINA5	psi-mi:“MI:0915”(physical association)	0.370
EPSTI1	CST4	psi-mi:“MI:0914”(association)	0.350
SERPINA5		psi-mi:“MI:0914”(association)	0.350
DHH	MANBA	psi-mi:“MI:0914”(association)	0.350
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350
sbcD	SERPINA5	psi-mi:“MI:0915”(physical association)	0.000
SERPINA5	COPS6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (47): SERPINA5 (Two-hybrid), SERPINA5 (Two-hybrid), SERPINA5 (Affinity Capture-MS), WWOX (Affinity Capture-MS), FURIN (Affinity Capture-MS), HGFAC (Affinity Capture-MS), CTAGE5 (Affinity Capture-MS), ZZEF1 (Affinity Capture-MS), MIA3 (Affinity Capture-MS), HECTD3 (Affinity Capture-MS), CANX (Affinity Capture-MS), FBXO2 (Affinity Capture-MS), COPS6 (Two-hybrid), SERPINA5 (Reconstituted Complex), MSMO1 (Proximity Label-MS)

ESM2 similar proteins: A2I7M9, A2I7N0, A2I7N1, A2I7N2, A2I7N3, A6QPQ2, B2D1U1, E1BF81, O54762, P01011, P05154, P05544, P05545, P07759, P08185, P09006, P22323, P22324, P22325, P22599, P26595, P29621, P29622, P31211, P50451, P70458, Q00896, Q00897, Q00898, Q03044, Q03734, Q3ZEJ6, Q5I2A0, Q5R536, Q5R9E3, Q5RCR2, Q60396, Q63556, Q63969, Q64118

Diamond homologs: A0A090BX51, A0A0K8RCY5, A0A0K8RJ89, A0A0K8RJV9, A2I7M9, A2I7N0, A2I7N1, A2I7N2, A2I7N3, A5PJK0, A6QPQ2, A9RA96, B0CMB0, B1MTC3, B2D1U1, B2KI30, B3RFC3, B4USX2, E2RVI8, O08800, O35684, O73790, O73860, O75830, P01008, P01012, P01014, P05120, P05121, P05154, P05619, P07092, P07093, P07759, P09006, P12388, P13909, P14754, P17475, P29508

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SERPINA5	“down-regulates activity”	FN1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	74
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1854 predictions. Top by Δscore:

Variant	Effect	Δscore
14:94569394:GA:G	acceptor_gain	1.0000
14:94587980:AGGT:A	donor_loss	1.0000
14:94587983:T:G	donor_loss	1.0000
14:94590036:TTTA:T	acceptor_loss	1.0000
14:94590037:TTA:T	acceptor_loss	1.0000
14:94590038:TAG:T	acceptor_loss	1.0000
14:94590039:A:AG	acceptor_gain	1.0000
14:94590040:G:GG	acceptor_gain	1.0000
14:94590040:GCT:G	acceptor_gain	1.0000
14:94590040:GCTA:G	acceptor_gain	1.0000
14:94590040:GCTAA:G	acceptor_gain	1.0000
14:94590181:G:T	donor_gain	1.0000
14:94590285:G:GT	donor_gain	1.0000
14:94561495:G:GG	donor_gain	0.9900
14:94566969:GCCCT:G	acceptor_gain	0.9900
14:94569391:CCA:C	acceptor_loss	0.9900
14:94569392:CAGAG:C	acceptor_gain	0.9900
14:94569393:A:AG	acceptor_gain	0.9900
14:94569393:AGAG:A	acceptor_gain	0.9900
14:94569394:G:GG	acceptor_gain	0.9900
14:94569394:GAGT:G	acceptor_gain	0.9900
14:94569394:GAGTT:G	acceptor_gain	0.9900
14:94569526:G:GA	donor_gain	0.9900
14:94569568:C:T	donor_gain	0.9900
14:94569628:G:GT	donor_gain	0.9900
14:94569631:G:GT	donor_gain	0.9900
14:94569642:G:T	donor_gain	0.9900
14:94587344:A:AG	acceptor_gain	0.9900
14:94587345:G:GG	acceptor_gain	0.9900
14:94590033:A:AG	acceptor_gain	0.9900

AlphaMissense

2714 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:94590088:T:C	F223L	0.987
14:94590090:C:A	F223L	0.987
14:94590090:C:G	F223L	0.987
14:94592180:T:C	F388L	0.985
14:94592182:T:A	F388L	0.985
14:94592182:T:G	F388L	0.985
14:94590048:G:C	W209C	0.983
14:94590048:G:T	W209C	0.983
14:94590058:T:C	F213L	0.981
14:94590060:C:A	F213L	0.981
14:94590060:C:G	F213L	0.981
14:94587762:T:C	F134L	0.980
14:94587764:C:A	F134L	0.980
14:94587764:C:G	F134L	0.980
14:94587573:A:C	S71R	0.978
14:94587575:C:A	S71R	0.978
14:94587575:C:G	S71R	0.978
14:94590046:T:A	W209R	0.977
14:94590046:T:C	W209R	0.977
14:94590837:T:C	F327L	0.974
14:94590839:C:A	F327L	0.974
14:94590839:C:G	F327L	0.974
14:94590175:T:C	C252R	0.970
14:94590289:T:A	W290R	0.970
14:94590289:T:C	W290R	0.970
14:94590769:C:A	P304H	0.966
14:94590177:C:G	C252W	0.961
14:94590224:T:A	I268N	0.960
14:94587585:A:C	S75R	0.957
14:94587587:C:A	S75R	0.957

dbSNP variants (sampled 300 via entrez): RS1000315694 (14:94587117 G>A,C), RS1000346888 (14:94586900 A>G), RS1000427980 (14:94592353 A>G,T), RS1000915146 (14:94582347 C>T), RS1001072859 (14:94582532 C>T), RS1001251271 (14:94581429 T>C), RS1001260165 (14:94586376 C>A,T), RS1001409925 (14:94581574 T>C,G), RS1001737010 (14:94591374 C>T), RS1001760796 (14:94581821 A>C,G), RS1001859704 (14:94586812 G>T), RS1002448055 (14:94581553 A>G), RS1002863369 (14:94585195 C>T), RS1002932103 (14:94585323 C>T), RS1003013199 (14:94580781 C>A)

Disease associations

OMIM: gene MIM:601841 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005988_11	Serum albumin levels	7.000000e-14
GCST005989_26	Serum total protein levels	2.000000e-11
GCST006585_2783	Blood protein levels	6.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs6113	Toxicity	3	carboplatin;gemcitabine	Non-Small Cell Lung Carcinoma;Thrombocytopenia
rs6118	Toxicity	3	carboplatin;gemcitabine	Non-Small Cell Lung Carcinoma;Thrombocytopenia
rs6119	Toxicity	3	carboplatin;gemcitabine	Non-Small Cell Lung Carcinoma;Thrombocytopenia

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6113	SERPINA5	3	2.50	1	carboplatin;gemcitabine
rs6118	SERPINA5	3	2.50	1	carboplatin;gemcitabine
rs6119	SERPINA5	3	2.50	1	carboplatin;gemcitabine

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression, increases expression	3
Cyclosporine	decreases expression	3
Aflatoxin B1	affects expression, decreases expression	3
perfluorooctanoic acid	affects methylation, decreases expression	2
entinostat	affects cotreatment, increases expression	2
ethinyl estradiol-desogestrel combination	increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Valproic Acid	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
sotorasib	affects cotreatment, decreases expression	1
bisphenol A	affects expression	1
kojic acid	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
sodium arsenite	decreases expression	1
cupric chloride	decreases expression	1
2,3-dimethoxy-1,4-naphthoquinone	decreases expression	1
cylindrospermopsin	decreases expression	1
LY 353381	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	increases expression, affects cotreatment	1
Temozolomide	increases expression	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Ethanol	increases expression	1

Clinical trials (associated diseases)

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