SERPING1

Summary

SERPING1 (serpin family G member 1, HGNC:1228) is a protein-coding gene on chromosome 11q12.1, encoding Plasma protease C1 inhibitor (P05155). Serine protease inhibitor, which acrs as a regulator of the classical complement pathway.

This gene encodes a highly glycosylated plasma protein involved in the regulation of the complement cascade. Its encoded protein, C1 inhibitor, inhibits activated C1r and C1s of the first complement component and thus regulates complement activation. It is synthesized in the liver, and its deficiency is associated with hereditary angioneurotic oedema (HANE). Alternative splicing results in multiple transcript variants encoding the same isoform.

Source: NCBI Gene 710 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary angioedema with C1Inh deficiency (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 880 total — 290 pathogenic, 83 likely-pathogenic
• Phenotypes (HPO): 42
• Druggable target: yes
• MANE Select transcript: NM_000062

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1228
Approved symbol	SERPING1
Name	serpin family G member 1
Location	11q12.1
Locus type	gene with protein product
Status	Approved
Aliases	C1IN, C1-INH, HAE1, HAE2, C1INH
Ensembl gene	ENSG00000149131
Ensembl biotype	protein_coding
OMIM	606860
Entrez	710

Gene structure

Transcript identifiers

Ensembl transcripts: 45 — 33 protein_coding, 8 nonsense_mediated_decay, 4 retained_intron

ENST00000278407, ENST00000340687, ENST00000378323, ENST00000378324, ENST00000403558, ENST00000405496, ENST00000457869, ENST00000528996, ENST00000530113, ENST00000531133, ENST00000531605, ENST00000531797, ENST00000619430, ENST00000676670, ENST00000676741, ENST00000677275, ENST00000677624, ENST00000677625, ENST00000677856, ENST00000677915, ENST00000678533, ENST00000678592, ENST00000879467, ENST00000879468, ENST00000879469, ENST00000879470, ENST00000879471, ENST00000879472, ENST00000879473, ENST00000879474, ENST00000879475, ENST00000879476, ENST00000879477, ENST00000879478, ENST00000879479, ENST00000879480, ENST00000879481, ENST00000879482, ENST00000879483, ENST00000879484, ENST00000879485, ENST00000879486, ENST00000879487, ENST00000879488, ENST00000948717

RefSeq mRNA: 2 — MANE Select: NM_000062 NM_000062, NM_001032295

CCDS: CCDS7962

Canonical transcript exons

ENST00000278407 — 8 exons

Exon	Start	End
ENSE00001769777	57614328	57614848
ENSE00001941568	57597685	57597722
ENSE00002142743	57598249	57598321
ENSE00003463488	57599879	57600377
ENSE00003499999	57606408	57606547
ENSE00003528440	57602035	57602169
ENSE00003567744	57606010	57606213
ENSE00003682693	57611717	57611936

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 180.4199 / max 15406.1349, expressed in 1327 samples.

FANTOM5 promoters (25 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114280	117.1214	1133
114284	32.8847	1250
114286	8.8255	922
114291	6.4976	825
114289	3.0301	674
114285	1.7322	510
114288	1.3891	412
114290	1.1741	312
114282	1.1187	515
114287	1.0402	263

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.86	gold quality
right lung	UBERON:0002167	99.78	gold quality
right coronary artery	UBERON:0001625	99.77	gold quality
mucosa of stomach	UBERON:0001199	99.75	gold quality
descending thoracic aorta	UBERON:0002345	99.74	gold quality
ascending aorta	UBERON:0001496	99.72	gold quality
thoracic aorta	UBERON:0001515	99.72	gold quality
aorta	UBERON:0000947	99.71	gold quality
left uterine tube	UBERON:0001303	99.71	gold quality
popliteal artery	UBERON:0002250	99.71	gold quality
tibial artery	UBERON:0007610	99.71	gold quality
artery	UBERON:0001637	99.70	gold quality
right ovary	UBERON:0002118	99.70	gold quality
left coronary artery	UBERON:0001626	99.69	gold quality
gall bladder	UBERON:0002110	99.69	gold quality
left ovary	UBERON:0002119	99.69	gold quality
coronary artery	UBERON:0001621	99.68	gold quality
peritoneum	UBERON:0002358	99.67	gold quality
upper lobe of left lung	UBERON:0008952	99.67	gold quality
omental fat pad	UBERON:0010414	99.67	gold quality
nerve	UBERON:0001021	99.65	gold quality
tibial nerve	UBERON:0001323	99.65	gold quality
endocervix	UBERON:0000458	99.64	gold quality
liver	UBERON:0002107	99.64	gold quality
body of uterus	UBERON:0009853	99.62	gold quality
upper lobe of lung	UBERON:0008948	99.59	gold quality
pericardium	UBERON:0002407	99.58	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.56	gold quality
adipose tissue of abdominal region	UBERON:0007808	99.54	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.53	gold quality

Single-cell (SCXA)

Detected in 27 experiment(s), a significant marker in 24.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	4209.63
E-CURD-126	yes	2996.55
E-GEOD-81547	yes	2672.23
E-HCAD-15	yes	2254.13
E-GEOD-135922	yes	1831.70
E-GEOD-83139	yes	1618.43
E-CURD-122	yes	1577.74
E-MTAB-8142	yes	1431.54
E-MTAB-6701	yes	1289.25
E-MTAB-8530	yes	919.90
E-HCAD-1	yes	100.82
E-MTAB-8410	yes	73.13
E-HCAD-9	yes	57.04
E-MTAB-6678	yes	28.85
E-MTAB-5061	yes	28.23

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF1A

miRNA regulators (miRDB)

27 targeting SERPING1, 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-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-129-1-3P	98.86	68.41	779
HSA-MIR-129-2-3P	98.86	68.41	779
HSA-MIR-4299	98.28	66.96	850
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-5007-5P	97.95	64.71	614
HSA-MIR-1233-3P	96.81	65.44	573
HSA-MIR-664B-5P	96.74	67.50	509
HSA-MIR-3918	96.13	64.65	1300

Literature-anchored findings (GeneRIF, showing 40)

• The soluble fraction of an N-terminally truncated recombinant C1-Inh produced in E. coli strain AD494(DE3) enabling disulfide bond formation inhibits C1s target protease in functional assays. (PMID:11437612)
• Five novel mutations in the C1 inhibitor gene (C1NH) leading to a premature stop codon in patients with type I hereditary angioedema (PMID:11933207)
• Study of stringently regulated expression of endogenous and transgenic human C1NH gene reveals local biosynthesis of C1 inhibitor at multiple sites in which the components of the macromolecular C1 complex are also produced. (PMID:12421980)
• Amidolytic activity was, however, present on HUVEC incubated with plasma indicating that the endogenous C1-INH did not completely abolish the activity of FXIIa generated during the incubation period (PMID:12492481)
• functional integrity of the serpin domain of C1-inhibitor depends on the unique N-terminal domain (PMID:12773530)
• Plasma C1INH expresses sialyl Lewis(x)-related moieties on its N-linked glycan, can bind to P- and E-selectins, and significantly inhibits in vitro leukocyte-endothelial cell adhesion in a dose-dependent manner. (PMID:14568956)
• HIV-1 protease cleavage site was found in N-terminal region of C1-inhibitor, and it was located between residues Leu-32 and Phe-33 (PMID:15325085)
• significantly and similarly reduced in PMBCs of patients with type I and type II Hereditary angioedema (40% and 47%, respectively; P <.0001) (PMID:15356570)
• the amino-terminal domain of C1-inhibitor has a role in inhibition of plasma kallikrein (PMID:15583734)
• The physiopathology of hereditary angioneurotic edema associated with a deficiency of this protein. (PMID:15596402)
• The physiopathology of hereditary angioedema associated with deficiency of this protein, with particular attention to the complement pathway. (PMID:15596403)
• the N-glycans of C1NH from patients with a heterozygous C1NH genetic deficiency were small, highly charged and lacked sialidase releasable N-acetylneuraminic acid in comparison with N-glycans from normal individuals (PMID:15607116)
• Direct involvement of C1INH in modulation of selectin-mediated cell adhesion may be an important mechanism in the physiologic suppression of inflammation. (PMID:15879149)
• SERPING1/C1NH mutations in coding regions differ from the canonical splice sites that affect splicing, which suggests the presence of an exonic splicing enhancer (PMID:15971231)
• mutations affecting splicing of exon 2 of the SERPING1/C1NH gene may have different consequences in monocytes versus other cell types (PMID:16470590)
• We suppose that the mutation within the 3’UTR (C1-INH protein) interferes with integral pathways of gene expression leading to pathogenic haploinsufficiency in this family. (PMID:16617246)
• results demonstrate that the ability of Bordetella pertussis to acquire high levels of C1inh & wild-type levels of serum resistance are well correlated, suggesting acquisition of C1inh is vital to B. pertussis resistance to complement-mediated killing (PMID:17230419)
• analysis of the first crystal structure of the serpin domain of human C1 inhibitor, representing a previously unreported latent form (PMID:17488724)
• These findings suggest that susceptibility to S. aureus nasal carriage is associated with the C1INH V480M polymorphism. (PMID:17498209)
• Hereditary C1INH deficiency should be included in the differential diagnosis of nonsystemic vasculitis neuropathy. (PMID:17502473)
• These findings indicate a novel role for C1INH in inhibition of vascular endothelial activation. (PMID:17521609)
• MASP-2 is a major physiological target of C1-inhibitor. (PMID:17709141)
• Determining C1-INH levels at 6 weeks after carotid endarterectomy and genotyping of MBL2 might be useful in the identification of patients at high risk for early restenosis. (PMID:17916775)
• The diagnosis and clinical features of hereditary angioedema with normal SERPING1 levels are reported in 138 patients. (PMID:17976427)
• iC1INH has an anti-vascular permeability independent on the serpin function. (PMID:18022239)
• study found a single nucleotide A deletion at codon 210 of the SERPING1 gene, 1210fsX210, a novel mutation that accounts for hereditary angioedema in a Taiwanese family (PMID:18035804)
• A new missense mutation in exon 2 of the C1-INH gene, c.1A>G; p.Met-22Val (p.Met1Val), in a heterozygous form was detected in 4 Greek patients of the same family. (PMID:18535392)
• Identification of a large number of new mutations related to hereditary angioedema providing additional evidence of the genetic heterogeneity of this disease. (PMID:18586324)
• results corroborate C1INH (SERPING1) deficiency as a disease of extreme allelic heterogeneity with almost each individual family carrying their own mutation (PMID:18758157)
• This study was performed to replicate the association between SERPING1 and age-related macular degeneration. (PMID:19169411)
• study describes the second autosomal recessive family with a novel mutation affecting the C1INH promoter region (c.-101A>G); identified sequence alteration in homozygous form causes moderate-to-severe life-threatening Hereditary angioedema symptoms (PMID:19201015)
• C1INH protein is present in the retina and choroid, where it may regulate complement activation. (PMID:19607829)
• study constitutes the first molecular analysis of hereditary angioedema (HAE) in Greece, where 11 patients from three unrelated families with recurrent angioedema attacks and decreased C1 inhibitor antigenic levels were analyzed for SERPING1 mutations. (PMID:19706314)
• The study of C1NH gene mutations in Middle Eastern Arab hereditary angioedema patients suggests that despite the numerous existing mutations in the C1NH gene, there are novel and recurrent mutations in patients of non-European origin. (PMID:19752569)
• We did not find a significant association between SERPING1 and exudative age-related macular degeneration in our study (PMID:19925520)
• Stduy find an association and linkage of the IL4 -524 and the C1INH 480 polymorphisms with susceptibility to meningococcal infection. (PMID:20016407)
• Hereditary angiodema 5esults from the deficiency of the Complement C1 Inhibitor gene. (PMID:20024535)
• Single nucleotide polymorphisms in SERPING1 are not significantly associated with age-related macular degeneration in the mainland Han Chinese population. (PMID:20062564)
• Newly found C1 inhibitor gene mutation in hereditary angioedema patients. (PMID:20120775)
• No evidence was found to support the role of any common SERPING1 variants, including the rs2511989 variant, in the susceptibility to polypoidal choroidal vasculopathy in a Chinese Han population. (PMID:20161815)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	serping1	ENSDARG00000058053
mus_musculus	Serping1	ENSMUSG00000023224
rattus_norvegicus	Serping1	ENSRNOG00000007457

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), 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), SERPINB4 (ENSG00000206073), SERPINB5 (ENSG00000206075), HMSD (ENSG00000221887), SERPINB10 (ENSG00000242550), SERPINE3 (ENSG00000253309), SERPINA2 (ENSG00000258597)

Protein

Protein identifiers

Plasma protease C1 inhibitor — P05155 (reviewed: P05155)

Alternative names: C1 esterase inhibitor, C1-inhibiting factor, Serpin G1

All UniProt accessions (15): P05155, A0A087WUD9, A0A0S2Z333, A0A348GSH7, A0A7I2V2D2, A0A7I2V2X2, A0A7I2V4I9, A0A7I2V5R3, B5MCB9, C9JZJ9, E9KL26, E9PGN7, E9PK97, H0YCA1, H9KV48

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease inhibitor, which acrs as a regulator of the classical complement pathway. Forms a proteolytically inactive stoichiometric complex with the C1r or C1s proteases. May also regulate blood coagulation, fibrinolysis and the generation of kinins. Very efficient inhibitor of FXIIa. Inhibits chymotrypsin and kallikrein.

Subunit / interactions. Interacts with MASP1. (Microbial infection) Binds to E.coli stcE which allows localization of SERPING1 to cell membranes thus protecting the bacteria against complement-mediated lysis.

Subcellular location. Secreted.

Post-translational modifications. Highly glycosylated (49%) with N- and O-glycosylation. O-glycosylated with core 1 or possibly core 8 glycans. N-glycan heterogeneity at Asn-25: Hex5HexNAc4 (minor), dHex1Hex5HexNAc4 (minor), Hex6HexNAc5 (major) and dHex1Hex6HexNAc5 (minor). Cleaved by C1S in vitro. (Microbial infection) Can be proteolytically cleaved by E.coli stcE.

Disease relevance. Angioedema, hereditary, 1 (HAE1) [MIM:106100] An autosomal dominant disorder characterized by episodic local swelling involving subcutaneous or submucous tissue of the upper respiratory and gastrointestinal tracts, face, extremities, and genitalia. Hereditary angioedema due to C1 esterase inhibitor deficiency is comprised of two clinically indistinguishable forms. In hereditary angioedema type 1, serum levels of C1 esterase inhibitor are decreased, while in type 2, the levels are normal or elevated, but the protein is non-functional. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. Chymotrypsin uses Ala-465 as its reactive site in normal plasma protease C1 inhibitor, and His-466 as its reactive site in the variant His-466.

Similarity. Belongs to the serpin family.

Isoforms (3)

UniProt ID	Names	Canonical?
P05155-1	1	yes
P05155-2	2
P05155-3	3

RefSeq proteins (2): NP_000053, NP_001027466 (=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 (126 total): sequence variant 48, strand 16, glycosylation site 15, helix 12, sequence conflict 9, repeat 7, turn 5, region of interest 3, site 3, compositionally biased region 2, disulfide bond 2, splice variant 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5DU3	X-RAY DIFFRACTION	2.1
2OAY	X-RAY DIFFRACTION	2.35
5DUQ	X-RAY DIFFRACTION	2.9
7AKV	ELECTRON MICROSCOPY	3.6
8W18	X-RAY DIFFRACTION	3.94

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05155-F1	80.63	0.68

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 (3): 465–466 (reactive bond for chymotrypsin); 466–467 (cleavage; by c1s); 466–467 (reactive bond)

Disulfide bonds (2): 123–428, 130–205

Glycosylation sites (15): 25, 47, 48, 64, 69, 71, 81, 83, 88, 92, 96, 238, 253, 272, 352

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-9657689	Defective SERPING1 causes hereditary angioedema
R-HSA-9769739	Regulation of clotting cascade
R-HSA-977606	Regulation of Complement cascade
R-HSA-9855719	Regulation of FXIIa and plasma kallikrein activity
R-HSA-140837

MSigDB gene sets: 471 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, REACTOME_INNATE_IMMUNE_SYSTEM, TSENG_IRS1_TARGETS_UP, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_REGULATION_OF_COAGULATION, GNF2_GSTM1, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GNF2_HPN, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, STAT3_01, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_COAGULATION

GO Biological Process (5): negative regulation of complement activation, lectin pathway (GO:0001869), blood coagulation (GO:0007596), blood circulation (GO:0008015), fibrinolysis (GO:0042730), hemostasis (GO:0007599)

GO Molecular Function (3): serine-type endopeptidase inhibitor activity (GO:0004867), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), extracellular matrix (GO:0031012), platelet alpha granule lumen (GO:0031093), extracellular exosome (GO:0070062), blood microparticle (GO:0072562)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Defects of contact activation system and kallikrein-kinin system	1
Coagulation pathway	1
Complement cascade	1
FXIIa activates plasma kallikrein-kinin system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
complement activation, lectin pathway	1
regulation of complement activation, lectin pathway	1
negative regulation of innate immune response	1
negative regulation of complement activation	1
hemostasis	1
wound healing	1
coagulation	1
circulatory system process	1
negative regulation of blood coagulation	1
regulation of body fluid levels	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
endoplasmic reticulum	1
intracellular organelle lumen	1
external encapsulating structure	1
platelet alpha granule	1
secretory granule lumen	1
extracellular vesicle	1
extracellular region	1

Protein interactions and networks

STRING

1992 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SERPING1	C1R	P00736	999
SERPING1	C1S	P09871	999
SERPING1	KLK4	Q9Y5K2	998
SERPING1	MASP2	O00187	990
SERPING1	KLKB1	P03952	989
SERPING1	F8W876	F8W876	986
SERPING1	F12	P00748	960
SERPING1	KNG1	P01042	941
SERPING1	C3	P01024	917
SERPING1	A2M	P01023	891
SERPING1	C4A	P01028	853
SERPING1	CFB	P00751	834
SERPING1	MBL2	P11226	800
SERPING1	ALB	P02768	786
SERPING1	CFP	P27918	770
SERPING1	CD59	P13987	770

IntAct

59 interactions, top by confidence:

A	B	Type	Score
	MASP2	psi-mi:“MI:0914”(association)	0.750
C1S	SERPING1	psi-mi:“MI:0194”(cleavage reaction)	0.720
C1S	SERPING1	psi-mi:“MI:0915”(physical association)	0.720
SERPING1	C1S	psi-mi:“MI:0407”(direct interaction)	0.720
C1S	SERPING1	psi-mi:“MI:0570”(protein cleavage)	0.720
SERPING1	MASP2	psi-mi:“MI:0194”(cleavage reaction)	0.680
SERPING1	MASP2	psi-mi:“MI:0915”(physical association)	0.680
SERPING1	MASP2	psi-mi:“MI:0407”(direct interaction)	0.680
stcE	SERPING1	psi-mi:“MI:0407”(direct interaction)	0.620
stcE	SERPING1	psi-mi:“MI:0570”(protein cleavage)	0.620
vag8	SERPING1	psi-mi:“MI:0407”(direct interaction)	0.610
SERPING1	CREB3	psi-mi:“MI:0915”(physical association)	0.560
C1R	SERPING1	psi-mi:“MI:0915”(physical association)	0.540
SERPING1	C1R	psi-mi:“MI:0407”(direct interaction)	0.540
ING4	KAT7	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
SERPING1	rep	psi-mi:“MI:0915”(physical association)	0.510
SERPING1	PLAT	psi-mi:“MI:0914”(association)	0.500
SERPING1	PLAT	psi-mi:“MI:0915”(physical association)	0.500
	SERPING1	psi-mi:“MI:0570”(protein cleavage)	0.440
SERPING1	MSP-3	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (53): SERPING1 (Biochemical Activity), CBWD3 (Affinity Capture-MS), PLAT (Affinity Capture-MS), ARFGAP2 (Affinity Capture-MS), GRN (Affinity Capture-MS), SLC30A2 (Two-hybrid), SELE (Affinity Capture-Western), SELP (Affinity Capture-Western), SERPING1 (Two-hybrid), SERPING1 (Two-hybrid), SERPING1 (Two-hybrid), SERPING1 (Two-hybrid), SERPING1 (Two-hybrid), SERPING1 (Two-hybrid), SERPING1 (Two-hybrid)

ESM2 similar proteins: A2I7N3, A6QPQ2, A6QQ92, A8MV23, B0UYL8, B2D1U1, E1BF81, P01017, P01019, P05154, P05155, P05545, P07758, P07759, P08185, P08697, P09006, P20757, P22323, P23035, P23775, P26595, P28800, P29621, P29622, P36955, P49920, P50448, P50451, P97298, Q00896, Q00898, Q03734, Q09055, Q5I2A0, Q5R9E3, Q5RDA8, Q60396, Q61247, Q63556

Diamond homologs: A2I7N0, A2I7N1, A2I7N3, P05155, P07759, P29621, P32759, P50448, P80229, P97290, Q03734, Q1JPB0, Q3ZEJ6, Q6P734, Q8VHP7, Q96P63, Q9TTE1, P08697, Q61247, Q5I0S8, Q9D7P9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SERPING1	“down-regulates activity”	F12	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 39 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
proteolysis	6	6.8×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	290
Likely pathogenic	83
Uncertain significance	236
Likely benign	160
Benign	43

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073879	NM_000062.3(SERPING1):c.1196C>T (p.Pro399Leu)	Pathogenic
1074911	NM_000062.3(SERPING1):c.221C>A (p.Ser74Ter)	Pathogenic
1299717	NM_000062.3(SERPING1):c.74del (p.Asn25fs)	Pathogenic
1299718	NM_000062.3(SERPING1):c.635dup (p.Phe213fs)	Pathogenic
1299719	NM_000062.3(SERPING1):c.673_675del (p.Phe225del)	Pathogenic
1299721	NM_000062.3(SERPING1):c.733_736dup (p.Ser246fs)	Pathogenic
1299722	NM_000062.3(SERPING1):c.779dup (p.Leu261fs)	Pathogenic
1299723	NM_000062.3(SERPING1):c.785dup (p.Asn263fs)	Pathogenic
1299724	NM_000062.3(SERPING1):c.941_942insTC (p.Phe315fs)	Pathogenic
1299725	NM_000062.3(SERPING1):c.951dup (p.Ser318fs)	Pathogenic
1299726	NM_000062.3(SERPING1):c.983_984delinsC (p.Lys328fs)	Pathogenic
1299727	NM_000062.3(SERPING1):c.1019del (p.Thr339_Leu340insTer)	Pathogenic
1299729	NM_000062.3(SERPING1):c.1051del (p.His351fs)	Pathogenic
1299730	NM_000062.3(SERPING1):c.1094dup (p.His365fs)	Pathogenic
1299732	NM_000062.3(SERPING1):c.1186del (p.Leu395_Leu396insTer)	Pathogenic
1299734	NM_000062.3(SERPING1):c.1193T>G (p.Leu398Arg)	Pathogenic
1299735	NM_000062.3(SERPING1):c.1249+2T>C	Pathogenic
1299736	NM_000062.3(SERPING1):c.1289T>G (p.Leu430Arg)	Pathogenic
1299739	NM_000062.3(SERPING1):c.172_181del (p.Pro58fs)	Pathogenic
1299742	NM_000062.3(SERPING1):c.197dup (p.Thr67fs)	Pathogenic
1299743	NM_000062.3(SERPING1):c.229A>T (p.Lys77Ter)	Pathogenic
1299744	NM_000062.3(SERPING1):c.232del (p.Lys77_Ile78insTer)	Pathogenic
1299745	NM_000062.3(SERPING1):c.538C>T (p.Gln180Ter)	Pathogenic
1299746	NM_000062.3(SERPING1):c.550+1G>T	Pathogenic
1299747	NM_000062.3(SERPING1):c.623dup (p.Ala209fs)	Pathogenic
1329453	NM_000062.3(SERPING1):c.330_331insC (p.Thr111fs)	Pathogenic
1329454	NM_000062.3(SERPING1):c.748_749del (p.Val250fs)	Pathogenic
1329455	NM_000062.3(SERPING1):c.1269T>A (p.Tyr423Ter)	Pathogenic
1346163	NC_000011.9:g.(?57369488)(57369662_?)dup	Pathogenic
1387977	NM_000062.3(SERPING1):c.51+1G>A	Pathogenic

SpliceAI

1100 predictions. Top by Δscore:

Variant	Effect	Δscore
11:57597723:G:GG	donor_gain	1.0000
11:57602033:AGG:A	acceptor_gain	1.0000
11:57602034:GGG:G	acceptor_gain	1.0000
11:57602170:G:GA	donor_loss	1.0000
11:57602170:G:GG	donor_gain	1.0000
11:57602171:T:A	donor_loss	1.0000
11:57606209:GAGTG:G	donor_gain	1.0000
11:57606211:GTG:G	donor_gain	1.0000
11:57611712:TCTA:T	acceptor_loss	1.0000
11:57611715:A:AG	acceptor_gain	1.0000
11:57611715:AG:A	acceptor_gain	1.0000
11:57611715:AGGT:A	acceptor_gain	1.0000
11:57611715:AGGTG:A	acceptor_gain	1.0000
11:57611716:G:GC	acceptor_gain	1.0000
11:57611716:GG:G	acceptor_gain	1.0000
11:57611716:GGT:G	acceptor_gain	1.0000
11:57611716:GGTG:G	acceptor_gain	1.0000
11:57611716:GGTGG:G	acceptor_gain	1.0000
11:57611852:TCC:T	donor_gain	1.0000
11:57611909:GA:G	donor_gain	1.0000
11:57611933:TTGG:T	donor_gain	1.0000
11:57611934:TGGG:T	donor_loss	1.0000
11:57611935:GG:G	donor_gain	1.0000
11:57611935:GGGT:G	donor_loss	1.0000
11:57611936:GG:G	donor_gain	1.0000
11:57611936:GGT:G	donor_loss	1.0000
11:57611937:G:GG	donor_gain	1.0000
11:57611937:G:T	donor_loss	1.0000
11:57611938:T:G	donor_loss	1.0000
11:57614320:T:TA	acceptor_gain	1.0000

AlphaMissense

3286 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:57606413:T:A	W299R	0.996
11:57606413:T:C	W299R	0.996
11:57600344:A:C	S173R	0.991
11:57600346:C:A	S173R	0.991
11:57600346:C:G	S173R	0.991
11:57606415:G:C	W299C	0.988
11:57606415:G:T	W299C	0.988
11:57614559:G:C	R494P	0.988
11:57606542:G:C	A342P	0.984
11:57614555:G:A	G493R	0.984
11:57614555:G:C	G493R	0.984
11:57614555:G:T	G493W	0.984
11:57606455:T:C	F313L	0.983
11:57606457:T:A	F313L	0.983
11:57606457:T:G	F313L	0.983
11:57602062:T:C	L193P	0.981
11:57600285:T:C	L153P	0.980
11:57614444:G:C	A456P	0.977
11:57611720:G:A	G345R	0.976
11:57611720:G:C	G345R	0.976
11:57600360:T:C	L178P	0.975
11:57611721:G:A	G345E	0.975
11:57611727:T:C	L347P	0.975
11:57611883:C:A	P399H	0.975
11:57614556:G:A	G493E	0.975
11:57602037:G:C	A185P	0.974
11:57614450:G:C	A458P	0.974
11:57614507:T:C	F477L	0.974
11:57614509:C:A	F477L	0.974
11:57614509:C:G	F477L	0.974

dbSNP variants (sampled 300 via entrez): RS1000676731 (11:57602761 A>C), RS1000842947 (11:57610323 G>A), RS1001100902 (11:57610608 A>G), RS1001170331 (11:57612421 T>TG), RS1001236006 (11:57602538 C>G,T), RS1001368578 (11:57605276 G>A), RS1001401138 (11:57604268 T>C), RS1001798433 (11:57605533 G>A), RS1002293849 (11:57609823 T>C), RS1002352750 (11:57604219 A>G), RS1002430281 (11:57597094 TG>T), RS1002803104 (11:57613497 T>A), RS1002963197 (11:57606974 G>A,T), RS1002997325 (11:57606380 G>A), RS1003209423 (11:57600401 C>G,T)

Disease associations

OMIM: gene MIM:606860 | disease phenotypes: MIM:106100, MIM:120790

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary angioedema with C1Inh deficiency	Strong	Autosomal dominant
hereditary angioedema type 1	Supportive	Autosomal dominant
hereditary angioedema type 2	Supportive	Autosomal dominant
C1 inhibitor deficiency	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hereditary angioedema with C1Inh deficiency	Definitive	AD

Mondo (5): hereditary angioedema type 1 (MONDO:0015053), hereditary angioedema with C1Inh deficiency (MONDO:0033946), C1 inhibitor deficiency (MONDO:0007361), angioedema (MONDO:0010481), hereditary angioedema type 2 (MONDO:0015054)

Orphanet (5): Hereditary angioedema type 1 (Orphanet:100050), Hereditary angioedema type 2 (Orphanet:100051), Hereditary angioedema (Orphanet:91378), Hereditary angioedema with C1Inh deficiency (Orphanet:528623), OBSOLETE: C1 inhibitor deficiency (Orphanet:459353)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000172	Abnormal uvula morphology
HP:0000282	Facial edema
HP:0001025	Urticaria
HP:0001324	Muscle weakness
HP:0001609	Hoarse voice
HP:0001939	Abnormality of metabolism/homeostasis
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002015	Dysphagia
HP:0002018	Nausea
HP:0002027	Abdominal pain
HP:0002094	Dyspnea
HP:0002098	Respiratory distress
HP:0002615	Hypotension
HP:0002725	Systemic lupus erythematosus
HP:0002960	Autoimmunity
HP:0003401	Paresthesia
HP:0003477	Peripheral axonal neuropathy
HP:0005225	Intestinal edema
HP:0005348	Inspiratory stridor
HP:0005483	Abnormal epiglottis morphology
HP:0007514	Edema of the dorsum of hands
HP:0010783	Erythema
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0011855	Pharyngeal edema
HP:0011971	Dermatographic urticaria
HP:0012027	Laryngeal edema

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001762_650	Obesity-related traits	9.000000e-06
GCST002539_6	Schizophrenia	2.000000e-09
GCST004521_290	Autism spectrum disorder or schizophrenia	5.000000e-08
GCST005232_71	Neuroticism	7.000000e-11
GCST006803_71	Schizophrenia	1.000000e-09
GCST90002395_84	Mean platelet volume	7.000000e-27
GCST90002402_348	Platelet count	3.000000e-16

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0004309	platelet count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000799	Angioedema	C14.907.079; C17.800.862.945.066; C20.543.480.904.066

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5305024 (SINGLE PROTEIN)

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1005510	SERPING1		0.00	0
rs2511989	SERPING1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression, affects expression	8
sodium arsenite	affects methylation, affects cotreatment, decreases expression	3
Cyclosporine	decreases expression, increases expression, affects expression	3
bisphenol A	decreases methylation, affects cotreatment, increases expression	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	decreases methylation, increases expression, affects methylation	2
Cadmium	decreases expression, increases abundance, affects binding	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	increases expression	2
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
lead acetate	affects cotreatment, decreases expression	1
sulforaphane	affects binding	1
butyraldehyde	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
monomethylpropion	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
incobotulinumtoxinA	increases expression	1
Olanzapine	affects phosphorylation	1
Air Pollutants, Occupational	affects expression	1
Arsenic	affects expression, increases abundance	1
Cacodylic Acid	affects expression, increases abundance	1
Copper	affects binding	1
Danazol	increases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1HH	Abcam A-549 SERPING1 KO 2	Cancer cell line	Male
CVCL_B2Q0	Abcam A-549 SERPING1 KO 1	Cancer cell line	Male
CVCL_E2JV	HAP1 SERPING1 (-) 1	Cancer cell line	Male
CVCL_E2JW	HAP1 SERPING1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02966314	PHASE4	COMPLETED	Treatment of Idiopathic Angioedema With Xolair as Add-on Therapy
NCT06818474	PHASE4	RECRUITING	Lanadelumab in Long-term Prophylaxis of Acquired Angioedema
NCT06343779	PHASE3	COMPLETED	Study of Oral Deucrictibant Soft Capsule for On-Demand Treatment of Angioedema Attacks in Adolescents and Adults With Hereditary Angioedema
NCT06960213	PHASE3	RECRUITING	STOP-HAE: A Phase 3 Study of ADX-324 in HAE
NCT07428499	PHASE3	RECRUITING	Phase 3 Extension Study of ADX-324 in Participants With Hereditary Angioedema (HAE)
NCT00097695	PHASE3	COMPLETED	Subcutaneous Treatment With Icatibant for Acute Attacks of Hereditary Angioedema
NCT00125151	PHASE3	COMPLETED	C1-Esteraseremmer-N for the Treatment of Hereditary (and Acquired) Angioedema
NCT00262301	PHASE3	COMPLETED	Recombinant Human C1 Inhibitor for the Treatment of Acute Attacks in Patients With Hereditary Angioedema
NCT01723072	PHASE3	COMPLETED	Impact of Omalizumab on Quality of Life Measures and Angioedema Occurrence in Patients With CSU Refractory to Therapy
NCT04206605	PHASE3	COMPLETED	A Study of Lanadelumab in Teenagers and Adults to Prevent Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH)
NCT04444895	PHASE3	COMPLETED	A Study of Long-Term Safety and Efficacy of Lanadelumab for Prevention of Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor
NCT04618211	PHASE2	COMPLETED	Dose-ranging Study of Oral PHA-022121 for Acute Treatment of Angioedema Attacks in Patients With Hereditary Angioedema
NCT05047185	PHASE2	COMPLETED	Dose-ranging Study of Oral PHA-022121 for Prophylaxis Against Angioedema Attacks in Patients With Hereditary Angioedema Type I or Type II
NCT00119431	PHASE2	COMPLETED	Kinetics, Efficacy and Safety of C1-Esteraseremmer-N
NCT00890162	PHASE2	COMPLETED	A Randomized, Double-Blind, Placebo-Controlled Study of Omalizumab for Idiopathic Anaphylaxis
NCT01036659	PHASE2	UNKNOWN	Evaluation of Ecallantide for the Acute Treatment of Angiotensin Converting Enzyme Inhibitor Induced Angioedema
NCT01154361	PHASE2	COMPLETED	AMelioration of Angiotensin Converting Enzyme Inhibitor Induced Angioedema Study
NCT03749135	PHASE2	COMPLETED	Dupilumab in Chronic Spontaneous Urticaria
NCT04128371	PHASE2	TERMINATED	Mepolizumab in Episodic Angioedema With Eosinophilia
NCT05936567	PHASE2	COMPLETED	Study Evaluating the Efficacy and Safety of Povorcitinib in Adults With Chronic Spontaneous Urticaria
NCT00517582	PHASE1	TERMINATED	Bradykinin Receptor Blocker in ACE Inhibitor-associated Angioedema
NCT05396105	PHASE2/PHASE3	ENROLLING_BY_INVITATION	Extension Study of Oral PHA-022121 for Acute Treatment of Angioedema Attacks in Patients With Hereditary Angioedema
NCT07448181	Not specified	RECRUITING	Real-life Ecological Momentary Assessment of Lived Burden in Hereditary AngioEdema
NCT07046806	PHASE1/PHASE2	RECRUITING	Oral Deucrictibant for Prophylactic and Acute Treatment in Hereditary Angioedema Patients
NCT06210698	Not specified	UNKNOWN	Angioedema Biomarker Research Study
NCT00125541	PHASE2/PHASE3	COMPLETED	C1-Esteraseremmer-N for the Treatment of Hereditary (and Acquired) Angioedema
NCT00225147	PHASE2/PHASE3	COMPLETED	Recombinant Human C1 Inhibitor for the Treatment of Acute Attacks in Patients With Hereditary Angioedema
NCT00004694	Not specified	COMPLETED	Study of Heparin Prophylaxis of Hereditary Angioedema Exacerbations
NCT00163839	Not specified	UNKNOWN	The Efficacy of a Pseudoallergen-Free Diet in the Treatment of Chronic Idiopathic Urticaria and/or Angioedema
NCT00385372	Not specified	COMPLETED	Significance of an Elimination and Provocation Diet in Patients With Chronic Urticaria
NCT00876369	Not specified	COMPLETED	Vitamin D Levels in Subjects With Chronic Urticaria and Angioedema
NCT01371877	Not specified	COMPLETED	The Role of Vitamin D in Chronic Urticaria and Angioedema Treatment
NCT02833675	Not specified	COMPLETED	Determination of Specific Biomarkers of Angioneurotic Crisis
NCT03240991	Not specified	COMPLETED	Study of Clinical, Biological Characteristics and Quality of Life of Patients With Hereditary or Acquired Non Drug-induced Bradykinin-mediated Angioedema, Monitored in Besançon’s Partner Site Reference Center for Studies of Kinin-mediated Angioedema (CREAK)
NCT03845946	Not specified	RECRUITING	CLOUD-R HAE REGISTRY
NCT04334031	Not specified	RECRUITING	Deployment o the Multidisciplinary Prospective Cohort Imminent
NCT04583007	Not specified	NO_LONGER_AVAILABLE	Expanded Access for the Prevention of Acute Attacks of 1) Hereditary Angioedema (HAE) in Children and 2) Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH) in Teenagers and Adults
NCT04597944	Not specified	UNKNOWN	Lanadelumab in Bradykinin Angioedema
NCT05578417	Not specified	COMPLETED	A Study to Review the Treatment and Outcomes of Teenagers and Adults With Non-histaminergic Angioedema With Normal C1 Inhibitor in Canada
NCT06096077	Not specified	COMPLETED	Evaluation of Tranexamic Acid for Angiotensin-converting Enzyme Inhibitor-induced Angioedema in the Emergency Department