SERPIND1

Summary

SERPIND1 (serpin family D member 1, HGNC:4838) is a protein-coding gene on chromosome 22q11.21, encoding Heparin cofactor 2 (P05546). Thrombin inhibitor activated by the glycosaminoglycans, heparin or dermatan sulfate.

This gene belongs to the serpin gene superfamily. Serpins play roles in many processes including inflammation, blood clotting, and cancer metastasis. Members of this family have highly conserved secondary structures with a reactive center loop that interacts with the protease active site to inhibit protease activity. This gene encodes a plasma serine protease that functions as a thrombin and chymotrypsin inhibitor. The protein is activated by heparin, dermatan sulfate, and glycosaminoglycans. Allelic variations in this gene are associated with heparin cofactor II deficiency.

Source: NCBI Gene 3053 — RefSeq curated summary.

At a glance

• Gene–disease (curated): heparin cofactor 2 deficiency (Definitive, ClinGen)
• Clinical variants (ClinVar): 4 total — 1 pathogenic
• Phenotypes (HPO): 4
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000185

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4838
Approved symbol	SERPIND1
Name	serpin family D member 1
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	HC-II, HLS2, HC2, D22S673
Ensembl gene	ENSG00000099937
Ensembl biotype	protein_coding
OMIM	142360
Entrez	3053

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000215727, ENST00000406799, ENST00000881285, ENST00000881286

RefSeq mRNA: 1 — MANE Select: NM_000185 NM_000185

CCDS: CCDS13783

Canonical transcript exons

ENST00000215727 — 5 exons

Exon	Start	End
ENSE00000650952	20783972	20784245
ENSE00000650953	20786004	20786148
ENSE00000879274	20786875	20787720
ENSE00001299470	20779297	20780201
ENSE00001320327	20774113	20774145

Expression profiles

Bgee: expression breadth ubiquitous, 129 present calls, max score 98.88.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.5488 / max 466.3849, expressed in 78 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191149	1.2559	61
191148	0.2749	21
191150	0.0181	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
liver	UBERON:0002107	98.88	gold quality
right lobe of liver	UBERON:0001114	98.61	gold quality
paraflocculus	UBERON:0005351	85.09	gold quality
frontal pole	UBERON:0002795	84.79	gold quality
middle frontal gyrus	UBERON:0002702	83.97	gold quality
endometrium epithelium	UBERON:0004811	82.21	gold quality
choroid plexus epithelium	UBERON:0003911	79.54	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.90	gold quality
Brodmann (1909) area 10	UBERON:0013541	72.51	gold quality
trigeminal ganglion	UBERON:0001675	68.33	gold quality
cerebellar vermis	UBERON:0004720	62.18	gold quality
nucleus accumbens	UBERON:0001882	60.50	gold quality
islet of Langerhans	UBERON:0000006	60.45	gold quality
right atrium auricular region	UBERON:0006631	59.76	gold quality
colonic epithelium	UBERON:0000397	59.37	gold quality
adrenal tissue	UBERON:0018303	59.22	gold quality
cardiac atrium	UBERON:0002081	58.91	gold quality
left ovary	UBERON:0002119	57.61	gold quality
bone marrow cell	CL:0002092	57.17	gold quality
ovary	UBERON:0000992	57.13	gold quality
endocervix	UBERON:0000458	56.59	gold quality
body of uterus	UBERON:0009853	56.32	gold quality
right ovary	UBERON:0002118	55.78	gold quality
corpus callosum	UBERON:0002336	55.12	gold quality
caudate nucleus	UBERON:0001873	54.99	gold quality
smooth muscle tissue	UBERON:0001135	54.75	gold quality
quadriceps femoris	UBERON:0001377	53.88	gold quality
myometrium	UBERON:0001296	53.78	gold quality
thymus	UBERON:0002370	53.73	gold quality
uterine cervix	UBERON:0000002	53.50	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.36

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, ESR2

miRNA regulators (miRDB)

28 targeting SERPIND1, 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-4481	100.00	66.42	1669
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-3675-3P	99.09	67.70	968
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-6871-5P	98.90	66.67	671
HSA-MIR-5008-3P	98.73	67.50	1433
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-26B-3P	98.71	67.49	1102
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-509-3P	98.12	67.25	612
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-6730-5P	98.03	68.12	1299
HSA-MIR-4308	97.56	67.13	1385
HSA-MIR-4474-3P	96.97	65.87	870
HSA-MIR-3189-3P	96.80	66.34	896
HSA-MIR-490-5P	96.75	65.81	661
HSA-MIR-1236-5P	96.62	66.38	856
HSA-MIR-2861	95.24	65.47	1056
HSA-MIR-5681B	94.82	69.30	514

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 24)

• Aspartic acid residues 72 and 75 and tyrosine-sulfate 73 of heparin cofactor II promote (PMID:11856753)
• role of basic amino acids of the A helix of heparin cofactor II in heparin- or dermatan sulfate-mediated thrombin inhibition. (PMID:12095635)
• Altering heparin cofactor II at VAL439 (P6) either impairs inhibition of thrombin or confers elastase resistance. (PMID:12152684)
• The interactions of HCII with various heparins in solution competition experiments using SPR show that while calcium enhances this interaction, the activity of heparin-HCII complex against thrombin is not calcium dependent but can be enhanced by it. (PMID:15247982)
• structure analysis of the thrombin-heparin cofactor II complex (PMID:15292227)
• An asymptomatic Glu428Lys mutation affecting a conserved glutamate at the hinge (P17) of the reactive loop confirms the key structural role of the P17 glutamate in serpins. (PMID:15337701)
• after receiving stent for peripheral artery disease, patients with a high HCII activity had a 0.39-fold reduced risk for instent restenosis (PMID:15543340)
• HCII activity increases during pregnancy, and HCII levels are significantly decreased in women with severe pre-eclampsia. (PMID:16339402)
• These results suggest that transfer of the N-terminal acidic extension of HCII to alpha1-PI M358R enhanced its inhibition of thrombin by conferring the ability to bind exosite 1 on HAPI M358R. (PMID:16981704)
• Beta2-glycoprotein I (B2G1) protected thrombin against inactivation by HCII (heparin cofactor II)/heparin (PMID:18383370)
• Plasma heparin cofactor II activity is an independent predictor of future cardiovascular events in patients after acute myocardial infarction. (PMID:18971786)
• These results suggest that HCII is in a position to inhibit thrombin in atherosclerotic lesions where thrombin can exert a proatherogenic inflammatory response. (PMID:19747479)
• potential for oversulfated disaccharides in controlling HCII-regulated thrombin generation (PMID:20053992)
• [REVIEW]HCII protects against vascular remodeling, including atherosclerosis (PMID:20671370)
• Plasma heparin cofactor II activity was independently and inversely associated with the development of cardiac remodeling, including cardiac concentric change, left atrial enlargement and left ventricular diastolic dysfunction. (PMID:21107326)
• HCII potentiates the activation of vascular endothelial cells and the promotion of angiogenesis in response to hindlimb ischemia via an AMPK-eNOS signaling pathway. (PMID:22904320)
• Molecular modelling of HCII 1-75 predicted those portions of the acidic extension that had been previously visualized in crystal structures, and suggested that an alpha-helix found between residues 26 and 36 stabilizes one found between residues 61-67. (PMID:23496873)
• In this study, we demonstrate a previously unknown role for HCII in host defense. (PMID:23656734)
• heparin co-factor II is a novel metastasis enhancer and may be used as a prognostic predictor for heparin treatment in non-small cell lung cancer (PMID:25130770)
• We found that SERPIND1 may act as a potential oncogene in the development of ovarian cancer (PMID:27430660)
• The plasma level of alpha2M was found positively correlated, while HCII level was negatively correlated with higher vulnerability of carotid plaques. Both proteins were efficient in differentiating stable and vulnerable carotid plaques. These provide potential new targets for the research of carotid plaque vulnerability. Plasma alpha2M and HCII may be potential biomarkers for evaluation of the vulnerability of carotid … (PMID:28087279)
• Loss of Heparin Cofactor is associated with insulin resistance . (PMID:28502917)
• Identification and characterization of a novel isoform of heparin cofactor II in human liver. (PMID:32827448)
• Plasma Heparin Cofactor II Activity Is Inversely Associated with Hepatic Fibrosis of Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus. (PMID:36244745)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	serpind1	ENSDARG00000021208
mus_musculus	Serpind1	ENSMUSG00000022766
rattus_norvegicus	Serpind1	ENSRNOG00000001865

Paralogs (36): SERPINB1 (ENSG00000021355), SERPINB3 (ENSG00000057149), 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), SERPINB4 (ENSG00000206073), SERPINB5 (ENSG00000206075), HMSD (ENSG00000221887), SERPINB10 (ENSG00000242550), SERPINE3 (ENSG00000253309), SERPINA2 (ENSG00000258597)

Protein

Protein identifiers

Heparin cofactor 2 — P05546 (reviewed: P05546)

Alternative names: Heparin cofactor II, Protease inhibitor leuserpin-2, Serpin D1

All UniProt accessions (1): P05546

UniProt curated annotations — full annotation on UniProt →

Function. Thrombin inhibitor activated by the glycosaminoglycans, heparin or dermatan sulfate. In the presence of the latter, HC-II becomes the predominant thrombin inhibitor in place of antithrombin III (AT-III). Also inhibits chymotrypsin, but in a glycosaminoglycan-independent manner. Peptides at the N-terminal of HC-II have chemotactic activity for both monocytes and neutrophils. Shows negligible inhibition, in vitro, of thrombin and tPA and no inhibition of factor Xa, in vitro.

Tissue specificity. Expressed predominantly in liver. Also present in plasma. Expressed in plasma (at protein level). Expressed in liver.

Post-translational modifications. Phosphorylated by FAM20C in the extracellular medium.

Disease relevance. Thrombophilia due to heparin cofactor 2 deficiency (THPH10) [MIM:612356] A hemostatic disorder characterized by a tendency to recurrent thrombosis. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal acidic repeat region mediates, in part, the glycosaminoglycan-accelerated thrombin inhibition.

Miscellaneous. Produced by alternative exon usage of exon 3b instead of exon 4.

Similarity. Belongs to the serpin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P05546-1	1, HCII	yes
P05546-2	2, HCII-N

RefSeq proteins (1): NP_000176* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000215	Serpin_fam	Family
IPR023795	Serpin_CS	Conserved_site
IPR023796	Serpin_dom	Domain
IPR033831	HCII_serpin_dom	Domain
IPR036186	Serpin_sf	Homologous_superfamily
IPR042178	Serpin_sf_1	Homologous_superfamily
IPR042185	Serpin_sf_2	Homologous_superfamily

Pfam: PF00079

UniProt features (76 total): strand 18, helix 17, sequence variant 9, mutagenesis site 6, turn 6, sequence conflict 4, modified residue 3, glycosylation site 3, region of interest 3, splice variant 2, repeat 2, signal peptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
1JMO	X-RAY DIFFRACTION	2.2
1JMJ	X-RAY DIFFRACTION	2.35
2NAT	SOLUTION NMR
2NCU	SOLUTION NMR
2NCV	SOLUTION NMR
2NCW	SOLUTION NMR
6J12	SOLUTION NMR
6KBO	SOLUTION NMR
6KBV	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05546-F1	80.25	0.65

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): 463–464 (reactive bond)

Post-translational modifications (3): 92, 37, 79

Glycosylation sites (3): 49, 188, 387

Mutagenesis-validated functional residues (6):

Position	Phenotype
122	normal thrombin inhibition and glycosaminoglycan affinity.
122	greatly reduced thrombin inhibition. normal glycosaminoglycan affinity.
204	reduced heparin- and no dermatan sulfate-activated inhibition.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation
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

MSigDB gene sets: 121 (showing top): GNF2_GSTM1, GNF2_HPN, KENNY_CTNNB1_TARGETS_UP, HUMMERICH_BENIGN_SKIN_TUMOR_UP, COUP_01, GOBP_WOUND_HEALING, GOBP_TAXIS, TGCTGAY_UNKNOWN, GNF2_LCAT, HSIAO_LIVER_SPECIFIC_GENES, GNF2_HPX, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_AND_BRAIN_QTL_TRANS, GOMF_GLYCOSAMINOGLYCAN_BINDING, MODULE_88, AACTTT_UNKNOWN

GO Biological Process (3): chemotaxis (GO:0006935), blood coagulation (GO:0007596), hemostasis (GO:0007599)

GO Molecular Function (5): endopeptidase inhibitor activity (GO:0004866), serine-type endopeptidase inhibitor activity (GO:0004867), heparin binding (GO:0008201), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Coagulation pathway	3
Metabolism of proteins	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to chemical	1
taxis	1
hemostasis	1
wound healing	1
coagulation	1
regulation of body fluid levels	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
glycosaminoglycan binding	1
sulfur compound binding	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
cellular anatomical structure	1
endoplasmic reticulum	1
intracellular organelle lumen	1
extracellular vesicle	1

Protein interactions and networks

STRING

1116 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SERPIND1	TFPI	P10646	873
SERPIND1	F2	P00734	866
SERPIND1	FGG	P02679	855
SERPIND1	FGA	P02671	847
SERPIND1	THBD	P07204	846
SERPIND1	FGB	P02675	836
SERPIND1	HRG	P04196	826
SERPIND1	F3	P13726	802
SERPIND1	PROS1	P07225	800
SERPIND1	A2M	P01023	744
SERPIND1	PLG	P00747	741
SERPIND1	HABP2	Q14520	738
SERPIND1	F7	P08709	726
SERPIND1	DGCR6L	Q9BY27	716
SERPIND1	KNG1	P01042	707

IntAct

21 interactions, top by confidence:

A	B	Type	Score
SERPIND1	VAT1L	psi-mi:“MI:0915”(physical association)	0.590
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
CFTR	SERPIND1	psi-mi:“MI:0915”(physical association)	0.370
	SERPIND1	psi-mi:“MI:0915”(physical association)	0.370
IGHA1	PLG	psi-mi:“MI:0914”(association)	0.350
TF	IGKV2D-40	psi-mi:“MI:0914”(association)	0.350
IGHG1	PDPK1	psi-mi:“MI:0914”(association)	0.350
DCAF4	IGLL5	psi-mi:“MI:0914”(association)	0.350
AGPAT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
PHF11	A2ML1	psi-mi:“MI:0914”(association)	0.350
RHBDD1	A2ML1	psi-mi:“MI:0914”(association)	0.350
UBE2U	IGLL5	psi-mi:“MI:0914”(association)	0.350
KLK10	IGLL5	psi-mi:“MI:0914”(association)	0.350
FGF4	QSOX1	psi-mi:“MI:0914”(association)	0.350
SERPIND1	LAMB3	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350

BioGRID (14): SERPIND1 (Reconstituted Complex), VAT1L (Affinity Capture-MS), SERPIND1 (Affinity Capture-MS), SERPIND1 (Co-crystal Structure), VAT1L (Affinity Capture-MS), SERPIND1 (Affinity Capture-MS), SERPIND1 (Affinity Capture-MS), SERPIND1 (Affinity Capture-MS), SERPIND1 (Affinity Capture-MS), SERPIND1 (Affinity Capture-MS), SERPIND1 (Affinity Capture-MS), SERPIND1 (PCA), SERPIND1 (Biochemical Activity), APP (Reconstituted Complex)

ESM2 similar proteins: A2I7N3, B0UYL8, O75830, P01015, P01017, P01019, P05121, P05154, P05155, P05544, P05545, P05546, P07759, P09006, P11859, P13909, P20757, P20961, P22777, P29622, P31211, P32759, P47776, P49182, P50448, P50449, P70458, P79335, P97290, Q03734, Q5I2A0, Q5RCR2, Q5RDA8, Q60396, Q62975, Q63556, Q64268, Q6P4P1, Q6P734, Q7TMF5

Diamond homologs: A2I7M9, A2I7N0, A2I7N1, A2I7N2, A2I7N3, A6QPQ2, B2D1U1, E1BF81, O00394, O54757, O54758, O54759, O54760, O54761, O54762, O54763, P01009, P01010, P01011, P05154, P05543, P05544, P05545, P05546, P05619, P07758, P07759, P08185, P09006, P12725, P17475, P20848, P22323, P22324, P22325, P22599, P23035, P23775, P26595, P29621

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CTSG	“down-regulates activity”	SERPIND1	cleavage
ELANE	“down-regulates activity”	SERPIND1	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	3
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3770234	GRCh37/hg19 22q11.21(chr22:18920000-21460000)x1	Pathogenic

SpliceAI

573 predictions. Top by Δscore:

Variant	Effect	Δscore
22:20774141:CAGAG:C	donor_gain	1.0000
22:20774142:AGAG:A	donor_gain	1.0000
22:20774143:GAG:G	donor_gain	1.0000
22:20774143:GAGG:G	donor_gain	1.0000
22:20774146:G:GG	donor_gain	1.0000
22:20781983:G:T	donor_gain	1.0000
22:20785997:T:A	acceptor_gain	1.0000
22:20786001:TA:T	acceptor_loss	1.0000
22:20786002:A:AG	acceptor_gain	1.0000
22:20786003:G:GG	acceptor_gain	1.0000
22:20786003:GA:G	acceptor_gain	1.0000
22:20786003:GAA:G	acceptor_gain	1.0000
22:20786003:GAAC:G	acceptor_gain	1.0000
22:20786003:GAACT:G	acceptor_gain	1.0000
22:20786133:G:GT	donor_gain	1.0000
22:20786146:CTGGT:C	donor_loss	1.0000
22:20786147:TGGTA:T	donor_loss	1.0000
22:20786149:G:C	donor_loss	1.0000
22:20786149:G:GG	donor_gain	1.0000
22:20786150:T:A	donor_loss	1.0000
22:20786871:ACAGT:A	acceptor_loss	1.0000
22:20786872:CA:C	acceptor_loss	1.0000
22:20786873:A:AC	acceptor_loss	1.0000
22:20786873:A:AG	acceptor_gain	1.0000
22:20786874:G:GG	acceptor_gain	1.0000
22:20786874:G:GT	acceptor_loss	1.0000
22:20786874:GTTCA:G	acceptor_gain	1.0000
22:20774144:AG:A	donor_gain	0.9900
22:20774145:GG:G	donor_gain	0.9900
22:20779483:C:A	acceptor_gain	0.9900

AlphaMissense

3359 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:20783977:T:A	W299R	0.997
22:20783977:T:C	W299R	0.997
22:20784223:T:A	W381R	0.997
22:20784223:T:C	W381R	0.997
22:20783989:T:C	F303L	0.995
22:20783990:T:C	F303S	0.995
22:20783991:C:A	F303L	0.995
22:20783991:C:G	F303L	0.995
22:20784019:T:C	F313L	0.995
22:20784020:T:C	F313S	0.995
22:20784021:C:A	F313L	0.995
22:20784021:C:G	F313L	0.995
22:20779686:G:C	R125P	0.994
22:20783979:G:C	W299C	0.994
22:20783979:G:T	W299C	0.994
22:20787037:G:A	G491R	0.994
22:20787037:G:C	G491R	0.994
22:20787038:G:A	G491E	0.993
22:20784116:T:C	L345P	0.992
22:20779926:T:C	L205P	0.991
22:20786030:T:C	F397S	0.991
22:20779722:T:C	L137P	0.990
22:20779935:G:C	R208P	0.990
22:20779983:T:C	L224P	0.990
22:20783990:T:G	F303C	0.990
22:20786989:T:C	F475L	0.990
22:20786991:T:A	F475L	0.990
22:20786991:T:G	F475L	0.990
22:20780201:G:A	G297R	0.989
22:20780201:G:C	G297R	0.989

dbSNP variants (sampled 300 via entrez): RS1000027408 (22:20781284 T>C), RS1000198760 (22:20774923 A>C), RS1000322066 (22:20782404 T>C), RS1000363942 (22:20776836 A>G), RS1000446858 (22:20773802 C>A,T), RS1000495038 (22:20772400 C>T), RS1000599066 (22:20779129 T>C), RS1000632876 (22:20775126 T>C), RS1000692658 (22:20778059 A>C), RS1000976012 (22:20772709 G>A,C), RS1001422897 (22:20783253 A>T), RS1001454181 (22:20783703 G>A), RS1001795267 (22:20778030 C>G), RS1002159561 (22:20772573 C>T), RS1002304670 (22:20778260 G>A,C,T)

Disease associations

OMIM: gene MIM:142360 | disease phenotypes: MIM:612356

GenCC curated gene-disease

Disease	Classification	Inheritance
heparin cofactor 2 deficiency	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
heparin cofactor 2 deficiency	Definitive	AD

Mondo (1): heparin cofactor 2 deficiency (MONDO:0012876)

Orphanet (0):

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0004761	Post-angioplasty coronary artery restenosis
HP:0004850	Recurrent deep vein thrombosis
HP:0005521	Disseminated intravascular coagulation

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562865	Heparin Cofactor II Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression, affects cotreatment, affects expression	4
bisphenol A	affects expression, decreases expression	2
sodium arsenite	decreases expression, increases expression	2
perfluorooctanoic acid	decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Ethinyl Estradiol	affects cotreatment, affects expression, increases expression	2
Valproic Acid	affects expression, decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
methyleugenol	decreases expression	1
Gestodene	affects cotreatment, increases expression	1
perfluorodecanoic acid	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
K 7174	decreases expression	1
ethinyl estradiol-desogestrel combination	increases expression	1
quercetin 3,7,3’,4’-tetrasulfate	decreases reaction, increases degradation, increases activity	1
quercetin 3-acetyl-7,3’,4’-trisulfate	increases degradation, increases reaction, increases activity	1
pentabrominated diphenyl ether 100	increases expression	1
perfluorododecanoic acid	decreases expression	1
(+)-JQ1 compound	decreases expression	1
perfluoroundecanoic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Arbutin	decreases expression	1
Cadmium	affects binding	1
Cholic Acids	affects cotreatment, affects expression	1
Copper	affects binding	1
Dermatan Sulfate	affects cotreatment, decreases activity	1
Doxorubicin	decreases expression	1

Clinical trials (associated diseases)

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