KNG1

Summary

KNG1 (kininogen 1, HGNC:6383) is a protein-coding gene on chromosome 3q27.3, encoding Kininogen-1 (P01042). Kininogens are inhibitors of thiol proteases.

This gene uses alternative splicing to generate two different proteins- high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK). HMWK is essential for blood coagulation and assembly of the kallikrein-kinin system. Also, bradykinin, a peptide causing numerous physiological effects, is released from HMWK. Bradykinin also functions as an antimicrobial peptide with antibacterial and antifungal activity. In contrast to HMWK, LMWK is not involved in blood coagulation. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduces or depletes angiotensin converting enzyme 2 (ACE2), which results in an increase in levels of des-Arg(9)-bradykinin, a bioactive metabolite of bradykinin that is associated with lung injury and inflammation. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3827 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital high-molecular-weight kininogen deficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 18
• Clinical variants (ClinVar): 149 total — 7 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 10
• MANE Select transcript: NM_001102416

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6383
Approved symbol	KNG1
Name	kininogen 1
Location	3q27.3
Locus type	gene with protein product
Status	Approved
Aliases	BK, HMWK
Ensembl gene	ENSG00000113889
Ensembl biotype	protein_coding
OMIM	612358
Entrez	3827

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 retained_intron

ENST00000287611, ENST00000447445, ENST00000644859, ENST00000645544, ENST00000897802, ENST00000897803, ENST00000897804, ENST00000897805, ENST00000897806, ENST00000897807, ENST00000897808, ENST00000897809

RefSeq mRNA: 3 — MANE Select: NM_001102416 NM_000893, NM_001102416, NM_001166451

CCDS: CCDS3281, CCDS43183, CCDS54695

Canonical transcript exons

ENST00000644859 — 10 exons

Exon	Start	End
ENSE00000781538	186722437	186722521
ENSE00000781539	186720105	186720215
ENSE00000871413	186727237	186727344
ENSE00001029482	186732502	186732674
ENSE00001029495	186739328	186739414
ENSE00001029497	186739099	186739206
ENSE00001151497	186731545	186731629
ENSE00001252220	186725088	186725260
ENSE00001874551	186741522	186744410
ENSE00003821982	186717359	186717737

Expression profiles

Bgee: expression breadth ubiquitous, 117 present calls, max score 99.84.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 6.4641 / max 2335.2534, expressed in 40 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40302	2.2272	22
40300	1.9881	22
40301	0.8780	15
40299	0.7682	14
40303	0.6026	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	99.84	gold quality
liver	UBERON:0002107	99.64	gold quality
right lobe of liver	UBERON:0001114	99.50	gold quality
nephron tubule	UBERON:0001231	98.54	gold quality
adult mammalian kidney	UBERON:0000082	96.66	gold quality
adult organism	UBERON:0007023	96.27	gold quality
kidney epithelium	UBERON:0004819	95.47	gold quality
metanephric glomerulus	UBERON:0004736	94.33	gold quality
kidney	UBERON:0002113	94.30	gold quality
renal glomerulus	UBERON:0000074	94.08	gold quality
metanephros cortex	UBERON:0010533	91.75	gold quality
cortex of kidney	UBERON:0001225	90.70	gold quality
metanephros	UBERON:0000081	86.67	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.55	gold quality
buccal mucosa cell	CL:0002336	65.51	gold quality
pancreatic ductal cell	CL:0002079	61.83	silver quality
rectum	UBERON:0001052	61.33	gold quality
oocyte	CL:0000023	59.09	gold quality
cranial nerve II	UBERON:0000941	56.85	silver quality
colonic epithelium	UBERON:0000397	56.79	gold quality
prefrontal cortex	UBERON:0000451	55.98	gold quality
endothelial cell	CL:0000115	55.53	gold quality
parotid gland	UBERON:0001831	55.04	gold quality
tibialis anterior	UBERON:0001385	54.70	silver quality
cerebellar vermis	UBERON:0004720	54.02	gold quality
deltoid	UBERON:0001476	53.00	silver quality
quadriceps femoris	UBERON:0001377	52.56	gold quality
adrenal tissue	UBERON:0018303	52.34	gold quality
myocardium	UBERON:0002349	52.29	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	51.54	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	61.95
E-HCAD-9	yes	58.92
E-MTAB-10553	yes	31.30
E-HCAD-10	yes	16.47
E-CURD-135	no	898.49
E-GEOD-131882	no	756.47
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AP1, CEBPB, CEBPD, GATA4, IRF6, NFKB, NR1H4

miRNA regulators (miRDB)

34 targeting KNG1, 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-433-3P	99.98	69.37	1203
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-142-5P	99.48	70.92	2416
HSA-MIR-5590-3P	99.48	70.91	2429
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-548L	99.06	70.90	2560
HSA-MIR-361-5P	98.95	70.16	1340
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-6731-3P	98.61	67.86	749
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334
HSA-MIR-12126	98.09	64.82	637
HSA-MIR-891A-3P	98.05	67.99	970
HSA-MIR-4638-3P	97.90	65.75	905
HSA-MIR-3074-3P	97.83	67.26	922
HSA-MIR-449C-3P	97.75	67.86	462
HSA-MIR-4329	97.68	66.26	1003

Literature-anchored findings (GeneRIF, showing 40)

• inhibition of vitronectin-mediated haptotaxis and haptoinvasion of MG-63 cells by domain 5 (PMID:11689005)
• Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII. (PMID:11792853)
• down-regulates cathepsin G-induced platelet activation by forming a complex with cathepsin G and thus prevents binding of cathepsin G to platelets (PMID:11920276)
• a defined region can abolish platelet adhesion to vitronectin and block platelet aggregation (PMID:11970955)
• the inhibitory role of HK domain 5 on platelet adhesion and aggregation; new anti-thrombotic compounds may become available on the basis of peptide Gly-486-Lys-502 of HK domain 5. (PMID:11970955)
• Ferritin binds to light chain of human H-kininogen and inhibits kallikrein-mediated bradykinin release. (PMID:12071855)
• kininogen has as role as a antithrombotic agent by inhibiting plasminogen activator inhibitor-1 (PMID:12082110)
• Bradykinin induces IL-6 production in human airway smooth muscle cells. (PMID:12594059)
• free HK, or HK in complex with prekallikrein but not in complex with factor XI, interacts with the endothelium and can maintain endothelial cell quiescence by preventing endothelial stimulation by thrombin. (PMID:12663668)
• transcriptional activation of the interleukin-8 promoter by bradykinin involves the prostanoid-independent activation of nuclear factor-kappaB, and prostanoid-dependent activation of activating protein-1 and nuclear factor-interleukin-6 (PMID:12748173)
• kininogen is a novel and direct target of farnesoid X receptor (PMID:12761213)
• Bradykinin is a powerful spasmogen via B(2) receptor activation in the normal and, especially, in the inflamed human gallbladder. (PMID:12851878)
• sequences in domain 5 of high molecular weight kininogen interact with heparin and zinc (PMID:12911595)
• High molecular weight kininogen regulates platelet-leukocyte interactions by bridging Mac-1 and glycoprotein Ib (PMID:12952972)
• His-Gly-Lys motif and lysine residue (Lys487) play essential roles in inhibition of cell adhesion and invasion in vitro and in prevention of metastasis of cancer cells in vivo (PMID:14506238)
• COX-2 induction by bradykinin in human pulmonary artery smooth muscle cells is mediated by the cyclic AMP response element through a novel autocrine loop involving endogenous prostaglandin E2, EP2 receptor, and EP4 receptor (PMID:14517215)
• binds with high specificity and affinity to microvascular endothelial cells, but with lower affinity to astrocytes; cytokeratin 1, u-PAR,and gC1qR were found to be high molecular weight kininogen binding proteins present at the surface of these cells (PMID:14597972)
• The rate of kallikrein formation by the assembly of factor XII, high molecular weight KNG and PK were similar in both heparinase-treated and non-treated HUVEC, indicating that heparan sulfate does not contribute significantly to HK binding to HUVEC. (PMID:14629481)
• physically disrupts the formation of a signaling complex containing uPAR, integrin alpha(v)beta3 or alpha5beta1, caveolin, and Src kinase Yes in endothelial cells in a manner that parallels its apoptotic effect (PMID:15044324)
• ACE-I-induced renoprotection, in the context of macrophage-stimulated mesangial cell scarring, is mediated, at least in part, via the actions of bradykinin. (PMID:15086463)
• high molecular weight kininogen has an antibacterial domain, called domain 5 (PMID:16091369)
• like filarial cystatins, T-KG inhibits ERK-dependent T cell proliferation, which suggests that it might have a role in immunosenescence (PMID:16140359)
• KNG modulate bone marrow derived stromal/preosteoblast cell proliferation and suppress etoposide-induced apoptosis through ERK and HSP27 activation, respectively. These results implicate a pathophysiologic role for KNG in patients with PD. (PMID:16598774)
• kininogen levels were found to be significantly lower in chorion laeve, placental plate chorion, fetal placenta and maternal placenta from women with Pregnancy Induced Hypertension when compared to those in similar tissues from normotensive pregnant women (PMID:17050061)
• The D5 active site of high molecular weight kininogen binds to endothelial cells and downregulates alpha(v)beta3 integrin bidirectional signaling and the downstream Rac1 activation pathway (PMID:17585065)
• Review highlights the release of bradykinin as a damage-associated endogenous signal that activates dendritic cells during inflammation. (PMID:17635790)
• interaction between LPS and high molecular weight kininogen (HK) (PMID:18083112)
• studies suggest that IL-1beta, BK, and TGF-beta1 impair IP receptor-mediated cAMP accumulation by multiple effects on different components of the signaling pathway and that these effects are PKA and p38 MAP kinase dependent. (PMID:18156442)
• 47kD HK levels, an indicator of bradykinin release, correlated with sepsis severity. (PMID:18330734)
• patients with IC with decreased THP and kininogen had worsening IC severity.Uromodulin and kininogen were significantly less present in the urine of the IC group vs the AC group. (PMID:18455532)
• a possible explanation for the potency of bradykinin in inducing ongoing airway inflammation (PMID:18783336)
• The authors show that bradykinin and the B(2)R play a role in early innate immune functions during listeria infection. (PMID:18810490)
• ferritin binds to HKa (cleaved high molecular weight kininogen) with high affinity (K(d) 13 nM). Further, ferritin antagonizes the antiangiogenic effects of HKa, enhancing the migration, assembly, and survival of HKa-treated endothelial cells (PMID:19126685)
• Bradykinin-induced dilation of human coronary arterioles requires NADPH oxidase-derived reactive oxygen species (PMID:19213944)
• Both single-locus and haplotype analyses indicated that the KNG1 gene was associated with essential hypertension and blood pressure traits in the Chinese male population. (PMID:19330902)
• expression of ACE is lowest in elderly women, despite the presence of similar BK degradation in pericardial fluid (PMID:19592120)
• KNG1 SNP rs710448 (allele frequency 42%) was associated with decreased risk (OR 0.44, 95% CI 0.3-0.8) among women but not men. (PMID:19716087)
• Bradykinin enhances the migration of chondrosarcoma cells by increasing alpha2beta1 integrin expression through the BK receptors/PLC/PKCdelta/NF-kappaB signal transduction pathway. (PMID:19885862)
• High-glucose stimulates tubular proinflammatory, profibrotic and angiogenic signals, which is partly mediated through bradykinin via MAPK signalling and partly through protein kinase C independent of bradykinin. (PMID:19923143)
• High molecular weight kininogen (HKa) mimics lipopolysaccharides by triggering a paracrine pathway in monocytes that depends on TNF-alpha and IL-1beta. Upregulation of tissue factor in monocytes by cleaved HKa is dependent on TNF-alpha and IL-1beta. (PMID:19966052)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Kng1	ENSMUSG00000022875
mus_musculus	Kng2	ENSMUSG00000060459
rattus_norvegicus	Kng1	ENSRNOG00000030387
rattus_norvegicus	Kng2	ENSRNOG00000065935
rattus_norvegicus	Kng2l1	ENSRNOG00000079266

Paralogs (3): FETUB (ENSG00000090512), HRG (ENSG00000113905), AHSG (ENSG00000145192)

Protein

Protein identifiers

Kininogen-1 — P01042 (reviewed: P01042)

Alternative names: Alpha-2-thiol proteinase inhibitor, Fitzgerald factor, High molecular weight kininogen, Williams-Fitzgerald-Flaujeac factor

All UniProt accessions (1): P01042

UniProt curated annotations — full annotation on UniProt →

Function. Kininogens are inhibitors of thiol proteases. HMW-kininogen plays an important role in blood coagulation by helping to position optimally prekallikrein and factor XI next to factor XII; HMW-kininogen inhibits the thrombin- and plasmin-induced aggregation of thrombocytes. LMW-kininogen inhibits the aggregation of thrombocytes. LMW-kininogen is in contrast to HMW-kininogen not involved in blood clotting. The active peptide bradykinin is a potent vasodilatator that is released from HMW-kininogen shows a variety of physiological effects: (A) influence in smooth muscle contraction, (B) induction of hypotension, (C) natriuresis and diuresis, (D) decrease in blood glucose level, (E) it is a mediator of inflammation and causes (E1) increase in vascular permeability, (E2) stimulation of nociceptors (4E3) release of other mediators of inflammation (e.g. prostaglandins), (F) it has a cardioprotective effect (directly via bradykinin action, indirectly via endothelium-derived relaxing factor action).

Subunit / interactions. Interacts (high molecular weight kininogen) (via amino acids 402-532) with triafestin-1 and triafestin-2, anticoagulant proteins from Triatoma infestans. Interacts (high molecular weight kininogen) (via amino acids 402-532) with short form salivary protein D7R1, an anticoagulant protein from Anopheles stephensi. Interacts (high molecular weight kininogen) (via amino acids 421-466 and 459-513) with haemaphysalin, an anticoagulant protein from Haemaphysalis longicornis.

Subcellular location. Secreted. Extracellular space.

Tissue specificity. Secreted in plasma. T-kinin is detected in malignant ovarian, colon and breast carcinomas, but not in benign tumors.

Post-translational modifications. Bradykinin is inactivated by ACE, which removes the dipeptide Arg-Phe from its C-terminus. Bradykinin is released from kininogen by plasma kallikrein. Hydroxylation of Pro-383 occurs prior to the release of bradykinin. Phosphorylated by FAM20C in the extracellular medium. N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. (Microbial infection) Bradykinin is generated upon proteolytic cleavage by S.pyogenes SpeB to produce hypotension during septic shock.

Disease relevance. High molecular weight kininogen deficiency (HMWK deficiency) [MIM:228960] Autosomal recessive coagulation defect. Patients with HWMK deficiency do not have a hemorrhagic tendency, but they exhibit abnormal surface-mediated activation of fibrinolysis. The disease is caused by variants affecting the gene represented in this entry. Angioedema, hereditary, 6 (HAE6) [MIM:619363] A form of angioedema, a disorder characterized by episodic local swelling involving subcutaneous or submucous tissue of the upper respiratory and gastrointestinal tracts, face, extremities, and genitalia. HAE6 is an autosomal dominant form with onset in adulthood. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. The T-kinin peptide is missing residues 378 to 380, probably as a result of a naturally occurring variant. The complete sequence of the T-kinin peptide is therefore ISRPPGFSPFR. This peptide is associated with malignant tumors but not with benign ones.

Isoforms (3)

UniProt ID	Names	Canonical?
P01042-1	HMW	yes
P01042-2	LMW
P01042-3	3

RefSeq proteins (3): NP_000884, NP_001095886, NP_001159923 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000010	Cystatin_dom	Domain
IPR002395	Kininogen	Family
IPR018073	Prot_inh_cystat_CS	Conserved_site
IPR027358	Kininogen-type_cystatin_dom	Domain
IPR046350	Cystatin_sf	Homologous_superfamily
IPR050735	Kininogen_Fetuin_HRG	Family

Pfam: PF00031

UniProt features (67 total): glycosylation site 12, sequence variant 10, disulfide bond 9, compositionally biased region 5, site 4, peptide 4, splice variant 4, chain 3, domain 3, repeat 3, modified residue 3, sequence conflict 3, region of interest 2, signal peptide 1, strand 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
2WOK	X-RAY DIFFRACTION	1.7
4ASR	X-RAY DIFFRACTION	1.9
4ASQ	X-RAY DIFFRACTION	1.99
4ECB	X-RAY DIFFRACTION	2.2
4ECC	X-RAY DIFFRACTION	2.2
1NY2	X-RAY DIFFRACTION	2.3
7QOX	X-RAY DIFFRACTION	2.32
7F6I	ELECTRON MICROSCOPY	2.8
5I25	X-RAY DIFFRACTION	2.85
8VJX	X-RAY DIFFRACTION	2.89
7F2O	ELECTRON MICROSCOPY	2.9
7F6H	ELECTRON MICROSCOPY	2.9
7EIB	ELECTRON MICROSCOPY	3
7QOT	X-RAY DIFFRACTION	3.24
6F27	SOLUTION NMR
6F3V	SOLID-STATE NMR
6F3W	SOLID-STATE NMR
6F3X	SOLID-STATE NMR
6F3Y	SOLID-STATE NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01042-F1	66.18	0.31

Antibody-complex structures (SAbDab): 1 — 7F2O

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 (4): 48 (not glycosylated); 379–380 (cleavage; by kallikrein); 387–388 (cleavage; by ace); 389–390 (cleavage; by kallikrein)

Post-translational modifications (3): 19, 332, 383

Disulfide bonds (9): 28–614, 83–94, 107–126, 142–145, 206–218, 229–248, 264–267, 328–340, 351–370

Glycosylation sites (12): 48, 169, 205, 294, 401, 533, 542, 546, 557, 571, 577, 628

Function

Pathways and Gene Ontology

Reactome pathways

21 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-416476	G alpha (q) signalling events
R-HSA-418594	G alpha (i) signalling events
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-9855719	Regulation of FXIIa and plasma kallikrein activity
R-HSA-9935598	FXIIa, PKa-dependent activation of coagulation pathway
R-HSA-9970672	FXIIa activates plasma kallikrein-kinin system
R-HSA-140837
R-HSA-109582	Hemostasis
R-HSA-140877
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-388396	GPCR downstream signalling
R-HSA-392499	Metabolism of proteins
R-HSA-500792	GPCR ligand binding
R-HSA-597592	Post-translational protein modification
R-HSA-76002	Platelet activation, signaling and aggregation
R-HSA-76005	Response to elevated platelet cytosolic Ca2+

MSigDB gene sets: 211 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_COAGULATION, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, MORF_RAD51L3, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GOBP_NEGATIVE_REGULATION_OF_COAGULATION, GOBP_WOUND_HEALING, BROWNE_HCMV_INFECTION_24HR_UP

GO Biological Process (12): inflammatory response (GO:0006954), negative regulation of cell adhesion (GO:0007162), positive regulation of cytosolic calcium ion concentration (GO:0007204), blood coagulation (GO:0007596), negative regulation of blood coagulation (GO:0030195), vasodilation (GO:0042311), positive regulation of apoptotic process (GO:0043065), negative regulation of proteolysis (GO:0045861), signal transduction (GO:0007165), hemostasis (GO:0007599), negative regulation of multicellular organismal process (GO:0051241), blood vessel diameter maintenance (GO:0097746)

GO Molecular Function (7): cysteine-type endopeptidase inhibitor activity (GO:0004869), signaling receptor binding (GO:0005102), hormone activity (GO:0005179), heparin binding (GO:0008201), zinc ion binding (GO:0008270), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), plasma membrane (GO:0005886), 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-12 pathways:

Category	Pathways
Metabolism of proteins	2
GPCR downstream signalling	2
Signaling by GPCR	2
Response to elevated platelet cytosolic Ca2+	1
Class A/1 (Rhodopsin-like receptors)	1
Post-translational protein modification	1
FXIIa activates plasma kallikrein-kinin system	1
Regulation of clotting cascade	1
Innate Immune System	1
Signal Transduction	1
GPCR ligand binding	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
defense response	1
cell adhesion	1
regulation of cell adhesion	1
negative regulation of cellular process	1
regulation of biological quality	1
hemostasis	1
wound healing	1
coagulation	1
blood coagulation	1
regulation of blood coagulation	1
negative regulation of coagulation	1
negative regulation of wound healing	1
negative regulation of hemostasis	1
blood vessel diameter maintenance	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
proteolysis	1
regulation of proteolysis	1
negative regulation of protein metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of body fluid levels	1
multicellular organismal process	1
negative regulation of biological process	1
regulation of multicellular organismal process	1
vascular process in circulatory system	1
blood circulation	1
regulation of tube diameter	1
cysteine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
protein binding	1
receptor ligand activity	1
glycosaminoglycan binding	1
sulfur compound binding	1
transition metal ion binding	1

Protein interactions and networks

STRING

4012 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KNG1	BDKRB1	P46663	999
KNG1	BDKRB2	P30411	999
KNG1	KLKB1	P03952	998
KNG1	KLK4	Q9Y5K2	997
KNG1	F11	P03951	995
KNG1	F12	P00748	990
KNG1	C1QBP	Q07021	987
KNG1	TAC1	P20366	987
KNG1	AGT	P01019	987
KNG1	ACE	P12821	960
KNG1	REN	P00797	951
KNG1	SERPING1	P05155	941
KNG1	AGTR1	P30556	938
KNG1	KLK1	P06870	935
KNG1	TRPA1	O75762	926

IntAct

41 interactions, top by confidence:

A	B	Type	Score
KNG1	Ance	psi-mi:“MI:0407”(direct interaction)	0.560
Ance	KNG1	psi-mi:“MI:0194”(cleavage reaction)	0.560
KNG1	C1QBP	psi-mi:“MI:0915”(physical association)	0.540
C1QBP	KNG1	psi-mi:“MI:0915”(physical association)	0.540
KNG1	C1QBP	psi-mi:“MI:0407”(direct interaction)	0.540
ZNF562	ISLR	psi-mi:“MI:0914”(association)	0.530
KNG1	CTSV	psi-mi:“MI:0914”(association)	0.530
KLKB1	KNG1	psi-mi:“MI:0407”(direct interaction)	0.440
FAM20C	KNG1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
	KNG1	psi-mi:“MI:0407”(direct interaction)	0.440
N	KNG1	psi-mi:“MI:0407”(direct interaction)	0.440
S	KNG1	psi-mi:“MI:0407”(direct interaction)	0.440
C1QBP	KNG1	psi-mi:“MI:0407”(direct interaction)	0.440
KNG1	F12	psi-mi:“MI:0407”(direct interaction)	0.440
F12	KNG1	psi-mi:“MI:0407”(direct interaction)	0.440
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
KNG1	Lamc1	psi-mi:“MI:0915”(physical association)	0.400
	KNG1	psi-mi:“MI:0915”(physical association)	0.370
COPS6	DDX3X	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
STX17	A2ML1	psi-mi:“MI:0914”(association)	0.350
SNX27	IGLL5	psi-mi:“MI:0914”(association)	0.350
GDPD1	CP	psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (73): KNG1 (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), ANAPC1 (Affinity Capture-MS), CAPN1 (Affinity Capture-MS), CTSO (Affinity Capture-MS), P3H4 (Affinity Capture-MS), CTSV (Affinity Capture-MS), ANAPC5 (Affinity Capture-MS), PPP2CA (Affinity Capture-MS), LEPREL2 (Affinity Capture-MS), TCTN1 (Affinity Capture-MS), CAPNS1 (Affinity Capture-MS), HLA-DPB1 (Affinity Capture-MS), VHL (Affinity Capture-MS), KNG1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1S3PBB7, B6S2X0, O08677, O70159, P01042, P01044, P01045, P01048, P02765, P08932, P08934, P12763, P24090, P25230, P29695, P29699, P29700, P29701, P33046, P49928, P49929, P49931, P51437, P54229, P80191, P97515, Q1KLX0, Q1KLX3, Q1KLX5, Q1KLX6, Q1KLX7, Q1KLX9, Q1KLY0, Q1KLY2, Q1KLY4, Q1KLY6, Q1KLY7, Q1KLY8, Q58D62, Q5KQS1

Diamond homologs: A0A1S3PBB7, O08677, P01042, P01044, P01045, P01048, P08932, P08934, P83856, P83857, G5ECM9, P90698, Q6QD55, E3P6P3, J3SE80, O19092, O19093, O76096, O89098, O97862, P01034, P01035, P01037, P01038, P08935, P09228, P14841, P21460, P22085, P35481, P81061, Q15828, Q2XXN5, Q6T6T4, Q7M429, Q80Y72, Q91195, Q98967, Q9H114, Q9JM84

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
KNG1	“up-regulates activity”	“GPIb-IX-V complex”	binding
KLKB1	“up-regulates activity”	KNG1	cleavage
KNG1	“up-regulates activity”	BDKRB2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	2
Uncertain significance	100
Likely benign	16
Benign	11

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1162306	NM_001102416.3(KNG1):c.1136T>A (p.Met379Lys)	Pathogenic
1162307	NM_001102416.3(KNG1):c.1720C>G (p.Pro574Ala)	Pathogenic
1803726	NM_001102416.3(KNG1):c.1165C>T (p.Arg389Ter)	Pathogenic
2578035	NM_001102416.3(KNG1):c.306+2T>A	Pathogenic
2578036	NM_001102416.3(KNG1):c.1038+1G>A	Pathogenic
2578037	NM_001102416.3(KNG1):c.718C>T (p.Arg240Ter)	Pathogenic
572	NM_001102416.3(KNG1):c.586C>T (p.Arg196Ter)	Pathogenic
4081477	NM_001102416.3(KNG1):c.1080G>A (p.Trp360Ter)	Likely pathogenic
4540961	NM_001102416.3(KNG1):c.1565_1566del (p.Glu522fs)	Likely pathogenic

SpliceAI

1374 predictions. Top by Δscore:

Variant	Effect	Δscore
3:186717734:GACG:G	donor_gain	1.0000
3:186717735:ACGG:A	donor_loss	1.0000
3:186717738:G:C	donor_loss	1.0000
3:186717738:G:GG	donor_gain	1.0000
3:186717739:T:A	donor_loss	1.0000
3:186717740:GAGT:G	donor_loss	1.0000
3:186720133:A:G	acceptor_gain	1.0000
3:186720213:GCA:G	donor_gain	1.0000
3:186720216:G:GG	donor_gain	1.0000
3:186722431:TTTTA:T	acceptor_loss	1.0000
3:186722433:TTA:T	acceptor_loss	1.0000
3:186722435:A:AG	acceptor_gain	1.0000
3:186722435:AGGC:A	acceptor_loss	1.0000
3:186722436:G:GA	acceptor_loss	1.0000
3:186722436:G:GG	acceptor_gain	1.0000
3:186722436:GGCC:G	acceptor_gain	1.0000
3:186722477:G:GG	donor_gain	1.0000
3:186725081:T:A	acceptor_gain	1.0000
3:186725085:A:AG	acceptor_gain	1.0000
3:186725085:AAGCC:A	acceptor_gain	1.0000
3:186725086:A:AG	acceptor_gain	1.0000
3:186725087:G:GG	acceptor_gain	1.0000
3:186725087:GCC:G	acceptor_gain	1.0000
3:186725087:GCCGA:G	acceptor_gain	1.0000
3:186725237:G:GT	donor_gain	1.0000
3:186727343:GT:G	donor_gain	1.0000
3:186731536:A:AG	acceptor_gain	1.0000
3:186731537:A:G	acceptor_gain	1.0000
3:186739093:TTTCA:T	acceptor_loss	1.0000
3:186739094:TTCAG:T	acceptor_loss	1.0000

AlphaMissense

4291 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:186720182:G:C	W91C	0.995
3:186720182:G:T	W91C	0.995
3:186722449:T:A	C107S	0.993
3:186722450:G:C	C107S	0.993
3:186731557:T:A	C229S	0.992
3:186731558:G:C	C229S	0.992
3:186739369:G:C	W360C	0.992
3:186739369:G:T	W360C	0.992
3:186739340:T:A	C351S	0.991
3:186739341:G:C	C351S	0.991
3:186722449:T:C	C107R	0.989
3:186717664:T:C	L41P	0.988
3:186720180:T:A	W91R	0.988
3:186720180:T:C	W91R	0.988
3:186727324:T:A	C218S	0.986
3:186727325:G:C	C218S	0.986
3:186739346:G:C	A353P	0.986
3:186725259:A:C	Q188P	0.985
3:186727288:T:A	C206S	0.985
3:186727289:G:C	C206S	0.985
3:186739136:C:A	A323D	0.985
3:186739340:T:C	C351R	0.985
3:186739397:T:A	C370S	0.984
3:186739398:G:C	C370S	0.984
3:186731557:T:C	C229R	0.983
3:186739341:G:A	C351Y	0.983
3:186739342:C:G	C351W	0.982
3:186731614:T:A	C248S	0.981
3:186731615:G:C	C248S	0.981
3:186741549:T:C	F385L	0.981

dbSNP variants (sampled 300 via entrez): RS1000136903 (3:186728611 G>A), RS1000307897 (3:186734374 A>G), RS1000311612 (3:186737987 T>C), RS1000505855 (3:186728808 C>T), RS1000580490 (3:186740649 G>A), RS1000761337 (3:186737785 C>T), RS1000796364 (3:186719208 A>C,G), RS1000801163 (3:186720900 C>T), RS1000999166 (3:186726841 A>C,G), RS1001046447 (3:186739525 T>C), RS1001132264 (3:186718894 A>T), RS1001162799 (3:186730198 G>A), RS1001303333 (3:186728185 G>A), RS1001324089 (3:186743505 G>C), RS1001380292 (3:186740012 C>G,T)

Disease associations

OMIM: gene MIM:612358 | disease phenotypes: MIM:619363, MIM:228960

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital high-molecular-weight kininogen deficiency	Definitive	Autosomal recessive
angioedema, hereditary, 6	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital high-molecular-weight kininogen deficiency	Definitive	AR

Mondo (3): angioedema, hereditary, 6 (MONDO:0023660), congenital high-molecular-weight kininogen deficiency (MONDO:0009234), hereditary angioedema with normal C1Inh (MONDO:0100567)

Orphanet (2): Congenital high-molecular-weight kininogen deficiency (Orphanet:483), Hereditary angioedema with normal C1Inh (Orphanet:528647)

HPO phenotypes

10 total (10 of 10 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000282	Facial edema
HP:0003596	Middle age onset
HP:0003645	Prolonged partial thromboplastin time
HP:0005527	Reduced kininogen activity
HP:0007514	Edema of the dorsum of hands
HP:0011462	Young adult onset
HP:0031244	Swollen lip
HP:0100665	Angioedema

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST000631_2	Activated partial thromboplastin time	1.000000e-21
GCST000812_3	Adiponectin levels	2.000000e-09
GCST001574_6	Activated partial thromboplastin time	2.000000e-203
GCST002714_2	Plasma renin activity levels	9.000000e-09
GCST003390_1	Thrombosis	2.000000e-06
GCST004124_2	Factor XI	2.000000e-302
GCST005057_3	Small vessel stroke	9.000000e-06
GCST005934_3	Neuropathic pain in head and neck cancer	6.000000e-09
GCST005984_10	Glomerular filtration rate	5.000000e-09
GCST006018_7	Activated partial thromboplastin time	4.000000e-49
GCST007344_111	Estimated glomerular filtration rate	2.000000e-10
GCST007344_6	Estimated glomerular filtration rate	6.000000e-10
GCST007344_98	Estimated glomerular filtration rate	3.000000e-08
GCST007876_14	Estimated glomerular filtration rate	6.000000e-16
GCST008058_74	Estimated glomerular filtration rate	6.000000e-24
GCST008059_1	Estimated glomerular filtration rate	1.000000e-17
GCST008060_9	Estimated glomerular filtration rate	2.000000e-08
GCST008747_96	Estimated glomerular filtration rate	9.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004502	adiponectin measurement
EFO:0006828	plasma renin activity measurement
EFO:0003907	deep vein thrombosis
EFO:0004694	factor XI measurement
EFO:1001504	small vessel stroke
EFO:0005762	neuropathic pain

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537060	Flaujeac factor deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs710446	Toxicity	3	hormonal contraceptives for systemic use

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs710446	KNG1	3	2.50	1	hormonal contraceptives for systemic use

Binding affinities (BindingDB)

59 measured of 60 human assays (60 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[1-[[(1S)-5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]carbamoyl]cyclopropyl]pyrimidine-5-carboxamide	IC50	0.1 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[(1S)-5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]carbamoyl]cyclopropyl]-3-methoxy-1,2-oxazole-5-carboxamide	IC50	0.1 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[(1S)-5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]carbamoyl]cyclopropyl]-2-methoxypyrimidine-5-carboxamide	IC50	0.2 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[3-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]carbamoyl]cyclopropyl]-3-methoxy-1,2-oxazole-5-carboxamide	IC50	0.2 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[3-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]carbamoyl]cyclopropyl]pyridazine-4-carboxamide	IC50	0.2 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[3-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]carbamoyl]cyclopropyl]-2-methoxypyrimidine-5-carboxamide	IC50	0.2 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[6-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1-benzofuran-3-yl]carbamoyl]cyclopropyl]-2-methoxypyrimidine-5-carboxamide	IC50	0.2 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[3-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]carbamoyl]cyclopropyl]-2-methoxypyrimidine-5-carboxamide	IC50	0.2 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[6-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-2,3-dihydro-1-benzothiophen-3-yl]carbamoyl]cyclopropyl]pyrimidine-5-carboxamide	IC50	0.2 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[6-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-2,3-dihydro-1-benzothiophen-3-yl]carbamoyl]cyclopropyl]-3-methoxy-1,2-oxazole-5-carboxamide	IC50	0.2 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[(1S)-5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]carbamoyl]cyclopropyl]-1,2-oxazole-5-carboxamide	IC50	0.3 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[3-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]carbamoyl]cyclopropyl]-1,2-oxazole-5-carboxamide	IC50	0.3 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[3-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]carbamoyl]cyclopropyl]-3-methoxy-1,2-oxazole-5-carboxamide	IC50	0.3 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[(1S)-5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]carbamoyl]cyclopropyl]pyridazine-4-carboxamide	IC50	0.4 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[3-[[(1S)-5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]carbamoyl]oxetan-3-yl]pyrimidine-5-carboxamide	IC50	0.4 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[3-[[(1S)-5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]carbamoyl]oxetan-3-yl]-3-methoxy-1,2-oxazole-5-carboxamide	IC50	0.4 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[3-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]carbamoyl]cyclopropyl]-1,2-oxazole-5-carboxamide	IC50	0.4 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[3-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]carbamoyl]cyclopropyl]-3-methyl-1,2-oxazole-5-carboxamide	IC50	0.4 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[3-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]-1-[(2,2,2-trifluoroacetyl)amino]cyclopropane-1-carboxamide	IC50	0.5 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[3-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]-1-[(2,2,2-trifluoroacetyl)amino]cyclopropane-1-carboxamide	IC50	0.5 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-7-fluoro-2,3-dihydro-1H-inden-1-yl]-1-[(2,2,2-trifluoroacetyl)amino]cyclopropane-1-carboxamide	IC50	0.5 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[5-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-1-methyl-2,3-dihydroinden-1-yl]-1-[(2,2,2-trifluoroacetyl)amino]cyclopropane-1-carboxamide	IC50	0.5 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-7-fluoro-2,3-dihydro-1H-inden-1-yl]carbamoyl]cyclopropyl]-2-methoxypyrimidine-5-carboxamide	IC50	0.5 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-7-fluoro-2,3-dihydro-1H-inden-1-yl]carbamoyl]cyclopropyl]-3-methoxy-1,2-oxazole-5-carboxamide	IC50	0.5 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[6-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-2,3-dihydro-1-benzothiophen-3-yl]carbamoyl]cyclopropyl]-1,2-oxazole-5-carboxamide	IC50	0.5 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[(1S)-5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]-1-[(2,2,2-trifluoroacetyl)amino]cyclopropane-1-carboxamide	IC50	0.6 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-1-methyl-2,3-dihydroinden-1-yl]-1-[(2,2,2-trifluoroacetyl)amino]cyclopropane-1-carboxamide	IC50	0.6 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-7-fluoro-2,3-dihydro-1H-inden-1-yl]carbamoyl]cyclopropyl]pyridazine-4-carboxamide	IC50	0.6 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[6-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-2,3-dihydro-1-benzothiophen-3-yl]-1-[(2,2,2-trifluoroacetyl)amino]cyclopropane-1-carboxamide	IC50	0.8 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]-1-[(2,2,2-trifluoroacetyl)amino]cyclopropane-1-carboxamide	IC50	2 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[6-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1-benzothiophen-3-yl]-1-[(2,2,2-trifluoroacetyl)amino]cyclopropane-1-carboxamide	IC50	2.3 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[3-[[(1S)-5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]carbamoyl]oxetan-3-yl]-1,2-oxazole-5-carboxamide	IC50	2.7 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[(1S)-5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]carbamoyl]cyclopropyl]-5-methyl-1,3,4-oxadiazole-2-carboxamide	IC50	3.4 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[6-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-2,3-dihydro-1-benzofuran-3-yl]-1-[(2,2,2-trifluoroacetyl)amino]cyclopropane-1-carboxamide	IC50	3.6 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
tert-butyl N-[1-[[3-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]carbamoyl]cyclopropyl]carbamate	IC50	3.6 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[6-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-1,2,3,4-tetrahydronaphthalen-1-yl]-1-[(2,2,2-trifluoroacetyl)amino]cyclopropane-1-carboxamide	IC50	4 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[6-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1-benzofuran-3-yl]carbamoyl]cyclopropyl]-3-methoxy-1,2-oxazole-5-carboxamide	IC50	4 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[3-[[(1S)-5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]carbamoyl]oxetan-3-yl]-3-methyl-1,2-oxazole-5-carboxamide	IC50	4.3 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[6-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1-benzofuran-3-yl]-1-[(2,2,2-trifluoroacetyl)amino]cyclopropane-1-carboxamide	IC50	4.5 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[6-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1-benzofuran-3-yl]carbamoyl]cyclopropyl]pyridazine-4-carboxamide	IC50	4.7 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[1-[[6-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-2,3-dihydro-1-benzothiophen-3-yl]carbamoyl]cyclopropyl]-5-methyl-1,3,4-oxadiazole-2-carboxamide	IC50	4.8 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
1-amino-N-[(1S)-5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]cyclopropane-1-carboxamide	IC50	5 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
tert-butyl N-[1-[[3-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]carbamoyl]cyclopropyl]carbamate	IC50	5.8 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
1-amino-N-[6-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-2,3-dihydro-1-benzothiophen-3-yl]cyclopropane-1-carboxamide	IC50	17.4 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[(1S)-5-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]-3-[(2,2,2-trifluoroacetyl)amino]oxetane-3-carboxamide	IC50	24.4 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[7-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-3,4-dihydro-2H-chromen-4-yl]-1-[(2,2,2-trifluoroacetyl)amino]cyclopropane-1-carboxamide	IC50	24.6 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[7-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydro-2H-chromen-4-yl]-1-[(2,2,2-trifluoroacetyl)amino]cyclopropane-1-carboxamide	IC50	24.8 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
N-[(1S)-5-[5-chloro-3-fluoro-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,3-dihydro-1H-inden-1-yl]-3-[(2,2,2-trifluoroacetyl)amino]oxetane-3-carboxamide	IC50	28.6 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
methyl 2-chloro-6-[1-[[1-[(2,2,2-trifluoroacetyl)amino]cyclopropanecarbonyl]amino]-2,3-dihydro-1H-inden-5-yl]benzoate	IC50	47.4 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives
1-amino-N-[3-[5-chloro-3-fluoro-2-(2-methyltetrazol-5-yl)phenyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]cyclopropane-1-carboxamide	IC50	61.1 nM	US-8592426: Aryl-benzocycloalkyl amide derivatives

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
FR 173657	decreases reaction, increases activity, affects binding	2
Benzo(a)pyrene	decreases expression	2
Calcium	increases abundance, affects abundance, affects reaction	2
Lidocaine	affects cotreatment, decreases reaction, increases expression, decreases activity	2
Propofol	affects cotreatment, decreases reaction, increases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases methylation, affects expression, decreases expression	2
dicrotophos	decreases expression	1
7-ketocholesterol	affects cotreatment, decreases expression	1
2,4,6-tribromophenol	increases expression	1
methyleugenol	decreases expression	1
decabromobiphenyl ether	increases expression	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	increases expression	1
perfluorooctanoic acid	decreases expression	1
periodate-oxidized adenosine	affects expression	1
nafamostat	increases expression, affects cotreatment, decreases reaction	1
icatibant	affects binding, decreases reaction, increases activity	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases activity, increases phosphorylation, increases abundance	1
perfluoro-n-nonanoic acid	decreases expression	1
corosolic acid	increases expression	1
MEN 11270	affects binding, decreases reaction, increases activity	1
LF 16-0687	affects binding, decreases reaction, increases activity	1
GW 4064	decreases reaction, increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
Irinotecan	affects cotreatment, decreases expression	1
Olanzapine	affects phosphorylation	1
Acetaminophen	decreases expression	1
Angiotensin-Converting Enzyme Inhibitors	increases expression	1

Clinical trials (associated diseases)

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