hereditary angioedema with normal C1Inh

disease

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Also known as HAE with normal C1 inhibitorHAE with normal C1Inhhereditary angioedema with normal C1 inhibitorhereditary angioneurotic edema with normal C1 inhibitorhereditary angioneurotic edema with normal C1Inh

Summary

hereditary angioedema with normal C1Inh (MONDO:0100567) is a disease with 16 cohort genes. The dominant Reactome pathway is Regulation of FXIIa and plasma kallikrein activity (3 cohort genes).

At a glance

Cohort genes: 16
ClinVar variants: 20
Phenotypes (HPO): 13

Clinical features

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0100665	Angioedema	Very frequent (80-99%)
HP:0000282	Facial edema	Frequent (30-79%)
HP:0005225	Intestinal edema	Frequent (30-79%)
HP:0010742	Edema of the upper limbs	Frequent (30-79%)
HP:0012027	Laryngeal edema	Frequent (30-79%)
HP:0001892	Abnormal bleeding	Occasional (5-29%)
HP:0002027	Abdominal pain	Occasional (5-29%)
HP:0002099	Asthma	Occasional (5-29%)
HP:0031188	Genital edema	Occasional (5-29%)
HP:0040315	Tongue edema	Occasional (5-29%)
HP:0001025	Urticaria	Excluded (0%)
HP:0045042	Decreased circulating complement C4 concentration	Excluded (0%)
HP:0012378	Fatigue	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary angioedema with normal C1Inh
Mondo ID	MONDO:0100567
Orphanet	528647
UMLS	C1960459
MedGen	743231
GARD	0022195
Is cancer (heuristic)	no

Also known as: HAE with normal C1 inhibitor · HAE with normal C1Inh · hereditary angioedema with normal C1 inhibitor · hereditary angioneurotic edema with normal C1 inhibitor · hereditary angioneurotic edema with normal C1Inh

Data availability: 20 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › dermatitis › urticaria › angioedema › hereditary angioedema › hereditary angioedema with normal C1Inh

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

20 retrieved; paginated sample, class counts are floors:

16 not provided, 2 pathogenic, 1 likely benign, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
827586	NM_000789.4(ACE):c.1473_1475delinsA (p.Asp491fs)	ACE	Pathogenic	criteria provided, multiple submitters, no conflicts
827591	NM_000301.5(PLG):c.2183T>A (p.Val728Glu)	PLG	Pathogenic	no assertion criteria provided
827597	NM_000295.5(SERPINA1):c.1070T>C (p.Val357Ala)	SERPINA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
827590	NM_001102416.3(KNG1):c.421G>A (p.Asp141Asn)	KNG1	Likely benign	criteria provided, single submitter
827587	NM_000789.4(ACE):c.1744C>A (p.Gln582Lys)	ACE	not provided	no classification provided
827588	NM_001379692.1(BDKRB2):c.*21T>A	BDKRB2	not provided	no classification provided
827599	NM_001734.5(C1S):c.34T>C (p.Trp12Arg)	C1S	not provided	no classification provided
827594	NM_001308.3(CPN1):c.1219G>A (p.Glu407Lys)	CPN1	not provided	no classification provided
827595	NM_001935.4(DPP4):c.571G>T (p.Glu191Ter)	DPP4	not provided	no classification provided
827604	NM_001972.4(ELANE):c.*2A>G	ELANE	not provided	no classification provided
827592	NM_001648.2(KLK3):c.116dup (p.Val40fs)	KLK3	not provided	no classification provided
827593	NM_001648.2(KLK3):c.*4C>T	KLK3	not provided	no classification provided
827589	NM_001102416.3(KNG1):c.-85T>A	KNG1	not provided	no classification provided
827602	NM_006121.4(KRT1):c.*197T>G	KRT1	not provided	no classification provided
827605	NM_000250.2(MPO):c.-56C>T	LOC106694315	not provided	no classification provided
827598	NM_000930.5(PLAT):c.1323_1325delinsTAT (p.Trp441_Thr442delinsCysMet)	PLAT	not provided	no classification provided
827603	NM_000312.4(PROC):c.245T>C (p.Phe82Ser)	PROC	not provided	no classification provided
827596	NM_000295.5(SERPINA1):c.349C>T (p.His117Tyr)	SERPINA1	not provided	no classification provided
827600	NM_001318789.2(TLR2):c.582G>C (p.Leu194Phe)	TLR2	not provided	no classification provided
827601	NM_138554.5(TLR4):c.2474G>A (p.Gly825Glu)	TLR4	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 24 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TLR4	Orphanet:117	Behçet disease
C1S	Orphanet:169147	Immunodeficiency due to a classical component pathway complement deficiency
C1S	Orphanet:75392	Periodontal Ehlers-Danlos syndrome
ACE	Orphanet:97369	Renal tubular dysgenesis of genetic origin
ELANE	Orphanet:2686	Cyclic neutropenia
ELANE	Orphanet:486	Autosomal dominant severe congenital neutropenia
KLKB1	Orphanet:749	Congenital prekallikrein deficiency
KNG1	Orphanet:483	Congenital high-molecular-weight kininogen deficiency
KNG1	Orphanet:599418	Hereditary angioedema with normal C1Inh not related to F12 or PLG variant
KRT1	Orphanet:2199	Epidermolytic palmoplantar keratoderma
KRT1	Orphanet:281139	Annular epidermolytic ichthyosis
KRT1	Orphanet:281190	Congenital reticular ichthyosiform erythroderma
KRT1	Orphanet:312	Autosomal dominant epidermolytic ichthyosis
KRT1	Orphanet:50942	Striate palmoplantar keratoderma
KRT1	Orphanet:530838	KRT1-related diffuse nonepidermolytic keratoderma
KRT1	Orphanet:538574	Palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome
KRT1	Orphanet:79503	Ichthyosis hystrix of Curth-Macklin
SERPINA1	Orphanet:178396	Hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation
SERPINA1	Orphanet:586	Cystic fibrosis
SERPINA1	Orphanet:60	Alpha-1-antitrypsin deficiency
PLAT	Orphanet:480528	Lethal hydranencephaly-diaphragmatic hernia syndrome
PLG	Orphanet:537072	PLG-related hereditary angioedema with normal C1Inh
PLG	Orphanet:722	Hypoplasminogenemia
PROC	Orphanet:745	Severe hereditary thrombophilia due to congenital protein C deficiency

Cohort genes → proteins

16 cohort genes, 16 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	16

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BDKRB2	HGNC:1030	ENSG00000168398	P30411	B2 bradykinin receptor	clinvar
TLR2	HGNC:11848	ENSG00000137462	O60603	Toll-like receptor 2	clinvar
TLR4	HGNC:11850	ENSG00000136869	O00206	Toll-like receptor 4	clinvar
C1S	HGNC:1247	ENSG00000182326	P09871	Complement C1s subcomponent	clinvar
CPN1	HGNC:2312	ENSG00000120054	P15169	Carboxypeptidase N catalytic chain	clinvar
ACE	HGNC:2707	ENSG00000159640	P12821	Angiotensin-converting enzyme	clinvar
DPP4	HGNC:3009	ENSG00000197635	P27487	Dipeptidyl peptidase 4	clinvar
ELANE	HGNC:3309	ENSG00000197561	P08246	Neutrophil elastase	clinvar
KLK3	HGNC:6364	ENSG00000142515	P07288	Prostate-specific antigen	clinvar
KLKB1	HGNC:6371	ENSG00000164344	P03952	Plasma kallikrein	clinvar
KNG1	HGNC:6383	ENSG00000113889	P01042	Kininogen-1	clinvar
KRT1	HGNC:6412	ENSG00000167768	P04264	Keratin, type II cytoskeletal 1	clinvar
SERPINA1	HGNC:8941	ENSG00000197249	P01009	Alpha-1-antitrypsin	clinvar
PLAT	HGNC:9051	ENSG00000104368	P00750	Tissue-type plasminogen activator	clinvar
PLG	HGNC:9071	ENSG00000122194	P00747	Plasminogen	clinvar
PROC	HGNC:9451	ENSG00000115718	P04070	Vitamin K-dependent protein C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BDKRB2	B2 bradykinin receptor	Receptor for bradykinin.
TLR2	Toll-like receptor 2	Cooperates with LY96 to mediate the innate immune response to bacterial lipoproteins and other microbial cell wall components.
TLR4	Toll-like receptor 4	Transmembrane receptor that functions as a pattern recognition receptor recognizing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) to induce innate immune responses via downstream signaling pathways.
C1S	Complement C1s subcomponent	Component of the complement C1 complex, a multiprotein complex that initiates the classical pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the ad…
CPN1	Carboxypeptidase N catalytic chain	Protects the body from potent vasoactive and inflammatory peptides containing C-terminal Arg or Lys (such as kinins or anaphylatoxins) which are released into the circulation.
ACE	Angiotensin-converting enzyme	Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte hom…
DPP4	Dipeptidyl peptidase 4	Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation.
ELANE	Neutrophil elastase	Serine protease that modifies the functions of natural killer cells, monocytes and granulocytes.
KLK3	Prostate-specific antigen	Hydrolyzes semenogelin-1 thus leading to the liquefaction of the seminal coagulum.
KLKB1	Plasma kallikrein	Participates in the surface-dependent activation of blood coagulation.
KNG1	Kininogen-1	Kininogens are inhibitors of thiol proteases.
KRT1	Keratin, type II cytoskeletal 1	May regulate the activity of kinases such as PKC and SRC via binding to integrin beta-1 (ITB1) and the receptor of activated protein C kinase 1 (RACK1).
SERPINA1	Alpha-1-antitrypsin	Inhibitor of serine proteases.
PLAT	Tissue-type plasminogen activator	Converts the abundant, but inactive, zymogen plasminogen to plasmin by hydrolyzing a single Arg-Val bond in plasminogen.
PLG	Plasminogen	Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation.
PROC	Vitamin K-dependent protein C	Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids.

Protein-family classification

Druggable: 11 · Difficult: 0 · Unknown: 5 · Druggable fraction: 0.69

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	10	22.9×	4e-12
GPCR	1	1.5×	0.742
Other/Unknown	5	0.6×	0.987

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BDKRB2	GPCR	yes		GPCR_Rhodpsn, Brdyknn_rcpt, Brdyknn_2_rcpt
TLR2	Other/Unknown	no		TIR_dom, Cys-rich_flank_reg_C, Leu-rich_rpt
TLR4	Other/Unknown	no		TIR_dom, Cys-rich_flank_reg_C, Leu-rich_rpt
C1S	Protease	yes	3.4.21.42	EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, CUB_dom
CPN1	Protease	yes	3.4.17.3	Peptidase_M14, CarboxyPept-like_regulatory, M14_CPN
ACE	Protease	yes	3.4.15.1	Peptidase_M2
DPP4	Protease	yes	3.4.14.5	Peptidase_S9_cat, Peptidase_S9B_N, Pept_S9_AS
ELANE	Protease	yes	3.4.21.37	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
KLK3	Protease	yes	3.4.21.77	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
KLKB1	Protease	yes	3.4.21.34	Apple, Trypsin_dom, Peptidase_S1A
KNG1	Other/Unknown	no		Cystatin_dom, Kininogen, Prot_inh_cystat_CS
KRT1	Other/Unknown	no		Keratin_II, IF_conserved, Keratin_2_head
SERPINA1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom
PLAT	Protease	yes	3.4.21.68	Kringle, Fibronectin_type1, EGF
PLG	Protease	yes	3.4.21.7	Kringle, Trypsin_dom, Peptidase_S1A
PROC	Protease	yes	3.4.21.69	EGF-type_Asp/Asn_hydroxyl_site, GLA_domain, EGF

Expression context

Cohort genes with no expression data: 0.

15 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	16
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	7
liver	6
monocyte	3
pancreatic ductal cell	2
stromal cell of endometrium	2
leukocyte	2
mononuclear cell	2
primordial germ cell in gonad	2
mucosa of urinary bladder	1
parietal pleura	1
pericardium	1
ileal mucosa	1
left testis	1
right testis	1
calcaneal tendon	1
jejunal mucosa	1
parotid gland	1
bone marrow	1
bone marrow cell	1
frontal pole	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BDKRB2	215	broad	marker	stromal cell of endometrium, mucosa of urinary bladder, pancreatic ductal cell
TLR2	214	broad	marker	monocyte, mononuclear cell, leukocyte
TLR4	233	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
C1S	287	ubiquitous	marker	pericardium, right lobe of liver, parietal pleura
CPN1	35	tissue_specific	marker	right lobe of liver, liver, primordial germ cell in gonad
ACE	177	ubiquitous	marker	ileal mucosa, right testis, left testis
DPP4	219	ubiquitous	marker	calcaneal tendon, jejunal mucosa, parotid gland
ELANE	124	tissue_specific	marker	bone marrow, bone marrow cell, monocyte
KLK3	155	tissue_specific	marker	prostate gland, frontal pole, paraflocculus
KLKB1	196	tissue_specific	yes	right lobe of liver, liver, primordial germ cell in gonad
KNG1	117	tissue_specific	marker	renal medulla, liver, right lobe of liver
KRT1	177	tissue_specific	marker	mammalian vulva, upper leg skin, skin of hip
SERPINA1	133	ubiquitous	marker	right lobe of liver, liver, blood
PLAT	273	ubiquitous	marker	stromal cell of endometrium, pancreatic ductal cell, urethra
PLG	174	tissue_specific	marker	right lobe of liver, liver, adult organism
PROC	165	broad	marker	right lobe of liver, liver, adult mammalian kidney

Protein interactions among cohort

Intra-cohort edges: 16.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TLR4	6,974
TLR2	5,037
KNG1	4,126
DPP4	4,076
ACE	3,659
SERPINA1	3,617
PLG	3,441
PLAT	3,028
KLK3	2,858
ELANE	2,758

Intra-cohort edges

A	B	Sources
ACE	BDKRB2	biogrid_interaction, string_interaction
ACE	CPN1	string_interaction
ACE	DPP4	string_interaction
ACE	KNG1	string_interaction
BDKRB2	CPN1	string_interaction
BDKRB2	KLKB1	string_interaction
BDKRB2	KNG1	intact, string_interaction
CPN1	KNG1	string_interaction
ELANE	KNG1	biogrid_interaction
ELANE	SERPINA1	biogrid_interaction, intact, string_interaction
KLK3	SERPINA1	biogrid_interaction, string_interaction
KLKB1	KNG1	biogrid_interaction, intact, string_interaction
KNG1	KRT1	string_interaction
KNG1	SERPINA1	string_interaction
PLAT	PLG	string_interaction
TLR2	TLR4	string_interaction

Structural data

PDB: 16 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DPP4	P27487	117
ACE	P12821	97
PLG	P00747	49
SERPINA1	P01009	46
ELANE	P08246	38
KLKB1	P03952	22
KNG1	P01042	19
TLR4	O00206	15
C1S	P09871	14
PROC	P04070	12
PLAT	P00750	11
TLR2	O60603	7
BDKRB2	P30411	6
KLK3	P07288	6
KRT1	P04264	3
CPN1	P15169	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 97. Enrichment computed across 16 evidence-associated genes (16 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of FXIIa and plasma kallikrein activity	3	214.1×	3e-05	KLKB1, KNG1, KRT1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	5	27.0×	4e-05	KLK3, KNG1, SERPINA1, PLG, PROC
Activation of Matrix Metalloproteinases	3	57.9×	6e-04	ELANE, KLKB1, PLG
Regulation of Complement cascade	3	43.7×	1e-03	C1S, CPN1, ELANE
R-HSA-140837	2	178.4×	1e-03	KLKB1, KNG1
FXIIa, PKa-dependent activation of coagulation pathway	2	142.8×	0.001	KLKB1, KNG1
FXIIa activates plasma kallikrein-kinin system	3	32.4×	0.001	KLKB1, KNG1, KRT1
R-HSA-140877	2	119.0×	0.001	KLKB1, KNG1
Dissolution of Fibrin Clot	2	102.0×	0.002	PLAT, PLG
Complement cascade	2	79.3×	0.003	C1S, CPN1
MyD88 deficiency (TLR2/4)	2	75.1×	0.003	TLR2, TLR4
Degradation of the extracellular matrix	3	22.1×	0.003	ELANE, KLKB1, PLG
IRAK4 deficiency (TLR2/4)	2	71.4×	0.003	TLR2, TLR4
Regulation of TLR by endogenous ligand	2	62.1×	0.003	TLR2, TLR4
Post-translational protein phosphorylation	3	18.8×	0.003	KNG1, SERPINA1, PROC
Platelet degranulation	3	16.5×	0.004	KNG1, SERPINA1, PLG
Signaling by PDGF	2	31.7×	0.010	PLAT, PLG
Innate Immune System	4	6.4×	0.016	C1S, CPN1, KRT1, SERPINA1
R-HSA-9651496	1	237.9×	0.018	KLKB1
Defective cleavage of FV variant at a.a.534	1	237.9×	0.018	PROC
Defective cleavage of FV variant at R334	1	237.9×	0.018	PROC
Response to elevated platelet cytosolic Ca2+	2	20.4×	0.018	KNG1, SERPINA1
Neutrophil degranulation	4	5.8×	0.018	TLR2, ELANE, KRT1, SERPINA1
RSV-host interactions	2	19.6×	0.018	TLR2, TLR4
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	2	19.0×	0.019	TLR2, TLR4
Defective factor XII causes hereditary angioedema	1	178.4×	0.019	KLKB1
Defective SERPING1 causes hereditary angioedema	1	178.4×	0.019	KLKB1
Diseases of hemostasis	1	178.4×	0.019	KLKB1
ER-Phagosome pathway	2	16.2×	0.022	TLR2, TLR4
Expression of NOTCH2NL genes	1	142.8×	0.023	ELANE

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
blood coagulation	6	65.2×	3e-08	KLKB1, KNG1, SERPINA1, PLAT, PLG, PROC
proteolysis	9	19.3×	3e-08	C1S, ACE, DPP4, ELANE, KLK3, KLKB1, PLAT, PLG (+1 more)
fibrinolysis	4	210.7×	2e-07	KLKB1, KRT1, PLAT, PLG
positive regulation of cellular response to macrophage colony-stimulating factor stimulus	2	1053.2×	5e-05	TLR2, TLR4
trans-synaptic signaling by BDNF, modulating synaptic transmission	2	702.2×	1e-04	PLAT, PLG
positive regulation of matrix metallopeptidase secretion	2	702.2×	1e-04	TLR2, TLR4
positive regulation of fibrinolysis	2	421.3×	3e-04	KLKB1, PLG
bradykinin catabolic process	2	300.9×	5e-04	CPN1, ACE
positive regulation of interleukin-8 production	3	45.8×	9e-04	TLR2, TLR4, ELANE
cellular response to lipoteichoic acid	2	191.5×	0.001	TLR2, TLR4
negative regulation of fibrinolysis	2	175.5×	0.001	PLAT, PLG
plasminogen activation	2	162.0×	0.001	KLKB1, PLAT
negative regulation of blood coagulation	2	150.5×	0.001	KNG1, PROC
regulation of vasoconstriction	2	100.3×	0.003	BDKRB2, ACE
negative regulation of inflammatory response	3	25.7×	0.003	ELANE, KRT1, PROC
arachidonate secretion	2	87.8×	0.003	BDKRB2, ACE
zymogen activation	2	84.3×	0.003	KLK3, KLKB1
negative regulation of proteolysis	2	84.3×	0.003	KNG1, PLAT
toll-like receptor signaling pathway	2	75.2×	0.004	TLR2, TLR4
nitric oxide production involved in inflammatory response	1	1053.2×	0.007	TLR4
biosynthetic process of antibacterial peptides active against Gram-negative bacteria	1	1053.2×	0.007	ELANE
mononuclear cell proliferation	1	1053.2×	0.007	ACE
glucagon processing	1	1053.2×	0.007	DPP4
negative regulation of intrinsic apoptotic signaling pathway in response to osmotic stress by p53 class mediator	1	1053.2×	0.007	BDKRB2
intrinsic apoptotic signaling pathway in response to osmotic stress by p53 class mediator	1	1053.2×	0.007	BDKRB2
positive regulation of interferon-beta production	2	49.0×	0.007	TLR2, TLR4
positive regulation of interleukin-12 production	2	49.0×	0.007	TLR2, TLR4
positive regulation of chemokine production	2	46.8×	0.007	TLR2, TLR4
extracellular matrix disassembly	2	45.8×	0.007	ELANE, PLG
vasodilation	2	45.8×	0.007	BDKRB2, KNG1

Therapeutics

Drug target analysis

Approved (phase 4): 10 · Phase ≥3: 11 · Phased (≥1): 11 · Undrugged: 5

Druggability breadth: 13 of 16 evidence-associated genes (81%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
BDKRB2	PYRVINIUM
TLR4	METHOTREXATE
ACE	TELMISARTAN
DPP4	VIDARABINE
ELANE	BOCEPREVIR
KLK3	ENZALUTAMIDE
KLKB1	BEROTRALSTAT
PLAT	ARGATROBAN
PLG	AMINOCAPROIC ACID
PROC	MELAGATRAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DPP4	33	4
ACE	31	4
BDKRB2	18	4
ELANE	11	4
PLG	11	4
KLKB1	10	4
PLAT	8	4
TLR4	6	4
PROC	2	4
C1S	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PYRVINIUM	4	BDKRB2
INDOCYANINE GREEN ACID FORM	4	BDKRB2
NITAZOXANIDE	4	BDKRB2
RIFAXIMIN	4	BDKRB2
ICATIBANT	4	BDKRB2
RIFAMPIN	4	BDKRB2
AMSACRINE	4	BDKRB2
SUNITINIB	4	BDKRB2
NIMESULIDE	4	BDKRB2
AMIODARONE	4	BDKRB2
TAMOXIFEN	4	BDKRB2
METHOTREXATE	4	TLR4
POLYMYXIN B	4	TLR4
CARVEDILOL	4	TLR4
TELMISARTAN	4	ACE
MOEXIPRIL	4	ACE
RAMIPRIL	4	ACE
LISINOPRIL ANHYDROUS	4	ACE
SITAGLIPTIN	4	ACE, DPP4
TRANDOLAPRIL	4	ACE
CAPTOPRIL	4	ACE
PERINDOPRIL	4	ACE
QUINAPRIL	4	ACE
LOSARTAN	4	ACE
FOSINOPRIL	4	ACE
IMIDAPRIL	4	ACE
ENALAPRILAT ANHYDROUS	4	ACE
ENALAPRIL	4	ACE
BENAZEPRIL	4	ACE
VIDARABINE	4	DPP4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 10.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ELANE	801	Binding:758, Functional:35, ADMET:6, Toxicity:2
DPP4	635	Binding:584, ADMET:41, Functional:10
PLG	480	Binding:467, ADMET:7, Functional:6
ACE	304	Binding:288, Functional:8, ADMET:5, Unclassified:3
KLKB1	300	Binding:283, ADMET:17
TLR4	267	Binding:254, Functional:10, ADMET:3
PLAT	249	Binding:243, Functional:5, ADMET:1
BDKRB2	225	Binding:186, Functional:38, ADMET:1
TLR2	225	Binding:202, Functional:23
PROC	117	Binding:117
KLK3	51	Binding:26, ADMET:25
C1S	30	Binding:28, Functional:2
CPN1	8	Binding:6, ADMET:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
C1S	3.4.21.42	complement subcomponent C1s
CPN1	3.4.17.3	lysine carboxypeptidase
ACE	3.4.15.1	peptidyl-dipeptidase A
DPP4	3.4.14.5	dipeptidyl-peptidase IV
ELANE	3.4.21.37	leukocyte elastase
KLK3	3.4.21.77	semenogelase
KLKB1	3.4.21.34	plasma kallikrein
PLAT	3.4.21.68	t-Plasminogen activator
PLG	3.4.21.7	plasmin
PROC	3.4.21.69	activated protein C (thrombin-activated peptidase)

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
BDKRB2	225
TLR2	225
TLR4	267
ACE	304
DPP4	635
ELANE	801
KLKB1	300
PLAT	249
PLG	480
PROC	117

Pharmacogenomics

Cohort genes with a PharmGKB record: 16; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PYRVINIUM	4	BDKRB2
INDOCYANINE GREEN ACID FORM	4	BDKRB2
NITAZOXANIDE	4	BDKRB2
RIFAXIMIN	4	BDKRB2
ICATIBANT	4	BDKRB2
RIFAMPIN	4	BDKRB2
AMSACRINE	4	BDKRB2
SUNITINIB	4	BDKRB2
NIMESULIDE	4	BDKRB2
AMIODARONE	4	BDKRB2
TAMOXIFEN	4	BDKRB2
METHOTREXATE	4	TLR4
POLYMYXIN B	4	TLR4
CARVEDILOL	4	TLR4
TELMISARTAN	4	ACE
MOEXIPRIL	4	ACE
RAMIPRIL	4	ACE
LISINOPRIL ANHYDROUS	4	ACE
SITAGLIPTIN	4	ACE, DPP4
TRANDOLAPRIL	4	ACE
CAPTOPRIL	4	ACE
PERINDOPRIL	4	ACE
QUINAPRIL	4	ACE
LOSARTAN	4	ACE
FOSINOPRIL	4	ACE
IMIDAPRIL	4	ACE
ENALAPRILAT ANHYDROUS	4	ACE
ENALAPRIL	4	ACE
BENAZEPRIL	4	ACE
VIDARABINE	4	DPP4

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	10	BDKRB2, TLR4, ACE, DPP4, ELANE, KLK3, KLKB1, PLAT, PLG, PROC
B	Phased (≥1) drug, not yet approved	1	C1S
C	Druggable family + PDB, no drug	1	CPN1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	TLR2, KNG1, KRT1, SERPINA1

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
KNG1	0	BDKRB2, KLKB1
SERPINA1	0	ELANE
TLR2	225	—
CPN1	8	—
KRT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: BDKRB2, TLR2, TLR4, C1S, CPN1, ACE, DPP4, ELANE, KLK3, KLKB1, KNG1, KRT1, SERPINA1, PLAT, PLG, PROC