Angioedema

Summary

Angioedema (MONDO:0010481) is a disease with 10 cohort genes (57 GWAS associations across 7 studies) and 35 clinical trials. Top therapeutic interventions include lanadelumab, icatibant, and omalizumab.

At a glance

• Cohort genes: 10
• GWAS associations: 57
• ClinVar variants: 16
• Clinical trials: 35

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	angioedema
Mondo ID	MONDO:0010481
EFO	EFO:0005532
MeSH	D000799
DOID	DOID:1558
SNOMED CT	400075008
UMLS	C0002994
MedGen	1543
Is cancer (heuristic)	no

Also known as: angioedemas · angioneurotic edema · angioneurotic Edemas · angioneurotic oedema · edema, angioneurotic · edema, Quincke’s · Edemas, angioneurotic · giant urticaria · giant Urticarias · Quincke edema · Quincke oedema · Quincke’s edema · Quincke’s oedema · Quinckes edema · Quinckes oedema · urticaria, giant · Urticarias, giant

Data availability: 16 ClinVar variants · 57 GWAS associations (7 studies) · 1 HPO phenotype.

Disease family

An umbrella term covering 3 Mondo subtypes.

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

Related subtypes (13): allergic urticaria, physical urticaria, Melkersson-Rosenthal syndrome, pruritic urticarial papules and plaques of pregnancy, urticaria, aquagenic, urticaria, familial localized heat, drug rash with eosinophilia and systemic symptoms, cutaneous mastocytosis, cold urticaria, autoimmune urticaria, papular urticaria, idiopathic urticaria, chronic urticaria

Subtypes (3): non-histaminic angioedema, hereditary angioedema, acquired angioedema

Genetics & variants

GWAS landscape

57 GWAS associations across 7 studies. Top hits map to 28 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs12888576	4e-13	C14orf132 - BDKRB2	A	1.5
rs35136400	1e-12	C14orf132 - BDKRB2	A	1.5
rs34485356	1e-10	C14orf132 - BDKRB2	T	1.62
rs6687813	1e-10	SLC19A2 - F5	A	1.7
rs141521143	2e-08	EDEM2	A	0.67
rs6060237	3e-08	TRPC4AP - EDEM2	A	0.7
rs2253201	4e-08	KCNMA1	G	2.47
rs866539	7e-08	KCNMA1	C	2.4
rs2401902	8e-08	TRIO	A	0.25
rs6913724	2e-07	POM121L2	A	1.8
rs11070816	2e-07	TRPM1	T	1.78
rs9833094	5e-07	ABI3BP	T	2.95
rs77440358	5e-07	LINC02441 - LINC02369	T	2.27
rs113325073	6e-07	DCLK1	A	3.97
rs9323624	1e-06	IFT43	A	2.88
rs79445594	1e-06	THSD7A - TMEM106B	C	3.11
rs114514212	1e-06	PDE4D	A	2.63
rs193153064	1e-06	LINC01899 - CBLN2	T	3.84
rs181415750	1e-06	KDM2A	G	3.79
rs1051924	1e-06	TMEM119	A	0.41
chr2:38180325	1e-06		A	1.04
rs9310952	1e-06	GADL1	A	0.29
rs2350090	2e-06	KCNQ5	A	3.82
rs114930791	2e-06	AMY1C - THAP3P1	T	3.73
rs55636532	2e-06	FGF12	C	3.5
rs4704331	2e-06	IQGAP2	C	0.3
rs6885949	2e-06	LINC02208	T	0.25
rs61740878	2e-06	DAPL1	A	0.29
rs461409	3e-06	CTBP2P4 - DDX18P4	?
chr19:41942508	3e-06		T	1.23

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90492732	Mathey CM	2024	1,060	77,799	Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.
GCST90492733	Mathey CM	2024	1,060	77,799	Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.
GCST90027157	Ghouse J	2021	462	53,391	Association of Variants Near the Bradykinin Receptor B2 Gene With Angioedema in Patients Taking ACE Inhibitors.
GCST010246	Rasmussen ER	2020	172	1,345	Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.
GCST010247	Rasmussen ER	2020	172	4,890	Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.
GCST002263	Cornejo-Garcia JA	2013	112	0	Genome-wide association study in NSAID-induced acute urticaria/angioedema in Spanish and Han Chinese populations.
GCST002091	Pare G	2013	0	0	Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	3
Tier 3: regulatory	0
Tier 4: intronic/intergenic	47

MAF distribution

Bucket	Variants
common (>=0.05)	34
low_freq (0.01-0.05)	12
rare (<0.01)	0
unknown	4

Functional consequences

Consequence	Count
intron_variant	26
intergenic_variant	17
3_prime_UTR_variant	2
unknown	2
splice_polypyrimidine_tract_variant	1
synonymous_variant	1
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs12888576	14	96145054	A>G,T	0.05	splice_polypyrimidine_tract_variant	C14orf132 - BDKRB2	4e-13	Tier 2: splice/UTR
rs35136400	14	96153143	A>G	0.05	intergenic_variant	C14orf132 - BDKRB2	1e-12	Tier 4: intronic/intergenic
rs34485356	14	96144934	T>C	0.23	intron_variant	C14orf132 - BDKRB2	1e-10	Tier 4: intronic/intergenic
rs6687813	1	169508336	A>C	0.05	intergenic_variant	SLC19A2 - F5	1e-10	Tier 4: intronic/intergenic
rs141521143	20	35135653			intron_variant	EDEM2	2e-08	Tier 4: intronic/intergenic
rs6060237	20	35106407	A>G	0.05	intergenic_variant	TRPC4AP - EDEM2	3e-08	Tier 4: intronic/intergenic
rs2253201	10	77596639	G>A,C	0.063	intron_variant	KCNMA1	4e-08	Tier 4: intronic/intergenic
rs866539	10	77490046	T>C	0.068	intron_variant	KCNMA1	7e-08	Tier 4: intronic/intergenic
rs2401902	5	14528478	G>A,T	0.05	intergenic_variant	TRIO	8e-08	Tier 4: intronic/intergenic
rs6913724	6	27287064	A>C,T	0.432	intergenic_variant	POM121L2	2e-07	Tier 4: intronic/intergenic
rs11070816	15	31114132	T>A,C,G	0.425	intron_variant	TRPM1	2e-07	Tier 4: intronic/intergenic
rs9833094	3	100872081	C>A,T	0.168	intron_variant	ABI3BP	5e-07	Tier 4: intronic/intergenic
rs77440358	12	128074297	C>T	0.073	intergenic_variant	LINC02441 - LINC02369	5e-07	Tier 4: intronic/intergenic
rs113325073	13	35943293	C>A	0.013	intron_variant	DCLK1	6e-07	Tier 4: intronic/intergenic
rs9323624	14	76033960	T>A,C	0.356	intron_variant	IFT43	1e-06	Tier 4: intronic/intergenic
rs79445594	7	12050026	T>C	0.024	intron_variant	THSD7A - TMEM106B	1e-06	Tier 4: intronic/intergenic
rs114514212	5	60103418	G>A	0.035	intron_variant	PDE4D	1e-06	Tier 4: intronic/intergenic
rs193153064	18	72418127	C>T	0.013	intergenic_variant	LINC01899 - CBLN2	1e-06	Tier 4: intronic/intergenic
rs181415750	11	67212032	A>G	0.013	intron_variant	KDM2A	1e-06	Tier 4: intronic/intergenic
rs1051924	12	108590201	A>C,G	0.05	3_prime_UTR_variant	TMEM119	1e-06	Tier 2: splice/UTR
chr2:38180325							1e-06	Tier 4: intronic/intergenic
rs9310952	3	30840854	A>G	0.05	intron_variant	GADL1	1e-06	Tier 4: intronic/intergenic
rs2350090	6	72867964	C>A,G	0.013	intron_variant	KCNQ5	2e-06	Tier 4: intronic/intergenic
rs114930791	1	103825222	C>T	0.015	intergenic_variant	AMY1C - THAP3P1	2e-06	Tier 4: intronic/intergenic
rs55636532	3	192194678	T>C	0.019	intron_variant	FGF12	2e-06	Tier 4: intronic/intergenic
rs4704331	5	76545901	C>G	0.05	intron_variant	IQGAP2	2e-06	Tier 4: intronic/intergenic
rs6885949	5	118464112	T>A,C	0.05	intron_variant	LINC02208	2e-06	Tier 4: intronic/intergenic
rs61740878	2	158815740	G>A,T	0.05	synonymous_variant	DAPL1	2e-06	Tier 4: intronic/intergenic
rs461409	5	98594262	C>A,G,T	0.05	intergenic_variant	CTBP2P4 - DDX18P4	3e-06	Tier 4: intronic/intergenic
chr19:41942508							3e-06	Tier 4: intronic/intergenic

ClinVar germline variants

16 retrieved; paginated sample, class counts are floors:

6 pathogenic, 5 uncertain significance, 4 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1170	NM_000505.4(F12):c.983C>G (p.Thr328Arg)	F12	Pathogenic	criteria provided, single submitter
2811807	NM_000062.3(SERPING1):c.382dup (p.Thr128fs)	SERPING1	Pathogenic	criteria provided, multiple submitters, no conflicts
3248557	NM_000062.3(SERPING1):c.550+1G>A	SERPING1	Pathogenic	criteria provided, multiple submitters, no conflicts
3248618	NM_000062.3(SERPING1):c.523_526delinsTG (p.Ala175fs)	SERPING1	Pathogenic	criteria provided, single submitter
3255484	NM_000062.3(SERPING1):c.136_139delinsTTG (p.Ala46fs)	SERPING1	Pathogenic	criteria provided, single submitter
3255493	NM_000062.3(SERPING1):c.1195C>T (p.Pro399Ser)	SERPING1	Pathogenic	criteria provided, multiple submitters, no conflicts
252940	NM_000062.3(SERPING1):c.587T>A (p.Ile196Asn)	SERPING1	Likely pathogenic	criteria provided, single submitter
3255495	NM_000062.3(SERPING1):c.1058T>C (p.Leu353Pro)	SERPING1	Likely pathogenic	criteria provided, single submitter
3384138	NM_000062.3(SERPING1):c.1431C>G (p.Phe477Leu)	SERPING1	Likely pathogenic	criteria provided, single submitter
689535	NM_000062.3(SERPING1):c.51+1del	SERPING1	Likely pathogenic	no assertion criteria provided
3001332	NM_000062.3(SERPING1):c.52-5C>T	SERPING1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3336721	NM_000062.3(SERPING1):c.656C>T (p.Thr219Ile)	SERPING1	Uncertain significance	criteria provided, single submitter
427759	NM_000062.3(SERPING1):c.1475T>C (p.Met492Thr)	SERPING1	Uncertain significance	criteria provided, multiple submitters, no conflicts
689536	NM_000062.3(SERPING1):c.369C>G (p.Cys123Trp)	SERPING1	Uncertain significance	no assertion criteria provided
689537	NM_000062.3(SERPING1):c.1249+5G>C	SERPING1	Uncertain significance	no assertion criteria provided
375385	NM_206927.4(SYTL2):c.893del (p.Ser298fs)	SYTL2	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SERPING1	Orphanet:100050	Hereditary angioedema type 1
SERPING1	Orphanet:100051	Hereditary angioedema type 2
RIMS1	Orphanet:1872	Cone rod dystrophy
IFT43	Orphanet:1515	Cranioectodermal dysplasia
IFT43	Orphanet:791	Retinitis pigmentosa
F12	Orphanet:100054	F12-related hereditary angioedema with normal C1Inh
F12	Orphanet:330	Congenital factor XII deficiency
F12	Orphanet:617919	F12-associated cold autoinflammatory syndrome
AKAP9	Orphanet:101016	Romano-Ward syndrome
AKAP9	Orphanet:130	Brugada syndrome
HLF	Orphanet:641375	B-lymphoblastic leukemia/lymphoma with t(17;19)

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	7
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SERPING1	HGNC:1228	ENSG00000149131	P05155	Plasma protease C1 inhibitor	clinvar
SYTL2	HGNC:15585	ENSG00000137501	Q9HCH5	Synaptotagmin-like protein 2	clinvar
ABI3BP	HGNC:17265	ENSG00000154175	Q7Z7G0	Target of Nesh-SH3	gwas
RIMS1	HGNC:17282	ENSG00000079841	Q86UR5	Regulating synaptic membrane exocytosis protein 1	gwas
RGMB	HGNC:26896	ENSG00000174136	Q6NW40	Repulsive guidance molecule B	gwas
IFT43	HGNC:29669	ENSG00000119650	Q96FT9	Intraflagellar transport protein 43 homolog	gwas
F12	HGNC:3530	ENSG00000131187	P00748	Coagulation factor XII	clinvar
AKAP9	HGNC:379	ENSG00000127914	Q99996	A-kinase anchor protein 9	gwas
HLF	HGNC:4977	ENSG00000108924	Q16534	Hepatic leukemia factor	gwas
RAD51B	HGNC:9822	ENSG00000182185	O15315	DNA repair protein RAD51 homolog 2	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SERPING1	Plasma protease C1 inhibitor	Serine protease inhibitor, which acrs as a regulator of the classical complement pathway.
SYTL2	Synaptotagmin-like protein 2	Isoform 1 acts as a RAB27A effector protein and plays a role in cytotoxic granule exocytosis in lymphocytes.
RIMS1	Regulating synaptic membrane exocytosis protein 1	Rab effector involved in exocytosis.
RGMB	Repulsive guidance molecule B	Member of the repulsive guidance molecule (RGM) family that contributes to the patterning of the developing nervous system.
IFT43	Intraflagellar transport protein 43 homolog	As a component of IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is involved in ciliogenesis.
F12	Coagulation factor XII	Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin.
AKAP9	A-kinase anchor protein 9	Scaffolding protein that assembles several protein kinases and phosphatases on the centrosome and Golgi apparatus.
RAD51B	DNA repair protein RAD51 homolog 2	Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 7 · Druggable fraction: 0.2

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	1	3.7×	0.392
Antibody/Immunoglobulin	1	2.9×	0.392
Other/Unknown	7	1.2×	0.392
Transcription factor	1	0.8×	0.725

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SERPING1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom
SYTL2	Other/Unknown	no		C2_dom, Rab_BD, C2_domain_sf
ABI3BP	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, FN3_sf
RIMS1	Transcription factor	no		C2_dom, PDZ, Rab_BD
RGMB	Other/Unknown	no		RGM_C, RGM_N, RGM
IFT43	Other/Unknown	no		IFT43
F12	Protease	yes	3.4.21.38	Kringle, Fibronectin_type1, FN_type2_dom
AKAP9	Other/Unknown	no		ELK_dom, PACT_domain, AKAP9/Pericentrin
HLF	Other/Unknown	no		bZIP, PAR_bZIP, bZIP_sf
RAD51B	Other/Unknown	no		AAA+_ATPase, Rad51_C, DNA_recomb/repair_RecA-like

Expression context

Cohort genes with no expression data: 0.

10 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
calcaneal tendon	2
bronchial epithelial cell	2
right coronary artery	1
right lung	1
mucosa of sigmoid colon	1
rectum	1
saphenous vein	1
decidua	1
synovial joint	1
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1
ileal mucosa	1
pylorus	1
upper arm skin	1
bronchus	1
right uterine tube	1
gingival epithelium	1
liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SERPING1	299	ubiquitous	marker	right lobe of liver, right lung, right coronary artery
SYTL2	263	ubiquitous	marker	saphenous vein, rectum, mucosa of sigmoid colon
ABI3BP	256	ubiquitous	marker	decidua, synovial joint, calcaneal tendon
RIMS1	175	broad	marker	cerebellar cortex, cerebellar hemisphere, cerebellum
RGMB	254	ubiquitous	marker	ileal mucosa, pylorus, upper arm skin
IFT43	252	ubiquitous	marker	right uterine tube, bronchial epithelial cell, bronchus
F12	191	broad	marker	right lobe of liver, liver, gingival epithelium
AKAP9	292	ubiquitous	marker	jejunal mucosa, bronchial epithelial cell, cortical plate
HLF	275	broad	marker	calcaneal tendon, orbitofrontal cortex, Brodmann (1909) area 46
RAD51B	193	ubiquitous	marker	sural nerve, buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
F12	3,850
AKAP9	3,537
RAD51B	2,993
SERPING1	2,104
RIMS1	1,987
HLF	903
SYTL2	793
ABI3BP	767
IFT43	635
RGMB	531

Intra-cohort edges

A	B	Sources
F12	SERPING1	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
F12	P00748	17
RGMB	Q6NW40	11
SYTL2	Q9HCH5	9
SERPING1	P05155	5
RAD51B	O15315	5
IFT43	Q96FT9	3
RIMS1	Q86UR5	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HLF	Q16534	72.55
ABI3BP	Q7Z7G0	54.33
AKAP9	Q99996

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 55. Enrichment computed across 10 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SERPING1 causes hereditary angioedema	2	713.8×	1e-04	SERPING1, F12
Regulation of FXIIa and plasma kallikrein activity	2	285.5×	5e-04	SERPING1, F12
Aggregated β-amyloid induces FXII autocatalysis	1	713.8×	0.026	F12
Defective factor XII causes hereditary angioedema	1	356.9×	0.038	F12
Phase 3 - rapid repolarisation	1	142.8×	0.057	AKAP9
FXIIa, PKa-dependent activation of coagulation pathway	1	142.8×	0.057	F12
Phase 2 - plateau phase	1	95.2×	0.057	AKAP9
Acetylcholine Neurotransmitter Release Cycle	1	84.0×	0.057	RIMS1
Serotonin Neurotransmitter Release Cycle	1	79.3×	0.057	RIMS1
Norepinephrine Neurotransmitter Release Cycle	1	79.3×	0.057	RIMS1
GABA synthesis, release, reuptake and degradation	1	79.3×	0.057	RIMS1
Dopamine Neurotransmitter Release Cycle	1	62.1×	0.057	RIMS1
Glutamate Neurotransmitter Release Cycle	1	57.1×	0.057	RIMS1
Impaired BRCA2 binding to PALB2	1	57.1×	0.057	RAD51B
Netrin-1 signaling	1	54.9×	0.057	RGMB
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	52.9×	0.057	RAD51B
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	52.9×	0.057	RAD51B
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	52.9×	0.057	RAD51B
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	49.2×	0.057	RAD51B
Homologous DNA Pairing and Strand Exchange	1	47.6×	0.057	RAD51B
Resolution of D-loop Structures through Holliday Junction Intermediates	1	37.6×	0.069	RAD51B
Presynaptic phase of homologous DNA pairing and strand exchange	1	34.0×	0.069	RAD51B
Regulation of MITF-M-dependent genes involved in pigmentation	1	33.2×	0.069	SYTL2
Centrosome maturation	1	31.7×	0.069	AKAP9
Oncogenic MAPK signaling	1	31.0×	0.069	AKAP9
Regulation of clotting cascade	1	29.1×	0.069	SERPING1
Regulation of Complement cascade	1	29.1×	0.069	SERPING1
Intraflagellar transport	1	25.0×	0.077	IFT43
HDR through Homologous Recombination (HRR)	1	23.8×	0.078	RAD51B
MITF-M-dependent gene expression	1	22.7×	0.079	SYTL2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
fibrinolysis	2	168.5×	0.004	SERPING1, F12
negative regulation of complement activation, lectin pathway	1	842.6×	0.020	SERPING1
plasma kallikrein-kinin cascade	1	842.6×	0.020	F12
Factor XII activation	1	561.7×	0.020	F12
response to misfolded protein	1	561.7×	0.020	F12
blood coagulation	2	34.8×	0.020	SERPING1, F12
positive regulation of fibrinolysis	1	337.0×	0.022	F12
blastocyst growth	1	280.9×	0.022	RAD51B
maintenance of centrosome location	1	280.9×	0.022	AKAP9
acrosomal vesicle exocytosis	1	280.9×	0.022	RIMS1
positive regulation of inhibitory postsynaptic potential	1	280.9×	0.022	RIMS1
blood coagulation, intrinsic pathway	1	210.7×	0.024	F12
secretion	1	210.7×	0.024	RIMS1
positive regulation of plasminogen activation	1	187.2×	0.024	F12
regulation of cardiac muscle cell action potential involved in regulation of contraction	1	187.2×	0.024	AKAP9
obsolete synaptic vesicle docking	1	129.6×	0.028	RIMS1
regulation of membrane repolarization	1	129.6×	0.028	AKAP9
positive regulation of blood coagulation	1	112.3×	0.028	F12
intraciliary retrograde transport	1	112.3×	0.028	IFT43
somite development	1	112.3×	0.028	RAD51B
regulation of Golgi organization	1	112.3×	0.028	AKAP9
calcium-ion regulated exocytosis	1	99.1×	0.028	RIMS1
protein-containing complex localization	1	99.1×	0.028	AKAP9
intracellular protein transport	2	13.0×	0.028	SYTL2, RIMS1
regulated exocytosis	1	88.7×	0.029	RIMS1
regulation of ventricular cardiac muscle cell membrane repolarization	1	84.3×	0.029	AKAP9
synaptic vesicle priming	1	80.2×	0.029	RIMS1
synaptic vesicle exocytosis	1	76.6×	0.029	RIMS1
regulation of neurotransmitter secretion	1	76.6×	0.029	RIMS1
positive regulation of dendrite extension	1	73.3×	0.029	RIMS1

Therapeutics

Drugs indicated for this disease

1 approved, 7 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Epinephrine	Approved (phase 4)
Clemastine	Phase 3 (in late-stage trials)
Cortisone Acetate	Phase 3 (in late-stage trials)
HUMAN C1-ESTERASE INHIBITOR	Phase 3 (in late-stage trials)
Icatibant	Phase 3 (in late-stage trials)
Lanadelumab	Phase 3 (in late-stage trials)
Omalizumab	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Dupilumab, Ecallantide.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 9

Druggability breadth: 2 of 10 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
F12	3	3
SERPING1	0	0
SYTL2	0	0
ABI3BP	0	0
RIMS1	0	0
RGMB	0	0
IFT43	0	0
AKAP9	0	0
HLF	0	0
RAD51B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NAFAMOSTAT	3	F12
GABEXATE	3	F12
SEPIMOSTAT	2	F12

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
F12	128	Binding:123, Functional:3, ADMET:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
F12	3.4.21.38	coagulation factor XIIa

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
F12	128

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
NAFAMOSTAT	3	F12
GABEXATE	3	F12
SEPIMOSTAT	2	F12

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	F12
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ABI3BP
E	Difficult family or no structure, no drug	8	SERPING1, SYTL2, RIMS1, RGMB, IFT43, AKAP9, HLF, RAD51B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SERPING1	0	—
SYTL2	0	—
ABI3BP	0	—
RIMS1	0	—
RGMB	0	—
IFT43	0	—
AKAP9	0	—
HLF	0	—
RAD51B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 35.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	16
PHASE2	7
PHASE3	6
PHASE4	2
PHASE2/PHASE3	2
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06818474	PHASE4	RECRUITING	Lanadelumab in Long-term Prophylaxis of Acquired Angioedema
NCT02966314	PHASE4	COMPLETED	Treatment of Idiopathic Angioedema With Xolair as Add-on Therapy
NCT00097695	PHASE3	COMPLETED	Subcutaneous Treatment With Icatibant for Acute Attacks of Hereditary Angioedema
NCT00125151	PHASE3	COMPLETED	C1-Esteraseremmer-N for the Treatment of Hereditary (and Acquired) Angioedema
NCT00125541	PHASE2/PHASE3	COMPLETED	C1-Esteraseremmer-N for the Treatment of Hereditary (and Acquired) Angioedema
NCT00225147	PHASE2/PHASE3	COMPLETED	Recombinant Human C1 Inhibitor for the Treatment of Acute Attacks in Patients With Hereditary Angioedema
NCT00262301	PHASE3	COMPLETED	Recombinant Human C1 Inhibitor for the Treatment of Acute Attacks in Patients With Hereditary Angioedema
NCT01723072	PHASE3	COMPLETED	Impact of Omalizumab on Quality of Life Measures and Angioedema Occurrence in Patients With CSU Refractory to Therapy
NCT04206605	PHASE3	COMPLETED	A Study of Lanadelumab in Teenagers and Adults to Prevent Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH)
NCT04444895	PHASE3	COMPLETED	A Study of Long-Term Safety and Efficacy of Lanadelumab for Prevention of Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor
NCT07046806	PHASE1/PHASE2	RECRUITING	Oral Deucrictibant for Prophylactic and Acute Treatment in Hereditary Angioedema Patients
NCT00119431	PHASE2	COMPLETED	Kinetics, Efficacy and Safety of C1-Esteraseremmer-N
NCT00890162	PHASE2	COMPLETED	A Randomized, Double-Blind, Placebo-Controlled Study of Omalizumab for Idiopathic Anaphylaxis
NCT01036659	PHASE2	UNKNOWN	Evaluation of Ecallantide for the Acute Treatment of Angiotensin Converting Enzyme Inhibitor Induced Angioedema
NCT01154361	PHASE2	COMPLETED	AMelioration of Angiotensin Converting Enzyme Inhibitor Induced Angioedema Study
NCT03749135	PHASE2	COMPLETED	Dupilumab in Chronic Spontaneous Urticaria
NCT04128371	PHASE2	TERMINATED	Mepolizumab in Episodic Angioedema With Eosinophilia
NCT05936567	PHASE2	COMPLETED	Study Evaluating the Efficacy and Safety of Povorcitinib in Adults With Chronic Spontaneous Urticaria
NCT00517582	PHASE1	TERMINATED	Bradykinin Receptor Blocker in ACE Inhibitor-associated Angioedema
NCT03845946	Not specified	RECRUITING	CLOUD-R HAE REGISTRY
NCT04334031	Not specified	RECRUITING	Deployment o the Multidisciplinary Prospective Cohort Imminent
NCT07001280	Not specified	RECRUITING	A Study Investigating the Effectiveness and Safety of Garadacimab for Treating Patients With Hereditary Angioedema (HAE)
NCT00004694	Not specified	COMPLETED	Study of Heparin Prophylaxis of Hereditary Angioedema Exacerbations
NCT00163839	Not specified	UNKNOWN	The Efficacy of a Pseudoallergen-Free Diet in the Treatment of Chronic Idiopathic Urticaria and/or Angioedema
NCT00385372	Not specified	COMPLETED	Significance of an Elimination and Provocation Diet in Patients With Chronic Urticaria
NCT00876369	Not specified	COMPLETED	Vitamin D Levels in Subjects With Chronic Urticaria and Angioedema
NCT01371877	Not specified	COMPLETED	The Role of Vitamin D in Chronic Urticaria and Angioedema Treatment
NCT02833675	Not specified	COMPLETED	Determination of Specific Biomarkers of Angioneurotic Crisis
NCT03240991	Not specified	COMPLETED	Study of Clinical, Biological Characteristics and Quality of Life of Patients With Hereditary or Acquired Non Drug-induced Bradykinin-mediated Angioedema, Monitored in Besançon’s Partner Site Reference Center for Studies of Kinin-mediated Angioedema (CREAK)
NCT04583007	Not specified	NO_LONGER_AVAILABLE	Expanded Access for the Prevention of Acute Attacks of 1) Hereditary Angioedema (HAE) in Children and 2) Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH) in Teenagers and Adults
NCT04597944	Not specified	UNKNOWN	Lanadelumab in Bradykinin Angioedema
NCT05578417	Not specified	COMPLETED	A Study to Review the Treatment and Outcomes of Teenagers and Adults With Non-histaminergic Angioedema With Normal C1 Inhibitor in Canada
NCT06096077	Not specified	COMPLETED	Evaluation of Tranexamic Acid for Angiotensin-converting Enzyme Inhibitor-induced Angioedema in the Emergency Department
NCT06210698	Not specified	UNKNOWN	Angioedema Biomarker Research Study
NCT07611032	Not specified	COMPLETED	A Single-Arm Exploratory Study of NatureU Histra Disslove on Chronic Urticaria Symptoms

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LANADELUMAB	4	4
ICATIBANT	4	3
OMALIZUMAB	4	3
CONESTAT ALFA	4	2
MEPOLIZUMAB	4	1
POVORCITINIB	3	1
RACEPINEPHRINE	2	1