Hereditary angioedema

Summary

Hereditary angioedema (MONDO:0019623) is a disease (an umbrella term covering 10 Mondo subtypes) with 2 cohort genes and 145 clinical trials. Top therapeutic interventions include berotralstat, icatibant, and lanadelumab.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Umbrella term: 10 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 2
• Clinical trials: 145

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	5	Europe	Validated
Point prevalence	1-9 / 100 000	1.4	Denmark	Validated
Point prevalence	1-9 / 100 000	1.51	Norway	Validated
Point prevalence	1-9 / 100 000	1.09	Spain	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary angioedema
Mondo ID	MONDO:0019623
MeSH	D054179
OMIM	106100
Orphanet	91378
DOID	DOID:14735
ICD-11	795969334
NCIT	C84758
SNOMED CT	82966003
UMLS	C0019243
MedGen	9229
GARD	0005979
MedDRA	10019860
Is cancer (heuristic)	no

Also known as: angioedema, hereditary · deficiency of C1 esterase inhibitor · familial angioneurotic edema · familial angioneurotic oedema · HAE · hereditary angioedema · hereditary angioneurotic edema · hereditary angioneurotic oedema · hereditary bradykinine-induced angioedema · hereditary non histamine-induced angioedema

Data availability: 2 ClinVar variants · 3 cell lines.

Disease family

An umbrella term covering 10 Mondo subtypes.

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

Related subtypes (2): non-histaminic angioedema, acquired angioedema

Subtypes (10): hereditary angioedema type 3, angioedema, hereditary, 6, angioedema, hereditary, 4, angioedema, hereditary, 7, angioedema, hereditary, 5, angioedema, hereditary, 8, hereditary angioedema with C1Inh deficiency, PLG-related hereditary angioedema with normal C1inh, hereditary angioedema with normal C1inh not related to F12 or PLG variant, 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

2 retrieved; paginated sample, class counts are floors:

2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1169	NM_000505.4(F12):c.983C>A (p.Thr328Lys)	F12	Pathogenic	criteria provided, multiple submitters, no conflicts
590291	NM_000301.5(PLG):c.988A>G (p.Lys330Glu)	PLG	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
PLG	Orphanet:537072	PLG-related hereditary angioedema with normal C1Inh
PLG	Orphanet:722	Hypoplasminogenemia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
F12	HGNC:3530	ENSG00000131187	P00748	Coagulation factor XII	clinvar
PLG	HGNC:9071	ENSG00000122194	P00747	Plasminogen	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	2	36.6×	7e-04

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
F12	Protease	yes	3.4.21.38	Kringle, Fibronectin_type1, FN_type2_dom
PLG	Protease	yes	3.4.21.7	Kringle, Trypsin_dom, Peptidase_S1A

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	2
right lobe of liver	2
gingival epithelium	1
adult organism	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
F12	191	broad	marker	right lobe of liver, liver, gingival epithelium
PLG	174	tissue_specific	marker	right lobe of liver, liver, adult organism

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
F12	3,850
PLG	3,441

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLG	P00747	49
F12	P00748	17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Aggregated β-amyloid induces FXII autocatalysis	1	2855.0×	0.003	F12
Defective factor XII causes hereditary angioedema	1	1427.5×	0.003	F12
Defective SERPING1 causes hereditary angioedema	1	1427.5×	0.003	F12
Regulation of FXIIa and plasma kallikrein activity	1	571.0×	0.004	F12
FXIIa, PKa-dependent activation of coagulation pathway	1	571.0×	0.004	F12
Dissolution of Fibrin Clot	1	407.9×	0.005	PLG
Activation of Matrix Metalloproteinases	1	154.3×	0.011	PLG
Signaling by PDGF	1	126.9×	0.012	PLG
FXIIa activates plasma kallikrein-kinin system	1	86.5×	0.015	F12
Degradation of the extracellular matrix	1	58.9×	0.020	PLG
Platelet degranulation	1	43.9×	0.023	PLG
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.023	PLG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of fibrinolysis	2	3370.4×	2e-06	F12, PLG
fibrinolysis	2	842.6×	2e-05	F12, PLG
blood coagulation	2	173.7×	2e-04	F12, PLG
protein processing	2	170.2×	2e-04	F12, PLG
plasma kallikrein-kinin cascade	1	4213.0×	0.001	F12
Factor XII activation	1	2808.7×	0.001	F12
response to misfolded protein	1	2808.7×	0.001	F12
trans-synaptic signaling by BDNF, modulating synaptic transmission	1	2808.7×	0.001	PLG
mononuclear cell migration	1	2106.5×	0.002	PLG
biological process involved in interaction with symbiont	1	1404.3×	0.002	PLG
blood coagulation, intrinsic pathway	1	1053.2×	0.003	F12
positive regulation of plasminogen activation	1	936.2×	0.003	F12
negative regulation of cell-cell adhesion mediated by cadherin	1	766.0×	0.003	PLG
negative regulation of fibrinolysis	1	702.2×	0.003	PLG
tissue remodeling	1	648.1×	0.003	PLG
trophoblast giant cell differentiation	1	601.9×	0.003	PLG
positive regulation of blood coagulation	1	561.7×	0.003	F12
negative regulation of cell-substrate adhesion	1	526.6×	0.003	PLG
myoblast differentiation	1	421.3×	0.004	PLG
labyrinthine layer blood vessel development	1	401.2×	0.004	PLG
tissue regeneration	1	383.0×	0.004	PLG
zymogen activation	1	337.0×	0.004	F12
protein autoprocessing	1	324.1×	0.004	F12
muscle cell cellular homeostasis	1	324.1×	0.004	PLG
positive regulation of blood vessel endothelial cell migration	1	195.9×	0.006	PLG
extracellular matrix disassembly	1	183.2×	0.006	PLG
negative regulation of cell population proliferation	1	21.1×	0.050	PLG
proteolysis	1	17.1×	0.059	PLG
innate immune response	1	16.8×	0.059	F12

Therapeutics

Drugs indicated for this disease

5 approved, 6 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Berotralstat	Approved (phase 4)
Conestat Alfa	Approved (phase 4)
Ecallantide	Approved (phase 4)
HUMAN C1-ESTERASE INHIBITOR	Approved (phase 4)
Lanadelumab	Approved (phase 4)
Avoralstat	Phase 3 (in late-stage trials)
Donidalorsen	Phase 3 (in late-stage trials)
Icatibant	Phase 3 (in late-stage trials)
Sebetralstat	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)
Tranexamic Acid	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Hyaluronidase (Human Recombinant).

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
PLG	AMINOCAPROIC ACID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLG	11	4
F12	3	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMINOCAPROIC ACID	4	PLG
TELAPREVIR	4	PLG
MELAGATRAN	4	PLG
BEROTRALSTAT	4	PLG
PENTAMIDINE	4	PLG
TRANEXAMIC ACID	4	PLG
NAFAMOSTAT	3	F12, PLG
GABEXATE	3	F12, PLG
MILVEXIAN	3	PLG
DABIGATRAN	3	PLG
SEPIMOSTAT	2	F12
EFEGATRAN	2	PLG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PLG	480	Binding:467, ADMET:7, Functional:6
F12	128	Binding:123, Functional:3, ADMET:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
F12	3.4.21.38	coagulation factor XIIa
PLG	3.4.21.7	plasmin

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
F12	128
PLG	480

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

10 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)
AMINOCAPROIC ACID	4	PLG
TELAPREVIR	4	PLG
MELAGATRAN	4	PLG
PENTAMIDINE	4	PLG
NAFAMOSTAT	3	F12, PLG
GABEXATE	3	F12, PLG
MILVEXIAN	3	PLG
DABIGATRAN	3	PLG
SEPIMOSTAT	2	F12
EFEGATRAN	2	PLG

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PLG
B	Phased (≥1) drug, not yet approved	1	F12
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 145.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	48
Not specified	43
PHASE2	19
PHASE1	16
PHASE4	7
PHASE2/PHASE3	7
PHASE1/PHASE2	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06806657	PHASE4	ACTIVE_NOT_RECRUITING	Safety Study in Subjects ≥ 12 Years of Age With Hereditary Angioedema Switching to Garadacimab
NCT00914966	PHASE4	COMPLETED	A Study to Evaluate the Safety and Effect of Escalating Doses of CINRYZE
NCT01151735	PHASE4	WITHDRAWN	C1-INH Compared to Placebo at the Time of Prodromal Symptoms for Hereditary Angioedema (HAE) Exacerbation
NCT01457430	PHASE4	COMPLETED	Efficacy, Safety and Tolerability of Icatibant for the Treatment of HAE
NCT01679912	PHASE4	COMPLETED	A Call Center During HAE Attacks (SOS HAE)
NCT06690047	PHASE4	COMPLETED	Treatment of Hereditary Angioedema Prodrome with Recombinant C1-esterase Inhibitor (Ruconest)
NCT07290855	PHASE4	COMPLETED	A Study to Evaluate the Safety and Efficacy of Icatibant in Patients With Bradykinin Induced Angioedema
NCT04933721	PHASE3	ENROLLING_BY_INVITATION	Open-label Berotralstat Access to HAE Patients Previously Enrolled in Berotralstat Studies
NCT05392114	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Assess the Long-Term Safety and Efficacy of Donidalorsen in the Prophylactic Treatment of Hereditary Angioedema (HAE)
NCT05396105	PHASE2/PHASE3	ENROLLING_BY_INVITATION	Extension Study of Oral PHA-022121 for Acute Treatment of Angioedema Attacks in Patients With Hereditary Angioedema
NCT05453968	PHASE3	ACTIVE_NOT_RECRUITING	Berotralstat Treatment in Children With Hereditary Angioedema
NCT05505916	PHASE3	ACTIVE_NOT_RECRUITING	An Open-label Extension Trial to Evaluate the Long-term Safety of KVD900 (Sebetralstat) for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients With Hereditary Angioedema (HAE)
NCT05511922	PHASE3	ACTIVE_NOT_RECRUITING	PK Subtrial in Adolescent Patients With HAE Type I or II Participating in the KVD900-302 Trial
NCT06634420	PHASE3	ACTIVE_NOT_RECRUITING	HAELO: A Phase 3 Study to Evaluate NTLA-2002 in Participants With Hereditary Angioedema (HAE)
NCT06669754	PHASE3	ACTIVE_NOT_RECRUITING	Study of Oral Deucrictibant Extended-Release Tablet for Prophylaxis Against Angioedema Attacks in Adolescents and Adults With HAE
NCT06679881	PHASE3	RECRUITING	Long-Term, Open-label Study of Oral Deucrictibant Extended-Release Tablet for Prophylaxis Against Angioedema Attacks in Adolescents and Adults With HAE
NCT06842823	PHASE3	RECRUITING	A Study of Navenibart in Participants With Hereditary Angioedema
NCT06960213	PHASE3	RECRUITING	STOP-HAE: A Phase 3 Study of ADX-324 in HAE
NCT07204938	PHASE3	ENROLLING_BY_INVITATION	A Long-Term Study of Navenibart in Participants With Hereditary Angioedema
NCT07298447	PHASE3	RECRUITING	Donidalorsen Treatment in Children With Hereditary Angioedema
NCT07428499	PHASE3	RECRUITING	Phase 3 Extension Study of ADX-324 in Participants With Hereditary Angioedema (HAE)
NCT00168103	PHASE2/PHASE3	COMPLETED	Human C1 Esterase Inhibitor (C1-INH) in Subjects With Acute Abdominal or Facial Hereditary Angioedema (HAE) Attacks
NCT00225147	PHASE2/PHASE3	COMPLETED	Recombinant Human C1 Inhibitor for the Treatment of Acute Attacks in Patients With Hereditary Angioedema
NCT00262080	PHASE3	COMPLETED	Efficacy and Safety Study of DX-88 to Treat Acute Attacks of Hereditary Angioedema (HAE)
NCT00262301	PHASE3	COMPLETED	Recombinant Human C1 Inhibitor for the Treatment of Acute Attacks in Patients With Hereditary Angioedema
NCT00289211	PHASE3	COMPLETED	C1 Esterase Inhibitor (C1INH-nf) for the Treatment of Acute Hereditary Angioedema (HAE) Attacks
NCT00292981	PHASE3	COMPLETED	C1 Esterase Inhibitor in Hereditary Angioedema (HAE)(Extension Study)
NCT00438815	PHASE3	COMPLETED	Open-Label C1 Esterase Inhibitor (C1INH-nf) for the Treatment of Acute Hereditary Angioedema (HAE) Attacks
NCT00456508	PHASE3	COMPLETED	Safety and Efficacy Study of Repeated Doses of DX-88 (Ecallantide) to Treat Attacks of Hereditary Angioedema (HAE)
NCT00457015	PHASE3	COMPLETED	Efficacy Study of DX-88 (Ecallantide) to Treat Acute Attacks of Hereditary Angioedema (HAE)
NCT00462709	PHASE3	COMPLETED	Open-Label C1 Esterase Inhibitor (C1INH-nf) for the Prevention of Acute Hereditary Angioedema (HAE) Attacks
NCT00500656	PHASE3	COMPLETED	Subcutaneous Treatment With Icatibant for Acute Attacks of Hereditary Angioedema (HAE)
NCT00748202	PHASE3	COMPLETED	Berinert P Study of Subcutaneous Versus Intravenous Administration
NCT00912093	PHASE3	COMPLETED	A Study of Icatibant in Patients With Acute Attacks of Hereditary Angioedema (FAST-3)
NCT00997204	PHASE3	COMPLETED	EASSI - Evaluation of the Safety of Self-Administration With Icatibant
NCT01005888	PHASE3	COMPLETED	C1 Esterase Inhibitor (C1INH-nf) for the Prevention of Acute Hereditary Angioedema (HAE) Attacks
NCT01188564	PHASE3	COMPLETED	Efficacy, Safety and Immunogenicity Study of Recombinant Human C1 Inhibitor for the Treatment of Acute HAE Attacks
NCT01253382	PHASE2/PHASE3	WITHDRAWN	Study to Evaluate Ecallantide in Paediatric Patients With Acute Attacks of Hereditary Angioedema
NCT01386658	PHASE3	COMPLETED	A Pharmacokinetic, Tolerability and Safety Study of Icatibant in Children and Adolescents With Hereditary Angioedema
NCT02052141	PHASE3	COMPLETED	Safety and Efficacy Study of CINRYZE for Prevention of Angioedema Attacks in Children Ages 6-11 With Hereditary Angioedema

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BEROTRALSTAT	4	11
ICATIBANT	4	9
LANADELUMAB	4	9
CONESTAT ALFA	4	7
ECALLANTIDE	4	6
HUMAN C1-ESTERASE INHIBITOR	4	5
TRANEXAMIC ACID	4	1
SEBETRALSTAT	3	8
DONIDALORSEN	3	6
AVORALSTAT	3	4
DEUCRICTIBANT	2	5
NAVENIBART	2	5
FENIRALSTAT	2	1