Hereditary angioedema type 1

Summary

Hereditary angioedema type 1 (MONDO:0015053) is a disease with 3 cohort genes and 7 clinical trials. Top therapeutic interventions include deucrictibant.

At a glance

• Prevalence: 1-9 / 100 000 (Italy) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 328
• Phenotypes (HPO): 26
• Clinical trials: 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.54	Italy	Validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000282	Facial edema	Very frequent (80-99%)
HP:0001025	Urticaria	Very frequent (80-99%)
HP:0001939	Abnormality of metabolism/homeostasis	Very frequent (80-99%)
HP:0002027	Abdominal pain	Very frequent (80-99%)
HP:0003401	Paresthesia	Very frequent (80-99%)
HP:0005225	Intestinal edema	Very frequent (80-99%)
HP:0007514	Edema of the dorsum of hands	Very frequent (80-99%)
HP:0011971	Dermatographic urticaria	Very frequent (80-99%)
HP:0012027	Laryngeal edema	Very frequent (80-99%)
HP:0012252	Abnormal respiratory system morphology	Very frequent (80-99%)
HP:0025349	Limbal edema	Very frequent (80-99%)
HP:0040315	Tongue edema	Very frequent (80-99%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002018	Nausea	Frequent (30-79%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0100755	Abnormality of salivation	Frequent (30-79%)
HP:0000172	Abnormality of the uvula	Occasional (5-29%)
HP:0001609	Hoarse voice	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002615	Hypotension	Occasional (5-29%)
HP:0005348	Inspiratory stridor	Occasional (5-29%)
HP:0005483	Abnormal epiglottis morphology	Occasional (5-29%)
HP:0011855	Pharyngeal edema	Occasional (5-29%)
HP:0100736	Abnormality of the soft palate	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary angioedema type 1
Mondo ID	MONDO:0015053
Orphanet	100050
SNOMED CT	234619000
UMLS	C2717906
MedGen	403466
GARD	0016933
Is cancer (heuristic)	no

Also known as: HAE 1 · HAE-I · hereditary angioneurotic edema type 1 · hereditary angioneurotic oedema type 1

Data availability: 328 ClinVar variants · 1 GenCC gene-disease record.

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 C1Inh deficiency › hereditary angioedema type 1

Related subtypes (1): hereditary angioedema type 2

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

328 retrieved; paginated sample, class counts are floors:

171 pathogenic, 52 likely pathogenic, 36 benign, 25 uncertain significance, 20 conflicting classifications of pathogenicity, 9 likely benign, 8 benign/likely benign, 7 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4686556	NC_000006.11:g.10791926_10791927insSVA	MAK	Pathogenic	criteria provided, single submitter
1299734	NM_000062.3(SERPING1):c.1193T>G (p.Leu398Arg)	SERPING1	Pathogenic	criteria provided, single submitter
1299736	NM_000062.3(SERPING1):c.1289T>G (p.Leu430Arg)	SERPING1	Pathogenic	criteria provided, single submitter
1299745	NM_000062.3(SERPING1):c.538C>T (p.Gln180Ter)	SERPING1	Pathogenic	criteria provided, single submitter
1299747	NM_000062.3(SERPING1):c.623dup (p.Ala209fs)	SERPING1	Pathogenic	criteria provided, single submitter
1382465	NM_000062.3(SERPING1):c.551-1G>C	SERPING1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1438889	NM_000062.3(SERPING1):c.1429T>C (p.Phe477Leu)	SERPING1	Pathogenic	criteria provided, multiple submitters, no conflicts
1675130	NM_000062.3(SERPING1):c.1450C>T (p.Gln484Ter)	SERPING1	Pathogenic	criteria provided, multiple submitters, no conflicts
1683559	NM_000062.3(SERPING1):c.346C>T (p.Gln116Ter)	SERPING1	Pathogenic	criteria provided, single submitter
1694638	NM_000062.3(SERPING1):c.1309C>T (p.Gln437Ter)	SERPING1	Pathogenic	criteria provided, multiple submitters, no conflicts
252941	NM_000062.3(SERPING1):c.550+745_685+308del	SERPING1	Pathogenic	no assertion criteria provided
252942	NM_000062.3(SERPING1):c.953C>G (p.Ser318Ter)	SERPING1	Pathogenic	no assertion criteria provided
2575091	NM_000062.3(SERPING1):c.1196C>G (p.Pro399Arg)	SERPING1	Pathogenic	criteria provided, single submitter
2761809	NM_000062.3(SERPING1):c.1157_1158del (p.Leu386fs)	SERPING1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280064	NM_000062.3(SERPING1):c.52-1G>A	SERPING1	Pathogenic	criteria provided, multiple submitters, no conflicts
2907408	NM_000062.3(SERPING1):c.51+3A>C	SERPING1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3242420	NM_000062.3(SERPING1):c.1029+1del	SERPING1	Pathogenic	criteria provided, single submitter
3242421	NM_000062.3(SERPING1):c.468del (p.Phe157fs)	SERPING1	Pathogenic	criteria provided, single submitter
3242423	NM_000062.3(SERPING1):c.963del (p.Val322fs)	SERPING1	Pathogenic	criteria provided, single submitter
3242424	NM_000062.3(SERPING1):c.1249+2T>G	SERPING1	Pathogenic	criteria provided, single submitter
3242425	NM_000062.3(SERPING1):c.312dup (p.Pro105fs)	SERPING1	Pathogenic	criteria provided, single submitter
3242430	NM_000062.3(SERPING1):c.-161A>G	SERPING1	Pathogenic	criteria provided, single submitter
3242449	NM_000062.3(SERPING1):c.732C>A (p.Tyr244Ter)	SERPING1	Pathogenic	criteria provided, single submitter
3242450	NM_000062.3(SERPING1):c.686-12A>G	SERPING1	Pathogenic	criteria provided, single submitter
3242452	NM_000062.3(SERPING1):c.1030delG	SERPING1	Pathogenic	criteria provided, single submitter
3242453	NM_000062.3(SERPING1):c.1030-1G>T	SERPING1	Pathogenic	criteria provided, multiple submitters, no conflicts
3242531	NM_000062.3(SERPING1):c.1337_1341del (p.Val446fs)	SERPING1	Pathogenic	criteria provided, single submitter
3242566	NM_000062.3(SERPING1):c.664_667del (p.Ser222fs)	SERPING1	Pathogenic	criteria provided, single submitter
3242567	NM_000062.3(SERPING1):c.950dup (p.Asn317fs)	SERPING1	Pathogenic	criteria provided, single submitter
3242568	NM_000062.3(SERPING1):c.1030-1G>C	SERPING1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

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

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SERPING1	Strong	Autosomal dominant	hereditary angioedema with C1Inh deficiency	5

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
MAK	Orphanet:791	Retinitis pigmentosa
PLG	Orphanet:537072	PLG-related hereditary angioedema with normal C1Inh
PLG	Orphanet:722	Hypoplasminogenemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SERPING1	HGNC:1228	ENSG00000149131	P05155	Plasma protease C1 inhibitor	gencc,clinvar
MAK	HGNC:6816	ENSG00000111837	P20794	Serine/threonine-protein kinase MAK	clinvar
PLG	HGNC:9071	ENSG00000122194	P00747	Plasminogen	clinvar

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.
MAK	Serine/threonine-protein kinase MAK	Essential for the regulation of ciliary length and required for the long-term survival of photoreceptors.
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: 1 · Druggable fraction: 0.67

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	12.2×	0.157
Kinase	1	9.2×	0.157
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SERPING1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom
MAK	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
PLG	Protease	yes	3.4.21.7	Kringle, Trypsin_dom, Peptidase_S1A

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
right coronary artery	1
right lung	1
choroid plexus epithelium	1
male germ cell	1
sperm	1
adult organism	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
MAK	184	broad	marker	sperm, male germ cell, choroid plexus 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
PLG	3,441
SERPING1	2,104
MAK	966

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLG	P00747	49
SERPING1	P05155	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAK	P20794	62.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 3 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
Platelet degranulation	2	87.8×	0.001	SERPING1, PLG
Defective SERPING1 causes hereditary angioedema	1	1427.5×	0.004	SERPING1
Regulation of FXIIa and plasma kallikrein activity	1	571.0×	0.006	SERPING1
Dissolution of Fibrin Clot	1	407.9×	0.006	PLG
Activation of Matrix Metalloproteinases	1	154.3×	0.011	PLG
Signaling by PDGF	1	126.9×	0.011	PLG
Regulation of clotting cascade	1	116.5×	0.011	SERPING1
Regulation of Complement cascade	1	116.5×	0.011	SERPING1
Degradation of the extracellular matrix	1	58.9×	0.019	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 3 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	561.7×	1e-04	SERPING1, PLG
blood coagulation	2	115.8×	0.002	SERPING1, PLG
negative regulation of complement activation, lectin pathway	1	2808.7×	0.003	SERPING1
negative regulation of non-motile cilium assembly	1	2808.7×	0.003	MAK
trans-synaptic signaling by BDNF, modulating synaptic transmission	1	1872.4×	0.003	PLG
mononuclear cell migration	1	1404.3×	0.004	PLG
positive regulation of fibrinolysis	1	1123.5×	0.004	PLG
biological process involved in interaction with symbiont	1	936.2×	0.004	PLG
negative regulation of cell-cell adhesion mediated by cadherin	1	510.7×	0.007	PLG
negative regulation of fibrinolysis	1	468.1×	0.007	PLG
tissue remodeling	1	432.1×	0.007	PLG
trophoblast giant cell differentiation	1	401.2×	0.007	PLG
negative regulation of cell-substrate adhesion	1	351.1×	0.007	PLG
myoblast differentiation	1	280.9×	0.008	PLG
labyrinthine layer blood vessel development	1	267.5×	0.008	PLG
tissue regeneration	1	255.3×	0.008	PLG
muscle cell cellular homeostasis	1	216.1×	0.009	PLG
intraciliary transport	1	187.2×	0.009	MAK
blood circulation	1	170.2×	0.010	SERPING1
positive regulation of blood vessel endothelial cell migration	1	130.6×	0.012	PLG
extracellular matrix disassembly	1	122.1×	0.012	PLG
photoreceptor cell maintenance	1	119.5×	0.012	MAK
non-motile cilium assembly	1	96.8×	0.014	MAK
protein processing	1	56.7×	0.023	PLG
protein autophosphorylation	1	48.4×	0.026	MAK
cilium assembly	1	24.5×	0.049	MAK
protein phosphorylation	1	22.6×	0.052	MAK
negative regulation of cell population proliferation	1	14.0×	0.079	PLG
intracellular signal transduction	1	12.7×	0.085	MAK
spermatogenesis	1	11.7×	0.088	MAK

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
MAK	7	3
SERPING1	0	0

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
ALVOCIDIB	3	MAK
LESTAURTINIB	3	MAK
NAFAMOSTAT	3	PLG
MILVEXIAN	3	PLG
DABIGATRAN	3	PLG
GABEXATE	3	PLG
FORETINIB	2	MAK
RG-547	2	MAK
AT-7519	2	MAK
EFEGATRAN	2	PLG
BMS-387032	1	MAK
AST-487	1	MAK

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
MAK	94	Binding:94

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MAK	2.7.11.22	cyclin-dependent kinase
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
PLG	480

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

18 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
BEROTRALSTAT	4	PLG
PENTAMIDINE	4	PLG
TRANEXAMIC ACID	4	PLG
ALVOCIDIB	3	MAK
LESTAURTINIB	3	MAK
NAFAMOSTAT	3	PLG
MILVEXIAN	3	PLG
DABIGATRAN	3	PLG
GABEXATE	3	PLG
FORETINIB	2	MAK
RG-547	2	MAK
AT-7519	2	MAK
EFEGATRAN	2	PLG
BMS-387032	1	MAK
AST-487	1	MAK

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	MAK
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SERPING1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SERPING1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	3
PHASE2	2
PHASE2/PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05396105	PHASE2/PHASE3	ENROLLING_BY_INVITATION	Extension Study of Oral PHA-022121 for Acute Treatment of Angioedema Attacks in Patients With Hereditary Angioedema
NCT06960213	PHASE3	RECRUITING	STOP-HAE: A Phase 3 Study of ADX-324 in HAE
NCT07428499	PHASE3	RECRUITING	Phase 3 Extension Study of ADX-324 in Participants With Hereditary Angioedema (HAE)
NCT06343779	PHASE3	COMPLETED	Study of Oral Deucrictibant Soft Capsule for On-Demand Treatment of Angioedema Attacks in Adolescents and Adults With Hereditary Angioedema
NCT04618211	PHASE2	COMPLETED	Dose-ranging Study of Oral PHA-022121 for Acute Treatment of Angioedema Attacks in Patients With Hereditary Angioedema
NCT05047185	PHASE2	COMPLETED	Dose-ranging Study of Oral PHA-022121 for Prophylaxis Against Angioedema Attacks in Patients With Hereditary Angioedema Type I or Type II
NCT07448181	Not specified	RECRUITING	Real-life Ecological Momentary Assessment of Lived Burden in Hereditary AngioEdema

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DEUCRICTIBANT	2	3