Hereditary angioedema type 3

Summary

Hereditary angioedema type 3 (MONDO:0012526) is a disease caused by F12 (GenCC Definitive), with 2 cohort genes and 2 clinical trials. Top therapeutic interventions include deucrictibant.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: F12 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 58
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary angioedema type 3
Mondo ID	MONDO:0012526
MeSH	D056828
OMIM	610618
Orphanet	100054
DOID	DOID:0080940
SNOMED CT	427167008
UMLS	C1857728
MedGen	346653
GARD	0016935
Is cancer (heuristic)	no

Also known as: angioedema, hereditary, 3 · angioedema, hereditary, type III · F12 hereditary angioedema · HAE 3 · HAE-III · HAE3 · hereditary angioedema caused by mutation in F12 · hereditary angioedema type 3 · hereditary angioneurotic edema type 3 · hereditary angioneurotic oedema type 3 · inherited estrogen-associated angioedema · inherited estrogen-associated angioneurotic edema · inherited estrogen-associated angioneurotic oedema · inherited estrogen-dependent angioedema · inherited estrogen-dependent angioneurotic edema · inherited estrogen-dependent angioneurotic oedema

Data availability: 58 ClinVar variants · 5 GenCC gene-disease records.

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 type 3

Related subtypes (9): 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

58 retrieved; paginated sample, class counts are floors:

19 conflicting classifications of pathogenicity, 17 uncertain significance, 7 benign, 7 benign/likely benign, 3 pathogenic, 3 likely benign, 1 likely pathogenic, 1 pathogenic/likely 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
1170	NM_000505.4(F12):c.983C>G (p.Thr328Arg)	F12	Pathogenic	criteria provided, single submitter
403709	NM_000505.4(F12):c.894_911dup (p.Gln300_Thr305dup)	F12	Pathogenic	no assertion criteria provided
441533	NM_000505.4(F12):c.971_1018+24del	F12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4086125	NM_000505.4(F12):c.312C>A (p.Cys104Ter)	F12	Likely pathogenic	criteria provided, single submitter
778400	NM_001146.5(ANGPT1):c.1151G>A (p.Arg384Gln)	ANGPT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1166	NM_000505.4(F12):c.1681-1G>A	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352992	NM_000505.4(F12):c.1107G>C (p.Ser369=)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352993	NM_000505.4(F12):c.1025C>T (p.Pro342Leu)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352994	NM_000505.4(F12):c.1018+13G>C	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
352995	NM_000505.4(F12):c.1018+12G>C	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353001	NM_000505.4(F12):c.418C>G (p.Leu140Val)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353003	NM_000505.4(F12):c.348C>A (p.Gly116=)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353004	NM_000505.4(F12):c.-3G>A	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
369462	NC_000005.10:g.177409584C>G	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904430	NM_000505.4(F12):c.1704G>A (p.Val568=)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904431	NM_000505.4(F12):c.1387+4C>G	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904493	NM_000505.4(F12):c.1018+11G>T	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904550	NM_000505.4(F12):c.129C>T (p.Thr43=)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904551	NM_000505.4(F12):c.120C>T (p.Leu40=)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
905230	NM_000505.4(F12):c.1251-9C>A	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907810	NM_000505.4(F12):c.1018+14G>T	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907866	NM_000505.4(F12):c.293G>A (p.Cys98Tyr)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
983442	NM_000505.4(F12):c.41T>C (p.Leu14Ser)	F12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
979220	NM_001146.5(ANGPT1):c.1110G>C (p.Gln370His)	ANGPT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1168	NM_000505.4(F12):c.158A>G (p.Tyr53Cys)	F12	Uncertain significance	criteria provided, single submitter
352990	NM_000505.4(F12):c.1251-12C>A	F12	Uncertain significance	criteria provided, single submitter
352991	NM_000505.4(F12):c.1212C>G (p.Pro404=)	F12	Uncertain significance	criteria provided, single submitter
352997	NM_000505.4(F12):c.928A>T (p.Arg310Trp)	F12	Uncertain significance	criteria provided, single submitter
353000	NM_000505.4(F12):c.630C>T (p.Asp210=)	F12	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 4 · 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
F12	Definitive	Autosomal dominant	hereditary angioedema type 3	7

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
ANGPT1	Orphanet:599418	Hereditary angioedema with normal C1Inh not related to F12 or PLG variant

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	gencc,clinvar
ANGPT1	HGNC:484	ENSG00000154188	Q15389	Angiopoietin-1	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.
ANGPT1	Angiopoietin-1	Binds and activates TEK/TIE2 receptor by inducing its dimerization and tyrosine phosphorylation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
F12	Protease	yes	3.4.21.38	Kringle, Fibronectin_type1, FN_type2_dom
ANGPT1	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_C_1, Fibrinogen_CS

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
gingival epithelium	1
liver	1
right lobe of liver	1
calcaneal tendon	1
cranial nerve II	1
lower lobe of lung	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
ANGPT1	250	ubiquitous	marker	lower lobe of lung, calcaneal tendon, cranial nerve II

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
F12	3,850
ANGPT1	2,194

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
F12	P00748	17
ANGPT1	Q15389	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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×	0.005	F12
FXIIa, PKa-dependent activation of coagulation pathway	1	571.0×	0.005	F12
Tie2 Signaling	1	300.5×	0.007	ANGPT1
FXIIa activates plasma kallikrein-kinin system	1	86.5×	0.021	F12
MAPK1/MAPK3 signaling	1	65.6×	0.025	ANGPT1
MAPK family signaling cascades	1	51.4×	0.027	ANGPT1
Cell surface interactions at the vascular wall	1	47.6×	0.027	ANGPT1
RAF/MAP kinase cascade	1	30.5×	0.038	ANGPT1
Hemostasis	1	18.0×	0.059	ANGPT1
Signal Transduction	1	5.1×	0.187	ANGPT1

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
blood coagulation	2	173.7×	0.002	F12, ANGPT1
regulation of macrophage migration inhibitory factor signaling pathway	1	8426.0×	0.003	ANGPT1
plasma kallikrein-kinin cascade	1	4213.0×	0.003	F12
Factor XII activation	1	2808.7×	0.003	F12
activation of transmembrane receptor protein tyrosine kinase activity	1	2808.7×	0.003	ANGPT1
response to misfolded protein	1	2808.7×	0.003	F12
glomerulus vasculature development	1	2106.5×	0.003	ANGPT1
Tie signaling pathway	1	1685.2×	0.003	ANGPT1
positive regulation of fibrinolysis	1	1685.2×	0.003	F12
positive regulation of blood-brain barrier permeability	1	1685.2×	0.003	ANGPT1
negative regulation of cytokine production involved in immune response	1	1404.3×	0.003	ANGPT1
regulation of skeletal muscle satellite cell proliferation	1	1404.3×	0.003	ANGPT1
positive regulation of coagulation	1	1404.3×	0.003	ANGPT1
blood coagulation, intrinsic pathway	1	1053.2×	0.003	F12
positive regulation of plasminogen activation	1	936.2×	0.003	F12
heparin proteoglycan biosynthetic process	1	842.6×	0.003	ANGPT1
regulation of tumor necrosis factor production	1	842.6×	0.003	ANGPT1
negative regulation of vascular endothelial growth factor signaling pathway	1	648.1×	0.004	ANGPT1
positive regulation of blood coagulation	1	561.7×	0.004	F12
negative regulation of vascular permeability	1	561.7×	0.004	ANGPT1
negative regulation of protein import into nucleus	1	468.1×	0.005	ANGPT1
fibrinolysis	1	421.3×	0.005	F12
positive regulation of peptidyl-tyrosine phosphorylation	1	401.2×	0.005	ANGPT1
positive chemotaxis	1	401.2×	0.005	ANGPT1
cell-substrate adhesion	1	383.0×	0.005	ANGPT1
positive regulation of receptor internalization	1	351.1×	0.005	ANGPT1
zymogen activation	1	337.0×	0.005	F12
protein autoprocessing	1	324.1×	0.005	F12
protein localization to cell surface	1	247.8×	0.006	ANGPT1
negative regulation of endothelial cell apoptotic process	1	247.8×	0.006	ANGPT1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
ANGPT1	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
ANGPT1	1	Binding:1

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: 2; 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	0
E	Difficult family or no structure, no drug	1	ANGPT1

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)
ANGPT1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2/PHASE3	1
PHASE3	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
NCT06343779	PHASE3	COMPLETED	Study of Oral Deucrictibant Soft Capsule for On-Demand Treatment of Angioedema Attacks in Adolescents and Adults With Hereditary Angioedema

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DEUCRICTIBANT	2	2