hereditary angioedema with C1Inh deficiency

Summary

hereditary angioedema with C1Inh deficiency (MONDO:0033946) is a disease caused by SERPING1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SERPING1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 35
• Phenotypes (HPO): 24

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		51	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0000282	Facial edema	Frequent (30-79%)
HP:0000988	Skin rash	Frequent (30-79%)
HP:0001386	Joint swelling	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002017	Nausea and vomiting	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0011855	Pharyngeal edema	Frequent (30-79%)
HP:0012027	Laryngeal edema	Frequent (30-79%)
HP:0012531	Pain	Frequent (30-79%)
HP:0025527	Serpiginous cutaneous lesion	Frequent (30-79%)
HP:0031188	Genital edema	Frequent (30-79%)
HP:0034204	Decreased circulating C1-esterase inhibitor concentration	Frequent (30-79%)
HP:0045042	Decreased circulating complement C4 concentration	Frequent (30-79%)
HP:0100665	Angioedema	Frequent (30-79%)
HP:0100748	Muscular edema	Frequent (30-79%)
HP:6000507	Non-pitting edema	Frequent (30-79%)
HP:6001012	Erythema marginatum	Frequent (30-79%)
HP:0002315	Headache	Occasional (5-29%)
HP:0003401	Paresthesia	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0025406	Asthenia	Occasional (5-29%)
HP:0000989	Pruritus	Excluded (0%)
HP:0001025	Urticaria	Excluded (0%)
HP:0012271	Episodic upper airway obstruction	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary angioedema with C1Inh deficiency
Mondo ID	MONDO:0033946
OMIM	106100
Orphanet	528623
DOID	DOID:0080939
UMLS	C4552294
MedGen	1812520
GARD	0022194
Is cancer (heuristic)	no

Also known as: angioedema, hereditary, 1 and 2 · angioedema, hereditary, type 1/2 · angioedema, hereditary, type I · HAE1

Data availability: 35 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

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

Related subtypes (9): hereditary angioedema type 3, angioedema, hereditary, 6, angioedema, hereditary, 4, angioedema, hereditary, 7, angioedema, hereditary, 5, angioedema, hereditary, 8, PLG-related hereditary angioedema with normal C1inh, hereditary angioedema with normal C1inh not related to F12 or PLG variant, hereditary angioedema with normal C1Inh

Subtypes (2): hereditary angioedema type 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

35 retrieved; paginated sample, class counts are floors:

27 pathogenic, 7 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1299717	NM_000062.3(SERPING1):c.74del (p.Asn25fs)	SERPING1	Pathogenic	no assertion criteria provided
1299718	NM_000062.3(SERPING1):c.635dup (p.Phe213fs)	SERPING1	Pathogenic	no assertion criteria provided
1299719	NM_000062.3(SERPING1):c.673_675del (p.Phe225del)	SERPING1	Pathogenic	no assertion criteria provided
1299721	NM_000062.3(SERPING1):c.733_736dup (p.Ser246fs)	SERPING1	Pathogenic	no assertion criteria provided
1299722	NM_000062.3(SERPING1):c.779dup (p.Leu261fs)	SERPING1	Pathogenic	no assertion criteria provided
1299723	NM_000062.3(SERPING1):c.785dup (p.Asn263fs)	SERPING1	Pathogenic	no assertion criteria provided
1299724	NM_000062.3(SERPING1):c.941_942insTC (p.Phe315fs)	SERPING1	Pathogenic	no assertion criteria provided
1299725	NM_000062.3(SERPING1):c.951dup (p.Ser318fs)	SERPING1	Pathogenic	no assertion criteria provided
1299726	NM_000062.3(SERPING1):c.983_984delinsC (p.Lys328fs)	SERPING1	Pathogenic	no assertion criteria provided
1299727	NM_000062.3(SERPING1):c.1019del (p.Thr339_Leu340insTer)	SERPING1	Pathogenic	no assertion criteria provided
1299729	NM_000062.3(SERPING1):c.1051del (p.His351fs)	SERPING1	Pathogenic	no assertion criteria provided
1299730	NM_000062.3(SERPING1):c.1094dup (p.His365fs)	SERPING1	Pathogenic	no assertion criteria provided
1299732	NM_000062.3(SERPING1):c.1186del (p.Leu395_Leu396insTer)	SERPING1	Pathogenic	criteria provided, single submitter
1299734	NM_000062.3(SERPING1):c.1193T>G (p.Leu398Arg)	SERPING1	Pathogenic	criteria provided, single submitter
1299735	NM_000062.3(SERPING1):c.1249+2T>C	SERPING1	Pathogenic	no assertion criteria provided
1299736	NM_000062.3(SERPING1):c.1289T>G (p.Leu430Arg)	SERPING1	Pathogenic	criteria provided, single submitter
1299739	NM_000062.3(SERPING1):c.172_181del (p.Pro58fs)	SERPING1	Pathogenic	no assertion criteria provided
1299742	NM_000062.3(SERPING1):c.197dup (p.Thr67fs)	SERPING1	Pathogenic	no assertion criteria provided
1299743	NM_000062.3(SERPING1):c.229A>T (p.Lys77Ter)	SERPING1	Pathogenic	no assertion criteria provided
1299744	NM_000062.3(SERPING1):c.232del (p.Lys77_Ile78insTer)	SERPING1	Pathogenic	no assertion criteria provided
1299745	NM_000062.3(SERPING1):c.538C>T (p.Gln180Ter)	SERPING1	Pathogenic	criteria provided, single submitter
1299746	NM_000062.3(SERPING1):c.550+1G>T	SERPING1	Pathogenic	no assertion criteria provided
1299747	NM_000062.3(SERPING1):c.623dup (p.Ala209fs)	SERPING1	Pathogenic	criteria provided, single submitter
1329453	NM_000062.3(SERPING1):c.330_331insC (p.Thr111fs)	SERPING1	Pathogenic	no assertion criteria provided
1329454	NM_000062.3(SERPING1):c.748_749del (p.Val250fs)	SERPING1	Pathogenic	no assertion criteria provided
1329455	NM_000062.3(SERPING1):c.1269T>A (p.Tyr423Ter)	SERPING1	Pathogenic	no assertion criteria provided
1690315	NM_000062.3(SERPING1):c.377del (p.Pro126fs)	SERPING1	Pathogenic	no assertion criteria provided
1299720	NM_000062.3(SERPING1):c.708T>G (p.Phe236Leu)	SERPING1	Likely pathogenic	no assertion criteria provided
1299731	NM_000062.3(SERPING1):c.1100T>G (p.Leu367Arg)	SERPING1	Likely pathogenic	no assertion criteria provided
1299733	NM_000062.3(SERPING1):c.1192C>G (p.Leu398Val)	SERPING1	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SERPING1	HGNC:1228	ENSG00000149131	P05155	Plasma protease C1 inhibitor	gencc,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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SERPING1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right coronary artery	1
right lobe of liver	1
right lung	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SERPING1	2,104

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SERPING1	P05155	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 evidence-associated genes (1 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 1 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	1	2855.0×	0.002	SERPING1
Regulation of FXIIa and plasma kallikrein activity	1	1142.0×	0.002	SERPING1
Regulation of clotting cascade	1	233.1×	0.005	SERPING1
Regulation of Complement cascade	1	233.1×	0.005	SERPING1
Platelet degranulation	1	87.8×	0.011	SERPING1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of complement activation, lectin pathway	1	8426.0×	5e-04	SERPING1
fibrinolysis	1	842.6×	0.002	SERPING1
blood circulation	1	510.7×	0.003	SERPING1
blood coagulation	1	173.7×	0.006	SERPING1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
SERPING1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
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: 0.