Congenital plasminogen activator inhibitor type 1 deficiency

Summary

Congenital plasminogen activator inhibitor type 1 deficiency (MONDO:0013227) is a disease caused by SERPINE1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: SERPINE1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 79
• Phenotypes (HPO): 25

Clinical features

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0001934	Persistent bleeding after trauma	Very frequent (80-99%)
HP:0004846	Prolonged bleeding after surgery	Very frequent (80-99%)
HP:0040228	Decreased level of plasminogen	Very frequent (80-99%)
HP:0040230	Decreased level of tissue plasminogen activator	Very frequent (80-99%)
HP:0040245	Reduced alpha-2-antiplasmin activity	Very frequent (80-99%)
HP:0040248	Reduced plasminogen activator inhibitor 1 activity	Very frequent (80-99%)
HP:0040249	Reduced plasminogen activator inhibitor 1 antigen	Very frequent (80-99%)
HP:0000132	Menorrhagia	Frequent (30-79%)
HP:0001622	Premature birth	Frequent (30-79%)
HP:0001933	Subcutaneous hemorrhage	Frequent (30-79%)
HP:0005268	Spontaneous abortion	Frequent (30-79%)
HP:0000421	Epistaxis	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0006298	Prolonged bleeding after dental extraction	Occasional (5-29%)
HP:0011891	Post-partum hemorrhage	Occasional (5-29%)
HP:0030657	Umbilical cord hematoma	Occasional (5-29%)
HP:0040184	Oral bleeding	Occasional (5-29%)
HP:0007420	Spontaneous hematomas	Excluded (0%)
HP:0011854	Hemoperitoneum	Very rare (<1-4%)
HP:0012233	Intramuscular hematoma	Very rare (<1-4%)
HP:0100310	Epidural hemorrhage	Very rare (<1-4%)
HP:0001058	Poor wound healing	Very rare (<1-4%)
HP:0001685	Myocardial fibrosis	Very rare (<1-4%)
HP:0005261	Joint hemorrhage	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital plasminogen activator inhibitor type 1 deficiency
Mondo ID	MONDO:0013227
MeSH	C567640
OMIM	613329
Orphanet	465
ICD-11	428643962
NCIT	C133884
SNOMED CT	717407006
UMLS	C2750067
MedGen	412870
GARD	0004381
Is cancer (heuristic)	no

Also known as: congenital PAI-1 deficiency · congenital plasminogen activator inhibitor type 1 deficiency · plasminogen activator inhibitor type 1 deficiency

Data availability: 79 ClinVar variants · 4 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood coagulation disease › coagulation protein disease › congenital plasminogen activator inhibitor type 1 deficiency

Related subtypes (27): factor XIII deficiency, factor VII deficiency, factor X deficiency, thrombophilia due to activated protein C resistance, hypoplasminogenemia, congenital high-molecular-weight kininogen deficiency, congenital factor XII deficiency, alpha-2-plasmin inhibitor deficiency, Tatsumi factor deficiency, East Texas bleeding disorder, inherited prekallikrein deficiency, thrombomodulin-related bleeding disorder, congenital vitamin K-dependent coagulation factors deficiency, hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation, multiple sclerosis-ichthyosis-factor VIII deficiency syndrome, congenital fibrinogen deficiency, combined deficiency of factor V and factor VIII, hemophilia, factor V deficiency, acquired coagulation factor deficiency, von Willebrand disease (hereditary or acquired), factor V short isoforms-related bleeding disorder, factor V amsterdam bleeding disorder, factor V atlanta bleeding disorder, combined deficiency of factor VII and factor X, plasminogen deficiency, type II, dysplasminogenemia

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

79 retrieved; paginated sample, class counts are floors:

53 uncertain significance, 13 benign, 6 likely benign, 3 benign/likely benign, 2 not provided, 1 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
13571	NM_000602.5(SERPINE1):c.699_700del (p.Tyr233_Thr234insTer)	SERPINE1	Pathogenic	no assertion criteria provided
358309	NM_000602.5(SERPINE1):c.456G>C (p.Val152=)	SERPINE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
560088	Single allele	AP1S1	Uncertain significance	criteria provided, single submitter
1031641	NM_000602.5(SERPINE1):c.719A>G (p.Asp240Gly)	SERPINE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1684474	NM_000602.5(SERPINE1):c.79C>A (p.Pro27Thr)	SERPINE1	Uncertain significance	no assertion criteria provided
3317620	NM_000602.5(SERPINE1):c.586G>A (p.Gly196Ser)	SERPINE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
358304	NM_000602.5(SERPINE1):c.-101G>A	SERPINE1	Uncertain significance	criteria provided, single submitter
358305	NM_000602.5(SERPINE1):c.-93C>T	SERPINE1	Uncertain significance	criteria provided, single submitter
358306	NM_000602.5(SERPINE1):c.-54C>T	SERPINE1	Uncertain significance	criteria provided, single submitter
358308	NM_000602.5(SERPINE1):c.191C>T (p.Ser64Leu)	SERPINE1	Uncertain significance	criteria provided, single submitter
358310	NM_000602.5(SERPINE1):c.537C>T (p.Ala179=)	SERPINE1	Uncertain significance	criteria provided, single submitter
358312	NM_000602.5(SERPINE1):c.649G>A (p.Gly217Ser)	SERPINE1	Uncertain significance	criteria provided, single submitter
358313	NM_000602.5(SERPINE1):c.845T>G (p.Ile282Ser)	SERPINE1	Uncertain significance	criteria provided, single submitter
358314	NM_000602.5(SERPINE1):c.1020C>T (p.Val340=)	SERPINE1	Uncertain significance	criteria provided, single submitter
358315	NM_000602.5(SERPINE1):c.*207C>T	SERPINE1	Uncertain significance	criteria provided, single submitter
358321	NM_000602.5(SERPINE1):c.*859C>T	SERPINE1	Uncertain significance	criteria provided, single submitter
358322	NM_000602.5(SERPINE1):c.*891C>T	SERPINE1	Uncertain significance	criteria provided, single submitter
358326	NM_000602.5(SERPINE1):c.*1006T>C	SERPINE1	Uncertain significance	criteria provided, single submitter
358327	NM_000602.5(SERPINE1):c.*1147G>C	SERPINE1	Uncertain significance	criteria provided, single submitter
358328	NM_000602.5(SERPINE1):c.*1155T>C	SERPINE1	Uncertain significance	criteria provided, single submitter
358330	NM_000602.5(SERPINE1):c.*1192G>C	SERPINE1	Uncertain significance	criteria provided, single submitter
358331	NM_000602.5(SERPINE1):c.*1266G>C	SERPINE1	Uncertain significance	criteria provided, single submitter
358332	NM_000602.5(SERPINE1):c.*1295C>T	SERPINE1	Uncertain significance	criteria provided, single submitter
358334	NM_000602.5(SERPINE1):c.*1388G>A	SERPINE1	Uncertain significance	criteria provided, single submitter
358335	NM_000602.5(SERPINE1):c.*1443C>A	SERPINE1	Uncertain significance	criteria provided, single submitter
358336	NM_000602.5(SERPINE1):c.*1590A>G	SERPINE1	Uncertain significance	criteria provided, single submitter
358337	NM_000602.5(SERPINE1):c.*1668G>C	SERPINE1	Uncertain significance	criteria provided, single submitter
3594190	NM_000602.5(SERPINE1):c.628C>T (p.Arg210Cys)	SERPINE1	Uncertain significance	criteria provided, single submitter
3892396	NM_000602.5(SERPINE1):c.992G>A (p.Ser331Asn)	SERPINE1	Uncertain significance	criteria provided, single submitter
908054	NM_000602.5(SERPINE1):c.626G>A (p.Arg209His)	SERPINE1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · 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
SERPINE1	Strong	Autosomal recessive	congenital plasminogen activator inhibitor type 1 deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SERPINE1	Orphanet:465	Congenital plasminogen activator inhibitor type 1 deficiency
SERPINE1	Orphanet:673556	Pseudomyogenic hemangioendothelioma
AP1S1	Orphanet:171851	MEDNIK syndrome

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
SERPINE1	HGNC:8583	ENSG00000106366	P05121	Plasminogen activator inhibitor 1	gencc,clinvar
AP1S1	HGNC:559	ENSG00000106367	P61966	AP-1 complex subunit sigma-1A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SERPINE1	Plasminogen activator inhibitor 1	Serine protease inhibitor.
AP1S1	AP-1 complex subunit sigma-1A	Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SERPINE1	Other/Unknown	no		Serpin_fam, Serpin_CS, Serpin_dom
AP1S1	Other/Unknown	no		Clathrin_sm-chain_CS, Longin-like_dom_sf, AP_complex_ssu

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
stromal cell of endometrium	2
decidua	1
vena cava	1
cortical plate	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SERPINE1	234	ubiquitous	marker	vena cava, stromal cell of endometrium, decidua
AP1S1	253	ubiquitous	marker	cortical plate, stromal cell of endometrium, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SERPINE1	3,888
AP1S1	1,164

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SERPINE1	P05121	29
AP1S1	P61966	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. 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
Nef mediated downregulation of MHC class I complex cell surface expression	1	571.0×	0.013	AP1S1
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	439.2×	0.013	SERPINE1
Dissolution of Fibrin Clot	1	407.9×	0.013	SERPINE1
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	1	335.9×	0.013	SERPINE1
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1	317.2×	0.013	AP1S1
The role of Nef in HIV-1 replication and disease pathogenesis	1	317.2×	0.013	AP1S1
BMAL1:CLOCK,NPAS2 activates circadian expression	1	211.5×	0.015	SERPINE1
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	184.2×	0.015	SERPINE1
Host Interactions of HIV factors	1	167.9×	0.015	AP1S1
Lysosome Vesicle Biogenesis	1	163.1×	0.015	AP1S1
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	154.3×	0.015	SERPINE1
trans-Golgi Network Vesicle Budding	1	126.9×	0.016	AP1S1
Regulation of clotting cascade	1	116.5×	0.016	SERPINE1
Golgi Associated Vesicle Biogenesis	1	100.2×	0.018	AP1S1
ECM proteoglycans	1	75.1×	0.022	SERPINE1
HIV Infection	1	59.5×	0.026	AP1S1
MHC class II antigen presentation	1	44.6×	0.031	AP1S1
Platelet degranulation	1	43.9×	0.031	SERPINE1
Membrane Trafficking	1	18.5×	0.070	AP1S1
Vesicle-mediated transport	1	17.4×	0.071	AP1S1
Viral Infection Pathways	1	15.4×	0.075	AP1S1
Adaptive Immune System	1	14.9×	0.075	AP1S1
Infectious disease	1	12.4×	0.086	AP1S1
Disease	1	6.5×	0.148	AP1S1
Immune System	1	6.5×	0.148	AP1S1

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 leukotriene production involved in inflammatory response	1	8426.0×	0.003	SERPINE1
negative regulation of smooth muscle cell-matrix adhesion	1	4213.0×	0.003	SERPINE1
negative regulation of thrombin-activated receptor signaling pathway	1	2808.7×	0.003	SERPINE1
negative regulation of integrin-mediated signaling pathway	1	2106.5×	0.003	SERPINE1
negative regulation of vascular wound healing	1	1685.2×	0.003	SERPINE1
basolateral protein secretion	1	1685.2×	0.003	AP1S1
positive regulation of coagulation	1	1404.3×	0.003	SERPINE1
negative regulation of plasminogen activation	1	1203.7×	0.003	SERPINE1
positive regulation of odontoblast differentiation	1	1203.7×	0.003	SERPINE1
dentinogenesis	1	1053.2×	0.004	SERPINE1
negative regulation of smooth muscle cell migration	1	766.0×	0.004	SERPINE1
negative regulation of fibrinolysis	1	702.2×	0.004	SERPINE1
negative regulation of cell adhesion mediated by integrin	1	648.1×	0.004	SERPINE1
negative regulation of wound healing	1	648.1×	0.004	SERPINE1
negative regulation of blood coagulation	1	601.9×	0.004	SERPINE1
positive regulation of blood coagulation	1	561.7×	0.004	SERPINE1
replicative senescence	1	495.6×	0.004	SERPINE1
melanosome assembly	1	443.5×	0.004	AP1S1
fibrinolysis	1	421.3×	0.004	SERPINE1
positive regulation of receptor-mediated endocytosis	1	401.2×	0.004	SERPINE1
positive regulation of monocyte chemotaxis	1	401.2×	0.004	SERPINE1
negative regulation of proteolysis	1	337.0×	0.005	SERPINE1
platelet dense granule organization	1	337.0×	0.005	AP1S1
negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	1	290.6×	0.005	SERPINE1
negative regulation of endothelial cell apoptotic process	1	247.8×	0.006	SERPINE1
positive regulation of interleukin-8 production	1	122.1×	0.012	SERPINE1
receptor-mediated endocytosis	1	110.9×	0.012	AP1S1
retrograde transport, endosome to Golgi	1	102.8×	0.013	AP1S1
defense response to Gram-negative bacterium	1	84.3×	0.015	SERPINE1
positive regulation of inflammatory response	1	72.6×	0.017	SERPINE1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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
SERPINE1	2	2
AP1S1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ALEPLASININ	2	SERPINE1
TIPLASININ	2	SERPINE1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SERPINE1	49	Binding:48, Functional:1
AP1S1	1	Binding:1

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

2 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)
ALEPLASININ	2	SERPINE1
TIPLASININ	2	SERPINE1

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	SERPINE1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	AP1S1

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)
AP1S1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.