Hypoplasminogenemia

Summary

Hypoplasminogenemia (MONDO:0009009) is a disease caused by PLG (GenCC Strong), with 1 cohort gene and 6 clinical trials. Top therapeutic interventions include plasminogen.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: PLG (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 153
• Phenotypes (HPO): 16
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.16	Europe	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000478	Abnormality of the eye	Very frequent (80-99%)
HP:0000504	Abnormality of vision	Very frequent (80-99%)
HP:0040228	Decreased level of plasminogen	Very frequent (80-99%)
HP:0000212	Gingival overgrowth	Frequent (30-79%)
HP:0000230	Gingivitis	Frequent (30-79%)
HP:0000137	Abnormality of the ovary	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000370	Abnormality of the middle ear	Occasional (5-29%)
HP:0000704	Periodontitis	Occasional (5-29%)
HP:0000787	Nephrolithiasis	Occasional (5-29%)
HP:0000951	Abnormality of the skin	Occasional (5-29%)
HP:0001305	Dandy-Walker malformation	Occasional (5-29%)
HP:0002086	Abnormality of the respiratory system	Occasional (5-29%)
HP:0002588	Duodenal ulcer	Occasional (5-29%)
HP:0011027	Abnormality of the fallopian tube	Occasional (5-29%)
HP:0030160	Cervicitis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypoplasminogenemia
Mondo ID	MONDO:0009009
MeSH	C580017
OMIM	217090
Orphanet	722, 97231
DOID	DOID:0111592
ICD-11	1240776230
SNOMED CT	403435005, 95840007
UMLS	C1968804
MedGen	369859
GARD	0004380
MedDRA	10071570
Is cancer (heuristic)	no

Also known as: hypoplasminogenemia · ligneous conjunctivitis · plasminogen deficiency type 1 · plasminogen deficiency, type 1 · plasminogen deficiency, type I · type 1 plasminogen deficiency

Data availability: 153 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood coagulation disease › coagulation protein disease › hypoplasminogenemia

Related subtypes (27): factor XIII deficiency, factor VII deficiency, factor X deficiency, thrombophilia due to activated protein C resistance, 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, congenital plasminogen activator inhibitor type 1 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

153 retrieved; paginated sample, class counts are floors:

112 uncertain significance, 10 conflicting classifications of pathogenicity, 10 benign, 7 likely pathogenic, 6 pathogenic, 5 likely benign, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13578	NM_000301.5(PLG):c.1848G>A (p.Trp616Ter)	LOC126859861	Pathogenic	no assertion criteria provided
13577	NM_000301.5(PLG):c.704G>A (p.Arg235His)	PLG	Pathogenic	no assertion criteria provided
13579	NM_000301.5(PLG):c.1435G>T (p.Glu479Ter)	PLG	Pathogenic	no assertion criteria provided
13582	NM_000301.5(PLG):c.2125+1del	PLG	Pathogenic	no assertion criteria provided
13583	NM_000301.5(PLG):c.112A>G (p.Lys38Glu)	PLG	Pathogenic/Likely 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
830236	NM_000301.5(PLG):c.886T>G (p.Cys296Gly)	PLG	Pathogenic	no assertion criteria provided
1179096	NM_000301.5(PLG):c.2019-1G>A	PLG	Likely pathogenic	criteria provided, single submitter
3593297	NM_000301.5(PLG):c.292+1G>C	PLG	Likely pathogenic	criteria provided, single submitter
3593317	NM_000301.5(PLG):c.910C>G (p.Pro304Ala)	PLG	Likely pathogenic	criteria provided, single submitter
3593319	NM_000301.5(PLG):c.948C>A (p.Cys316Ter)	PLG	Likely pathogenic	criteria provided, single submitter
3593351	NM_000301.5(PLG):c.1987C>T (p.Arg663Ter)	PLG	Likely pathogenic	criteria provided, single submitter
3764685	NM_000301.5(PLG):c.677del (p.Asn226fs)	PLG	Likely pathogenic	criteria provided, single submitter
4820655	NM_000301.5(PLG):c.1994A>T (p.Asp665Val)	PLG	Likely pathogenic	criteria provided, single submitter
13574	NM_000301.5(PLG):c.1858G>A (p.Ala620Thr)	LOC126859861	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1050571	NM_000301.5(PLG):c.185+14C>A	PLG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2081074	NM_000301.5(PLG):c.1335G>T (p.Arg445Ser)	PLG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2719862	NM_000301.5(PLG):c.313A>G (p.Thr105Ala)	PLG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3593321	NM_000301.5(PLG):c.992G>C (p.Arg331Thr)	PLG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3593335	NM_000301.5(PLG):c.1458G>T (p.Gly486=)	PLG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
692201	NM_000301.5(PLG):c.782G>A (p.Arg261His)	PLG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
692203	NM_000301.5(PLG):c.2045T>A (p.Ile682Asn)	PLG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
717878	NM_000301.5(PLG):c.1259G>A (p.Gly420Asp)	PLG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
76224	NM_000301.5(PLG):c.1469G>A (p.Arg490Gln)	PLG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029782	NM_000301.5(PLG):c.466G>A (p.Asp156Asn)	PLG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032300	NM_000301.5(PLG):c.266G>C (p.Arg89Thr)	PLG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1049859	NM_000301.5(PLG):c.646G>A (p.Ala216Thr)	PLG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1162997	NM_000301.5(PLG):c.115A>C (p.Lys39Gln)	PLG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1163000	NM_000301.5(PLG):c.368C>T (p.Thr123Ile)	PLG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1163002	NM_000301.5(PLG):c.514A>G (p.Arg172Gly)	PLG	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
PLG	Strong	Autosomal recessive	hypoplasminogenemia	6

Orphanet rare-disease linkage (cohort genes)

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

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
PLG	HGNC:9071	ENSG00000122194	P00747	Plasminogen	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 1 · 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	1	36.6×	0.027

Per-gene assignment

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

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
adult organism	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLG	P00747	49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Dissolution of Fibrin Clot	1	815.7×	0.007	PLG
Activation of Matrix Metalloproteinases	1	308.6×	0.008	PLG
Signaling by PDGF	1	253.8×	0.008	PLG
Degradation of the extracellular matrix	1	117.7×	0.012	PLG
Platelet degranulation	1	87.8×	0.012	PLG
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
trans-synaptic signaling by BDNF, modulating synaptic transmission	1	5617.3×	0.002	PLG
mononuclear cell migration	1	4213.0×	0.002	PLG
positive regulation of fibrinolysis	1	3370.4×	0.002	PLG
biological process involved in interaction with symbiont	1	2808.7×	0.002	PLG
negative regulation of cell-cell adhesion mediated by cadherin	1	1532.0×	0.002	PLG
negative regulation of fibrinolysis	1	1404.3×	0.002	PLG
tissue remodeling	1	1296.3×	0.002	PLG
trophoblast giant cell differentiation	1	1203.7×	0.002	PLG
negative regulation of cell-substrate adhesion	1	1053.2×	0.002	PLG
fibrinolysis	1	842.6×	0.002	PLG
myoblast differentiation	1	842.6×	0.002	PLG
labyrinthine layer blood vessel development	1	802.5×	0.002	PLG
tissue regeneration	1	766.0×	0.002	PLG
muscle cell cellular homeostasis	1	648.1×	0.002	PLG
positive regulation of blood vessel endothelial cell migration	1	391.9×	0.003	PLG
extracellular matrix disassembly	1	366.4×	0.003	PLG
blood coagulation	1	173.7×	0.007	PLG
protein processing	1	170.2×	0.007	PLG
negative regulation of cell population proliferation	1	42.1×	0.025	PLG
proteolysis	1	34.2×	0.029	PLG

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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

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	PLG
MILVEXIAN	3	PLG
DABIGATRAN	3	PLG
GABEXATE	3	PLG
EFEGATRAN	2	PLG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PLG	480	Binding:467, ADMET:7, Functional:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
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: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

11 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
NAFAMOSTAT	3	PLG
MILVEXIAN	3	PLG
DABIGATRAN	3	PLG
GABEXATE	3	PLG
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	0
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: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2/PHASE3	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01554956	PHASE2/PHASE3	COMPLETED	Efficacy/Safety of Human Plasminogen Eye Drop in Ligneous Conjunctivitis Patients
NCT02690714	PHASE2/PHASE3	COMPLETED	A Study of Prometic Plasminogen IV Infusion in Subjects With Hypoplasminogenemia
NCT02312180	PHASE1	COMPLETED	A Phase 1 Study of ProMetic Plasminogen (Human) Intravenous in Adults and Children With Plasminogen Deficiency
NCT04586062	Not specified	AVAILABLE	Sponsor Initiated Expanded Access Protocol, Intermediate-Size Patient Population
NCT03265171	Not specified	NO_LONGER_AVAILABLE	A Single-patient Study of Repeat-dose Administration of Prometic Plasminogen (Human) Intravenous
NCT03642691	Not specified	NO_LONGER_AVAILABLE	A Treatment Protocol for Expanded Access Administration of Prometic Plasminogen Due to Closure of Clinical Trial

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PLASMINOGEN	3	5