PLG

Chr 6ADAR

plasminogen

Also known as: HAE4

NCBI Gene: 5340 ENSG00000122194 UniProt: P00747 OMIM: 173350

Plasminogen is a serine protease zymogen that is activated to plasmin, which dissolves fibrin clots and degrades extracellular matrix proteins including fibronectin, laminin, and von Willebrand factor. Mutations cause plasminogen deficiency (type I), dysplasminogenemia, and hereditary angioedema type 4, with both autosomal dominant and autosomal recessive inheritance patterns reported. The gene is highly constrained against loss-of-function variants (LOEUF 0.443), indicating that complete loss of function is likely poorly tolerated.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 0.443 OMIM phenotypes

Clinical Summary— PLG

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Gene-Disease Validity (ClinGen)

hypoplasminogenemia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.44LOEUF

pLI 0.010

Z-score 4.57

OE 0.28 (0.18–0.44)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

0.21Z-score

OE missense 0.97 (0.90–1.05)

434 obs / 446.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.28 (0.18–0.44)

0≤0.351.4

Missense OE0.97 (0.90–1.05)

0≤0.61.4

Synonymous OE1.09

0≤1.21.6

LoF obs/exp: 13 / 46.7Missense obs/exp: 434 / 446.7Syn Z: -0.93

0.6161th %ile

GOF

0.6052th %ile

LOF

0.2680th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFStructural modeling and in vitro assays using purified proteins confirmed the PLG mutation c.988A>G; p.K330E to be a gain of function mutation resulting in an increased bradykinin release by direct cleavage of high molecular weight kininogen (HMWK).PMID:36685169

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

PLG · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Metastatic Thyroid Gland CarcinomaUnresectable Thyroid Gland Carcinoma

Dabrafenib and Lapatinib in Treating Patients With Refractory Thyroid Cancer That Cannot Be Removed by Surgery

ACTIVE NOT RECRUITING

NCT01947023Phase PHASE1National Cancer Institute (NCI)Started 2013-09-27

Biopsy ProcedureBiospecimen CollectionComputed Tomography

Relapsing Remitting Multiple Sclerosis (RRMS)

Indole-3-PROpionic Acid Clinical Trials - Multiple Sclerosis

RECRUITING

NCT07318129Phase NAGlostrup University Hospital, CopenhagenStarted 2026-01-26

PlaceboIndole-3-propionic acid (IPA)

Polycystic Ovary SyndromeHypothalamic Amenorrhea

Body Fat as Determinant of Female Gonadal Dysfunction

RECRUITING

NCT03841981Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y CajalStarted 2020-01-31

Anthropometric and physical examinationIndirect calorimetry, accelerometer and seven-day dietary recallBiochemical, hormonal and metabolic phenotyping

Cushing Syndrome

Cushing's Syndrome Before and After Treatment (CORRECT)

RECRUITING

NCT05521529University of AarhusStarted 2023-02-16

no intervention, as this is an observational study

Diabetes Mellitus, Type 1Inflammation

The Role of the Adrenergic System in Hypoglycaemia Induced Inflammatory Response in People With Type 1 Diabetes and People Without Type 1 Diabetes-RAID-II

ACTIVE NOT RECRUITING

NCT06422494Phase NARadboud University Medical CenterStarted 2025-01-01

hyperinsulinaemic hypoglycaemic clampPropranolol Hydrochloride 1 MG/MLPhentolamine

Plasminogen Deficiency

Study of Individuals Affected With Hypoplasminogenemia

RECRUITING

NCT03797495Indiana Hemophilia &Thrombosis Center, Inc.Started 2018-12-18

Obese Patients (BMI ≥ 30 kg/m²)AnxietyDepressive Disorder

Therapeutic Potential of a Synbiotic to Improve Mental Health in Subjects With Obesity.

RECRUITING

NCT06901739Phase NACelia BañulsStarted 2025-04-15

SynbioticPlacebo

ALS (Amyotrophic Lateral Sclerosis)

This Study Evaluates the Safety, Target Engagement, and Preliminary Efficacy of Galunisertib (TGF-βR1/ALK5 Inhibitor)Combined With Nerandomilast (PDE4 Inhibitor) in GREM2-positive ALS, a Biomarker-defined Subgroup Hypothesized to Reflect Heightened TGF-β/SMAD-driven Astrocytic and Fibrotic Signaling

NOT YET RECRUITING

NCT07321860Phase PHASE2, PHASE3Gipfel Life Sciences GmbHStarted 2026-06-30

Galunisertib + Nerandomilast Combination

HypertriglyceridemiaNormal

Cardiometabolic Properties of Omega-3 Functionalized With Hydroxytyrosol

ACTIVE NOT RECRUITING

NCT06992323Phase NANational Research Council, SpainStarted 2025-02-17

EPA + HTEPASunflower Oil

Acute-On-Chronic Liver FailureAlcoholic HepatitisLiver Cirrhosis, Alcoholic

A-TANGO Phase 2 Study

NOT YET RECRUITING

NCT06890039Phase PHASE2Yaqrit LtdStarted 2025-09-01