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

The plasminogen protein encoded by this gene is a serine protease that circulates in blood plasma as an inactive zymogen and is converted to the active protease, plasmin, by several plasminogen activators such as tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, and factor XII (Hageman factor). The conversion of plasminogen to plasmin involves the cleavage of the peptide bond between Arg-561 and Val-562. Plasmin cleavage also releases the angiostatin protein which inhibits angiogenesis. Plasmin degrades many blood plasma proteins, including fibrin-containing blood clots. As a serine protease, plasmin cleaves many products in addition to fibrin such as fibronectin, thrombospondin, laminin, and von Willebrand factor. Plasmin is inactivated by proteins such as alpha-2-macroglobulin and alpha-2-antiplasmin in addition to inhibitors of the various plasminogen activators. Plasminogen also interacts with plasminogen receptors which results in the retention of plasmin on cell surfaces and in plasmin-induced cell signaling. The localization of plasminogen on cell surfaces plays a role in the degradation of extracellular matrices, cell migration, inflamation, wound healing, oncogenesis, metastasis, myogenesis, muscle regeneration, neurite outgrowth, and fibrinolysis. This protein may also play a role in acute respiratory distress syndrome (ARDS) which, in part, is caused by enhanced clot formation and the suppression of fibrinolysis. Compared to other mammals, the cluster of plasminogen-like genes to which this gene belongs has been rearranged in catarrhine primates. [provided by RefSeq, May 2020]

OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 45 VUS of 97 total submissions

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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 OE?0.28 (0.18–0.44)

0≤0.351.4

Missense OE?0.97 (0.90–1.05)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

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

This gene — mechanism propensity

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).1

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

References

1.PMID 36685169 ↗

ClinVar Variant Classifications

97 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic2

VUS45

Likely Benign38

Benign1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	0	0	2
Likely Pathogenic	1	1	0	0	2
VUS	0	38	6	1	45
Likely Benign	0	0	17	21	38
Benign	0	0	1	0	1
Total	3	39	24	22	88

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

2 pathogenic / likely-pathogenic (of 3) ClinVar copy-number / structural variants overlap PLG — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

PLG · protein map & ClinVar variants

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

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

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

Heart Failure

Acute Reno-Cardiac Action of Dapagliflozin In Advanced Heart Failure Patients on Heart Transplant Waiting List

RECRUITING

NCT06868797Phase NACentral Hospital, Nancy, FranceStarted 2025-08-29

Biological sample for the measurement of suPAR levels.

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

Plasminogen Deficiency

Study of Individuals Affected With Hypoplasminogenemia

RECRUITING

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

IBS - Irritable Bowel Syndrome

Comparison Between Low FODMAP and SSRD in IBS

ENROLLING BY INVITATION

NCT05192603Phase NARegion SkaneStarted 2022-03-01

low FODMAP or SSRD