PCSK9
Chr 1ADproprotein convertase subtilisin/kexin type 9
Also known as: FH3, FHCL3, HCHOLA3, LDLCQ1, NARC-1, NARC1, PC9
The encoded protease regulates plasma cholesterol homeostasis by binding to low-density lipoprotein receptor family members and promoting their degradation, preventing cholesterol uptake from the bloodstream. Mutations cause autosomal dominant familial hypercholesterolemia, leading to elevated cholesterol levels and increased cardiovascular risk. This gene is not highly constrained against loss-of-function mutations and primarily affects lipid metabolism rather than neurological function.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Mild missense constraint
The Badonyi & Marsh model scores dominant-negative highest, but genomic evidence most strongly supports gain-of-function as the primary mechanism.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
PCSK9 · 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
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
EPIRUS FH Reverse Cascade Screening
NOT YET RECRUITINGLatvian Early Atherosclerosis Registry
RECRUITINGTargeting Risk Factors for Diabetes in Subjects With Normal Blood Cholesterol Using Omega-3 Fatty Acids
RECRUITINGA Study of Genetic Influence on LDL Hyper-responsiveness in Patients Following a Ketogenic Diet
RECRUITINGEarly-phase Study of ART002g1 Injection in HeFH: Safety, Tolerability and Preliminary Efficacy
NOT YET RECRUITINGRussian Familial Hypercholesterolemia Registry
RECRUITINGClinical Exploration Trial of YOLT-101 in the Treatment of Familial Hypercholesterolemia (FH)
RECRUITINGEAS Familial Hypercholesterolaemia Studies Collaboration
RECRUITINGA Study of VERVE-102 in Patients With Familial Hypercholesterolemia or Premature Coronary Artery Disease
RECRUITINGAn Open-label Study to Investigate ECUR-506 in Male Babies Less Than 9 Months of Age With Neonatal Onset OTC Deficiency
RECRUITINGA Study of STX-1150 in Participants With Elevated Low-Density Lipoprotein Cholesterol (LDL-C)
NOT YET RECRUITINGCholesterol Lowering and Residual Risk in Diabetes, Type 1
RECRUITINGExternal Resources
Links to major genomics databases and tools