PCSK9
Chr 1ADproprotein convertase subtilisin/kexin type 9
Also known as: FH3, FHCL3, HCHOLA3, LDLCQ1, NARC-1, NARC1, PC9
This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]
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
This gene — mechanism propensity
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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
References
ClinVar Variant Classifications
1542 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 1 | 8 | 1 | 0 | 10 |
Likely Pathogenic | 1 | 8 | 1 | 0 | 10 |
VUS | 38 | 629 | 81 | 13 | 761 |
Likely Benign | 49 | 31 | 145 | 331 | 556 |
Benign | 0 | 2 | 32 | 1 | 35 |
Conflicting | — | 165 | |||
| Total | 89 | 678 | 260 | 345 | 1,537 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →11 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap PCSK9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →
Protein Context — Lollipop Plot
PCSK9 · 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
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
EAS Familial Hypercholesterolaemia Studies Collaboration
RECRUITINGA Study of Genetic Influence on LDL Hyper-responsiveness in Patients Following a Ketogenic Diet
RECRUITINGClinical Exploration Trial of YOLT-101 in the Treatment of Familial Hypercholesterolemia (FH)
RECRUITINGA Study of STX-1150 in Participants With Elevated Low-Density Lipoprotein Cholesterol (LDL-C)
RECRUITINGGenetic Testing and Motivational Counseling for FH
ACTIVE NOT RECRUITINGA Study of VERVE-102 in Patients With Familial Hypercholesterolemia or Premature Coronary Artery Disease
RECRUITINGRussian Familial Hypercholesterolemia Registry
RECRUITINGAn Open-label Study to Investigate ECUR-506 in Male Babies Less Than 9 Months of Age With Neonatal Onset OTC Deficiency
RECRUITINGManagement Strategy of 1L Lorlatinib With Hyperlipidemia in Stage IIIB-IV ALK Positive NSCLC
NOT YET RECRUITINGCholesterol Lowering and Residual Risk in Diabetes, Type 1
RECRUITINGEPIRUS FH Reverse Cascade Screening
NOT YET RECRUITINGTargeting Risk Factors for Diabetes in Subjects With Normal Blood Cholesterol Using Omega-3 Fatty Acids
RECRUITINGExternal Resources
Links to major genomics databases and tools