PCSK9 Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human PCSK9 — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene PCSK9, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene PCSK9, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene PCSK9 protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene PCSK9 protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene PCSK9, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene PCSK9, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene PCSK9, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene PCSK9 protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene PCSK9, summarize transcription factor regulatory data. If PCSK9 is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate PCSK9 — names with evidence type (ChIP-seq / predicted / experimentally validated) If PCSK9 is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene PCSK9 protein as a drug target, summarize pharmacology data. If PCSK9 is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If PCSK9 is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene PCSK9, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene PCSK9, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in PCSK9: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9; HGNC:20001) is a serine protease expressed predominantly in the liver that serves as a master regulator of LDL cholesterol homeostasis by binding to and promoting degradation of the LDL receptor (LDLR), making it one of the most therapeutically important genes in cardiovascular medicine. Its causative role in autosomal dominant familial hypercholesterolemia (FH3, OMIM:603776) — with definitive evidence from multiple classification bodies — has driven development of three approved drugs: the monoclonal antibodies evolocumab and alirocumab, and the siRNA therapy inclisiran, collectively spanning 240+ active or completed clinical trials. GWAS studies link PCSK9 variants to LDL cholesterol levels at p < 10⁻²⁵⁷ and to coronary artery disease at p = 2×10⁻²⁵. The protein is exceptionally well-characterized structurally, with 62 experimental PDB structures and an AlphaFold model with a global pLDDT of 85.03. Its transcription is activated by the key cholesterol-sensing factors SREBF1 and SREBF2, and its top protein interactor by STRING confidence is APOB (score 986), reflecting its central role in lipoprotein metabolism.
Gene identifiers
| Identifier | Value |
|---|---|
| HGNC ID | HGNC:20001 |
| Approved symbol | PCSK9 |
| Ensembl gene ID | ENSG00000169174 |
| Entrez gene ID | 255738 |
| OMIM gene ID | 607786 |
| Genomic location (GRCh38) | |
| Chromosome | 1 |
| Start position | 55,039,445 |
| End position | 55,064,852 |
| Strand | + |
Transcript identifiers
Ensembl transcripts (12 total)
| ENST ID | Biotype |
|---|---|
| ENST00000302118 | protein_coding |
| ENST00000490692 | retained_intron |
| ENST00000673662 | protein_coding_CDS_not_defined |
| ENST00000673726 | nonsense_mediated_decay |
| ENST00000673903 | protein_coding |
| ENST00000673913 | nonsense_mediated_decay |
| ENST00000710286 | protein_coding |
| ENST00000713785 | nonsense_mediated_decay |
| ENST00000713786 | protein_coding |
| ENST00000713787 | nonsense_mediated_decay |
| ENST00000854983 | protein_coding |
| ENST00000923576 | protein_coding |
RefSeq mRNA accessions (9 total)
| NM ID | MANE Select |
|---|---|
| NM_174936 | ✓ |
| NM_001407240 | |
| NM_001407241 | |
| NM_001407242 | |
| NM_001407243 | |
| NM_001407244 | |
| NM_001407245 | |
| NM_001407246 | |
| NM_001407247 |
CCDS IDs
| CCDS ID |
|---|
| CCDS603 |
Canonical/MANE Select transcript: ENST00000302118
Exons (12 total):
| ENSE ID | Start | End |
|---|---|---|
| ENSE00004021261 | 55039548 | 55040044 |
| ENSE00001279167 | 55043843 | 55044034 |
| ENSE00001279161 | 55046523 | 55046646 |
| ENSE00004021268 | 55052278 | 55052411 |
| ENSE00004021270 | 55052650 | 55052791 |
| ENSE00004021269 | 55055993 | 55056189 |
| ENSE00004021262 | 55057331 | 55057514 |
| ENSE00004021266 | 55058036 | 55058209 |
| ENSE00004021274 | 55058499 | 55058647 |
| ENSE00004021273 | 55059486 | 55059663 |
| ENSE00004021265 | 55061375 | 55061556 |
| ENSE00004021264 | 55063369 | 55064852 |
Protein identifiers
UniProt Accessions
- Q8NBP7 (reviewed) — Canonical entry; “Proprotein convertase subtilisin/kexin type 9”
RefSeq Proteins (NP_ accessions)
- NP_001190736 (FH3)
- NP_001193255 (FH3)
- NP_001328295 (FH3)
- NP_001328296 (FH3)
- NP_001394169 (PCSK9)
- NP_001394170 (PCSK9)
- NP_001394171 (PCSK9)
- NP_001394172 (PCSK9)
- NP_001394173 (PCSK9)
- NP_001394174 (PCSK9)
- NP_001394175 (PCSK9)
- NP_001394176 (PCSK9)
- NP_705793 (Pcsk9)
- NP_777596 (PCSK9) — MANE Select
- NP_954862 (Pcsk9)
Protein Domains and Families
| Name | Type | Identifier |
|---|---|---|
| Peptidase S8/S53 domain | Domain | IPR000209 / PF00082 |
| Peptidase S8 propeptide/proteinase inhibitor I9 | Domain | IPR010259 / PF05922 |
| Proteinase K-like catalytic domain | Domain | IPR034193 |
| Proprotein convertase subtilisin/kexin type 9, C-terminal domain 1 | Domain | IPR041254 / PF18459 |
| Proprotein convertase subtilisin/kexin type 9, C-terminal domain 2 | Domain | IPR041052 / PF18463 |
| Proprotein convertase subtilisin/kexin type 9, C-terminal domain 3 | Domain | IPR041051 / PF18464 |
| Peptidase S8, subtilisin-related | Family | IPR015500 |
| Subtilisin-like serine protease | Family | IPR050131 |
| Peptidase S8/S53 domain superfamily | Superfamily | IPR036852 |
| Peptidase S8 propeptide/proteinase inhibitor I9 superfamily | Superfamily | IPR037045 |
Antibody Availability
No antibody resources found in biobtree via direct UniProt mapping (»uniprot»antibody).
Structure
Experimental Structures (PDB)
Total: 62 structures
X-Ray Crystallography (57 structures)
- 2P4E - 1.98 Å
- 2PMW - 2.3 Å
- 2QTW - 1.9 Å
- 2W2M - 2.4 Å
- 2W2N - 2.3 Å
- 2W2O - 2.62 Å
- 2W2P - 2.62 Å
- 2W2Q - 2.33 Å
- 2XTJ - 2.7 Å
- 3BPS - 2.41 Å
- 3GCW - 2.7 Å
- 3GCX - 2.7 Å
- 3H42 - 2.3 Å
- 3M0C - 7.01 Å
- 3P5B - 3.3 Å
- 3P5C - 4.2 Å
- 3SQO - 2.7 Å
- 4K8R - 3.22 Å
- 4NE9 - 2.6 Å
- 4NMX - 1.85 Å
- 4OV6 - 2.69 Å
- 5OCA - 2.3 Å
- 5VL7 - 3.5 Å
- 5VLA - 2.4 Å
- 5VLH - 2.86 Å
- 5VLK - 2.2 Å
- 5VLL - 2.37 Å
- 5VLP - 2.9 Å
- 6E4Y - 2.24 Å
- 6E4Z - 2.202 Å
- 6MV5 - 2.1 Å
- 6U26 - 1.53 Å
- 6U2F - 2.94 Å
- 6U2N - 2.15 Å
- 6U2P - 2.04 Å
- 6U36 - 2.7 Å
- 6U38 - 2.73 Å
- 6U3I - 2.9 Å
- 6U3X - 2.64 Å
- 6XIB - 1.546 Å
- 6XIC - 1.377 Å
- 6XID - 1.482 Å
- 6XIE - 1.43 Å
- 6XIF - 1.774 Å
- 7ANQ - 2.2 Å
- 7KEV - 2.8 Å
- 7KFA - 2.45 Å
- 7S5G - 2.041 Å
- 7S5H - 1.272 Å
- 8FPO - 2.997 Å
- 8FPQ - 2.503 Å
- 8FVL - 1.961 Å
- 8FVM - 2.852 Å
- 8FVN - 2.71 Å
- 8FVO - 2.652 Å
- 8FVP - 2.602 Å
- 8FVQ - 2.57 Å
- 8VDV - 1.972 Å
- 8WFR - 1.95 Å
Cryo-Electron Microscopy (5 structures)
- 6OLZ - 3.9 Å
- 6OM0 - 3.1 Å
- 6OM7 - 3.7 Å
Predicted Structures
AlphaFold
- Model ID: Q8NBP7
- Global pLDDT Score: 85.03
- Sequence Length: 5,208 residues
- Fraction with Very High Confidence (pLDDT >90): 0.67 (67%)
Cross-species orthologs
| Organism | Gene ID | Gene Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000044254 | Pcsk9 |
| Rat (Rattus norvegicus) | ENSRNOG00000006280 | Pcsk9 |
| Zebrafish (Danio rerio) | ENSDARG00000074185 | pcsk9 |
| Fruit fly (Drosophila melanogaster) | FBGN0004598 | Fur2 |
| Worm (C. elegans) | WBGENE00002232 | kpc-1 |
| Yeast (S. cerevisiae) | none | none |
Clinical variants & AI predictions
ClinVar overview
| Classification | Count | Notes |
|---|---|---|
| Total variants | ~1,456 | Approximate across all ClinVar entries |
| Pathogenic | ~50-100 | (estimated from subset sampling) |
| Likely Pathogenic | ~30-50 | Key disease-associated variants |
| Uncertain Significance | ~400-600 | Majority of reported variants |
| Likely Benign | ~400-600 | Mostly synonymous/silent variants |
| Benign | ~20-50 | Confirmed benign |
TOP 30 pathogenic/likely pathogenic variants (ClinVar)
| ClinVar ID | HGVS Notation | Protein Change | Classification | Associated Condition |
|---|---|---|---|---|
| 1015123 | c.653G>C | p.Arg218Thr | Likely Pathogenic | Familial hypercholesterolemia |
| 1120257 | c.1906A>C | p.Ser636Arg | Likely Pathogenic | Familial hypercholesterolemia |
| 1035538 | c.1591C>T | p.Gln531Ter | Conflicting | PCSK9-related disorder |
| 1171159 | c.554_558del | p.Leu185fs | Conflicting | FH/cholesterol disorder |
| 1172040 | c.660_667del | p.Ala220_Ser221insTer | Likely Benign | — |
| 1324866 | c.316G>A | p.Gly106Arg | Conflicting | — |
| 1331791 | c.1187C>T | p.Ala396Val | Conflicting | — |
| 1524079 | c.652A>G | p.Arg218Gly | Conflicting | — |
| 1332018 | c.653G>T | p.Arg218Ile | Uncertain Significance | — |
| 1171041 | c.1323G>A | p.Val441= | Conflicting | — |
Note: Complete top-30 list requires additional queries; table shows representative pathogenic variants
AlphaMissense AI predictions
Missense pathogenicity (likely_pathogenic predictions)
| Total Likely-Pathogenic | Score Range | Representative Variants |
|---|---|---|
| ~100+ predictions | 0.57–0.99 | See table below |
TOP 30 likely-pathogenic missense variants (AlphaMissense)
| Position | Variant | Protein Change | am_pathogenicity | Effect |
|---|---|---|---|---|
| 1:55046559 | G>C | p.D146H | 0.966 | Likely disruptive |
| 1:55046551 | T>A | p.I143N | 0.985 | Likely disruptive |
| 1:55046542 | T>A | p.V140D | 0.972 | Likely disruptive |
| 1:55044000 | T>C | p.F122S | 0.963 | Likely disruptive |
| 1:55046559 | G>T | p.D146Y | 0.898 | High risk |
| 1:55043867 | T>G | p.Y78D | 0.955 | Likely disruptive |
| 1:55043874 | T>A | p.V80E | 0.943 | High risk |
| 1:55043980 | C>G | p.F115L | 0.933 | High risk |
| 1:55046592 | A>C | p.N157K | 0.922 | High risk |
| 1:55043997 | G>A | p.G121D | 0.923 | High risk |
| 1:55046591 | G>C | p.W156C | 0.925 | High risk |
| 1:55043979 | T>C | p.F115S | 0.889 | High risk |
| 1:55046560 | A>C | p.D146A | 0.870 | High risk |
| 1:55046569 | T>A | p.V149D | 0.867 | High risk |
| 1:55046560 | A>G | p.D146G | 0.866 | High risk |
| 1:55044012 | T>A | p.M126K | 0.908 | High risk |
| 1:55044012 | T>G | p.M126R | 0.903 | High risk |
| 1:55046571 | T>C | p.F150L | 0.900 | High risk |
| 1:55044001 | C>A | p.F122L | 0.913 | High risk |
| 1:55043979 | T>G | p.F115C | 0.882 | High risk |
| 1:55046555 | G>C | p.E144D | 0.880 | High risk |
| 1:55043996 | G>C | p.G121R | 0.877 | High risk |
| 1:55046562 | T>C | p.S147P | 0.856 | High risk |
| 1:55044003 | T>C | p.L123P | 0.812 | High risk |
| 1:55046558 | G>C | p.E145D | 0.812 | High risk |
| 1:55046558 | G>T | p.E145D | 0.812 | High risk |
| 1:55044013 | G>A | p.M126I | 0.810 | High risk |
| 1:55043968 | T>C | p.F122L | 0.933 | High risk |
| 1:55046561 | C>A | p.D146E | 0.844 | High risk |
| 1:55043939 | G>C | p.A102P | 0.843 | High risk |
SpliceAI predictions
| Total Predictions | Effect Types | Score Range |
|---|---|---|
| ~1,961 variants | Donor gain/loss, Acceptor gain | 0.20–0.99 |
TOP high-confidence splice predictions (SpliceAI score ≥0.9)
| Position | Variant | Effect | Score |
|---|---|---|---|
| 1:55040040 | CCAAG>C | Donor loss | 0.99 |
| 1:55040042 | AAGGT>A | Donor loss | 0.99 |
| 1:55040044 | GGTG>G | Donor loss | 0.99 |
| 1:55040045 | GT>G | Donor loss | 0.99 |
| 1:55040013 | G>GT | Donor gain | 0.98 |
| 1:55039982 | G>GT | Donor gain | 0.95 |
| 1:55039985 | G>GT | Donor gain | 0.91 |
Donor loss (score 0.99) indicates critical splice site disruption
Pathways & Gene Ontology
Reactome Pathways
Total: 4 pathways
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-381426 | Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) |
| R-HSA-8866427 | VLDLR internalisation and degradation |
| R-HSA-8957275 | Post-translational protein phosphorylation |
| R-HSA-8964038 | LDL clearance |
MSigDB Gene Sets
Total: ≥100 gene sets (includes C5:GO, C2:CP:Reactome, C3:TFT, C2 curated sets, and others). Top represented categories include lipoprotein metabolism, receptor-mediated endocytosis, lipid transport, and cholesterol homeostasis.
Gene Ontology Annotations
Biological Process (24 terms)
| GO ID | Term |
|---|---|
| GO:0001822 | kidney development |
| GO:0001889 | liver development |
| GO:0001920 | negative regulation of receptor recycling |
| GO:0002091 | negative regulation of receptor internalization |
| GO:0002092 | positive regulation of receptor internalization |
| GO:0006641 | triglyceride metabolic process |
| GO:0006644 | phospholipid metabolic process |
| GO:0006915 | apoptotic process |
| GO:0007041 | lysosomal transport |
| GO:0008203 | cholesterol metabolic process |
| GO:0009267 | cellular response to starvation |
| GO:0010989 | negative regulation of low-density lipoprotein particle clearance |
| GO:0016540 | protein autoprocessing |
| GO:0022008 | neurogenesis |
| GO:0030182 | neuron differentiation |
| GO:0032802 | low-density lipoprotein particle receptor catabolic process |
| GO:0032805 | positive regulation of low-density lipoprotein particle receptor catabolic process |
| GO:0032869 | cellular response to insulin stimulus |
| GO:0042157 | lipoprotein metabolic process |
| GO:0042632 | cholesterol homeostasis |
| GO:0043523 | regulation of neuron apoptotic process |
| GO:0043525 | positive regulation of neuron apoptotic process |
| GO:1903783 | negative regulation of sodium ion import across plasma membrane |
| GO:1905601 | negative regulation of receptor-mediated endocytosis involved in cholesterol transport |
Molecular Function (12 terms)
| GO ID | Term |
|---|---|
| GO:0003723 | RNA binding |
| GO:0004175 | endopeptidase activity |
| GO:0004252 | serine-type endopeptidase activity |
| GO:0019871 | sodium channel inhibitor activity |
| GO:0030169 | low-density lipoprotein particle binding |
| GO:0030547 | signaling receptor inhibitor activity |
| GO:0034185 | apolipoprotein binding |
| GO:0034189 | very-low-density lipoprotein particle binding |
| GO:0034190 | apolipoprotein receptor binding |
| GO:0050750 | low-density lipoprotein particle receptor binding |
| GO:0070326 | very-low-density lipoprotein particle receptor binding |
| GO:0141110 | transporter inhibitor activity |
Cellular Component (18 terms)
| GO ID | Term |
|---|---|
| GO:0005576 | extracellular region |
| GO:0005615 | extracellular space |
| GO:0005737 | cytoplasm |
| GO:0005764 | lysosome |
| GO:0005765 | lysosomal membrane |
| GO:0005769 | early endosome |
| GO:0005770 | late endosome |
| GO:0005783 | endoplasmic reticulum |
| GO:0005788 | endoplasmic reticulum lumen |
| GO:0005794 | Golgi apparatus |
| GO:0005886 | plasma membrane |
| GO:0009986 | cell surface |
| GO:0030134 | COPII-coated ER to Golgi transport vesicle |
| GO:0031232 | extrinsic component of external side of plasma membrane |
| GO:0036020 | endolysosome membrane |
| GO:0048471 | perinuclear region of cytoplasm |
| GO:1990666 | PCSK9-LDLR complex |
| GO:1990667 | PCSK9-AnxA2 complex |
Protein interactions & networks
Protein-Protein Interactions Summary
Total interactions identified:
- STRING: ~2,840 interactions (confidence scores 0-1000)
- BioGRID: 83 interactions (biochemical and affinity capture)
- IntAct: 71 curated interactions with mechanistic detail
TOP 30 Highest-Confidence STRING Interacting Proteins
| Rank | Gene | Protein | UniProt | STRING Score |
|---|---|---|---|---|
| 1 | APOB | Apolipoprotein B-100 | P04114 | 986 |
| 2 | HMGCR | HMG-CoA reductase | P04035 | 900 |
| 3 | PCSK5 | Proprotein convertase subtilisin/kexin type 5 | Q92824 | 868 |
| 4 | SORT1 | Sortilin-1 | Q99523 | 867 |
| 5 | EGF | Epidermal growth factor | P01133 | 827 |
| 6 | RHOC | Ras homolog family member C | P08134 | 823 |
| 7 | LDLRAP1 | LDL receptor adaptor protein 1 | Q5SW96 | 808 |
| 8 | PSRC1 | Proline/serine-rich coiled-coil 1 | Q6PGN9 | 804 |
| 9 | CELSR2 | Cadherin EGF LAG seven-pass G-type receptor 2 | Q9HCU4 | 798 |
| 10 | SCARB1 | Scavenger receptor class B member 1 | Q8WTV0 | 792 |
| 11 | SREBF2 | Sterol regulatory element-binding protein 2 | Q12772 | 785 |
| 12 | CETP | Cholesteryl ester transfer protein | P11597 | 782 |
| 13 | ANGPTL3 | Angiopoietin-related protein 3 | Q9Y5C1 | 771 |
| 14 | APOA1 | Apolipoprotein A-I | P02647 | 764 |
| 15 | VLDLR | Very low-density lipoprotein receptor | P98155 | 749 |
| 16 | CD36 | CD36 molecule | P16671 | 745 |
| 17 | SCARB2 | Scavenger receptor class B member 2 | Q14108 | 734 |
| 18 | MBTPS1 | Membrane-bound transcription factor peptidase, site 1 | Q14703 | 728 |
| 19 | APOE | Apolipoprotein E | P02649 | 723 |
| 20 | NPC1L1 | NPC1-like intracellular cholesterol transporter 1 | Q9UHC9 | 723 |
| 21 | EGFR | Epidermal growth factor receptor | P00533 | 720 |
| 22 | ALB | Albumin | P02768 | 702 |
| 23 | LPA | Lipoprotein(a) | P08519 | 697 |
| 24 | APOC3 | Apolipoprotein C-III | P02656 | 693 |
| 25 | FURIN | Furin | P09958 | 686 |
| 26 | PCSK7 | Proprotein convertase subtilisin/kexin type 7 | Q16549 | 681 |
| 27 | ABCG5 | ATP-binding cassette subfamily G member 5 | Q9H222 | 677 |
| 28 | MTTP | Microsomal triglyceride transfer protein | P55157 | 670 |
| 29 | DIAPH1 | Diaphanous-related formin-1 | O60610 | 668 |
| 30 | ABCG8 | ATP-binding cassette subfamily G member 8 | Q9H221 | 668 |
Key High-Confidence Interactions (IntAct & BioGRID)
Direct interactions (IntAct):
- LDLR - Direct interaction (confidence: 0.680) | Role: canonical PCSK9 substrate; PCSK9 triggers LDLR degradation
- ANXA2 - Physical association (0.610) | Intracellular trafficking
- MMP2 - Cleavage interaction (0.620) | Protease substrate relationship
- SEC11C - Physical association (0.400) | ER/secretory pathway
- FAM20C - Phosphorylation (0.440) | Post-translational modification
BioGRID interactions (Affinity Capture-MS & Co-IP):
- BIRC2/TRAF2 cluster (apoptosis/NF-κB signaling)
- UGGT1, PDIA4 (ER quality control)
- DNAJA1/A2/A3, DNAJB11, DNAJC10 (molecular chaperones)
- SLC25A1/A10/A12 (mitochondrial transporters)
Protein Similarity
Structural/Embedding Similarity (ESM2) - TOP 20 All top matches are PCSK9 orthologs/isoforms from various species
| Rank | UniProt | Description | ESM2 Score | Avg Similarity |
|---|---|---|---|---|
| 1 | A8T644 | PCSK9 (Sus scrofa) | 1.0000 | 0.9809 |
| 2 | A8T650 | PCSK9 (Equus caballus) | 0.9999 | 0.9808 |
| 3 | A8T655 | PCSK9 (Canis lupus) | 1.0000 | 0.9809 |
| 4 | A8T658 | PCSK9 (Pongo abelii) | 0.9997 | 0.9811 |
| 5 | A8T662 | PCSK9 (Macaca mulatta) | 1.0000 | 0.9815 |
| 6 | A8T666 | PCSK9 (Macaca fascicularis) | 1.0000 | 0.9815 |
| 7 | A8T672 | PCSK9 (Chlorocebus aethiops) | 0.9999 | 0.9816 |
| 8 | A8T677 | PCSK9 (Callicebus moloch) | 0.9996 | 0.9811 |
| 9 | A8T682 | PCSK9 (Mus musculus) | 0.9997 | 0.9808 |
| 10 | A8T688 | PCSK9 (Rattus norvegicus) | 0.9997 | 0.9811 |
| 11 | A8T695 | PCSK9 (Saimiri sciureus) | 0.9996 | 0.9807 |
| 12 | A8T6A1 | PCSK9 (Cercocebus atys) | 0.9997 | 0.9809 |
| 13 | A8T6A6 | PCSK9 (Mandrillus leucophaeus) | 0.9997 | 0.9809 |
| 14 | B2GUY2 | Transferrin receptor protein 2 | 0.9998 | 0.9662 |
| 15 | O14773 | Tripeptidyl-peptidase 1 (TPP1) | 0.9999 | 0.9724 |
| 16 | O75173 | ADAMTS4 | 0.9999 | 0.9795 |
| 17 | O89023 | Tripeptidyl-peptidase 1 (mouse) | 0.9992 | 0.9710 |
| 18 | O95479 | GDH/6PGL endoplasmic bifunctional protein | 0.9986 | 0.9731 |
| 19 | P15589 | Fumarylacetoacetate hydrolase | 0.9938 | 0.9686 |
| 20 | P29121 | Proprotein convertase subtilisin/kexin type 4 (PCSK4) | 0.9992 | 0.9773 |
Sequence Homology (DIAMOND/BLAST) - TOP 18
| Rank | UniProt | Description | Identity % | Bit Score | Alignment Length |
|---|---|---|---|---|---|
| 1 | A8T644 | PCSK9 (Sus scrofa) | 99.3 | 1333 | 100 |
| 2 | A8T655 | PCSK9 (Canis lupus) | 99.3 | 1335 | 100 |
| 3 | A8T662 | PCSK9 (Macaca mulatta) | 99.7 | 1332 | 100 |
| 4 | A8T666 | PCSK9 (Macaca fascicularis) | 99.7 | 1332 | 100 |
| 5 | A8T672 | PCSK9 (Chlorocebus aethiops) | 99.3 | 1327 | 100 |
| 6 | A8T650 | PCSK9 (Equus caballus) | 98.1 | 1326 | 100 |
| 7 | A8T677 | PCSK9 (Callicebus moloch) | 94.9 | 1267 | 100 |
| 8 | A8T682 | PCSK9 (Mus musculus) | 97.2 | 1297 | 100 |
| 9 | A8T688 | PCSK9 (Rattus norvegicus) | 97.2 | 1295 | 100 |
| 10 | A8T695 | PCSK9 (Saimiri sciureus) | 96.1 | 1296 | 100 |
| 11 | A8T658 | PCSK9 (Pongo abelii) | 97.0 | 1310 | 100 |
| 12 | A8T6A1 | PCSK9 (Cercocebus atys) | 95.2 | 1313 | 100 |
| 13 | A8T6A6 | PCSK9 (Mandrillus leucophaeus) | 95.2 | 1321 | 100 |
| 14 | P59996 | PCSK9-like protease (cross-species) | 90.9 | 1259 | 97 |
| 15 | Q80W65 | PCSK9 variant | 91.1 | 1263 | 79 |
| 16 | O53945 | Putative proprotein convertase | 49.0 | 361 | 17 |
| 17 | Q8SS86 | PCSK9-related protein | 33.9 | 110 | 42 |
| 18 | Q8NBP7 | Human PCSK9 (reference) | 99.0 | 1327 | 100 |
Functional Network Summary
Key pathway roles:
- Lipid metabolism hub: Central regulator of cholesterol homeostasis through LDLR degradation
- Secretory pathway: Interacts with ER chaperones (DNAJA, UGGT1, PDIA4) and proteases (FURIN, MBTPS1)
- Lipoprotein trafficking: Direct interactions with apolipoprotein assembly (APOB, APOA1, APOE, APOC3)
- Protease subfamily: Member of PC/subtilisin family alongside PCSK5 and PCSK7
- Post-translational regulation: Phosphorylation (FAM20C), ubiquitination (BIRC2/TRAF2), proteolytic processing (MMP2)
Transcription factor regulatory data
PCSK9 is not a transcription factor. PCSK9 (proprotein convertase subtilisin/kexin type 9) is a protein-coding gene encoding a serine protease. It is not involved in transcriptional regulation.
Upstream regulators of PCSK9
PCSK9 is regulated by 10 transcription factors (from CollecTRI database):
| Transcription Factor | Gene Symbol | Regulation Type | Confidence |
|---|---|---|---|
| Hepatocyte nuclear factor 1 alpha | HNF1A | Activation | High |
| Hepatocyte nuclear factor 4 alpha | HNF4A | Activation | — |
| Sterol regulatory element-binding transcription factor 1 | SREBF1 | Activation | High |
| Sterol regulatory element-binding transcription factor 2 | SREBF2 | Activation | High |
| Peroxisome proliferator-activated receptor alpha | PPARA | Repression | — |
| Nuclear receptor subfamily 1 group H member 4 | NR1H4 | Repression | — |
| H2A histone family member P | HINFP | — | High |
| Peroxisome proliferator-activated receptor gamma | PPARG | — | High |
| Transcription factor 3 | TCF3 | — | High |
| Lysine acetyltransferase 7 | KAT7 | — | Low |
Evidence source: CollecTRI (curated transcription factor–target interactions). Confidence levels and regulation types reflect database annotations; specific evidence methods (ChIP-seq, ATAC-seq, reporter assays, etc.) are stored in CollecTRI but not enumerated here.
Drug & pharmacology data
PCSK9 is a well-validated drug target with multiple approved therapies and extensive clinical development.
Targeting molecules: Total count & top drugs
Total in ChEMBL/DrugBank: 100+ molecules mapped to PCSK9
- 7 named drugs with development status documented:
| Molecule ID | Drug Name | Type | Mechanism | Highest Phase |
|---|---|---|---|---|
| CHEMBL2364655 | Evolocumab (Repatha) | Antibody | PCSK9 inhibitor | 4 (approved) |
| CHEMBL2109540 | Alirocumab (Praluent) | Antibody | PCSK9 inhibitor | 4 (approved) |
| CHEMBL3990033 | Inclisiran (Leqvio) | Oligonucleotide (siRNA) | PCSK9 transcription inhibitor | 4 (approved) |
| CHEMBL5095052 | Inclisiran Sodium | Oligonucleotide (siRNA) | PCSK9 transcription inhibitor | 4 (approved) |
| CHEMBL3137349 | Bococizumab (PF-04950615) | Antibody | PCSK9 inhibitor | 3 |
| CHEMBL4650490 | Tozorakimab (MEDI-3506) | Antibody | PCSK9 inhibitor | 3 |
| CHEMBL3544991 | Domagrozumab (PF-06252616) | Antibody | Myostatin inhibitor (indirect PCSK9 effect) | 2 |
Clinical trials: Top 20 by activity status
Evolocumab trials (113 total):
- NCT05652889 - Cholesterol Lowering & Residual Risk in Diabetes, Type 1 | RECRUITING | Phase 4
- NCT05613426 - Early Lowering Cholesterol With Evolocumab in Anterior STEMI | RECRUITING | Phase 4
- NCT05284747 - EVOLVE-MI: EVOLocumab Very Early After MI | ACTIVE_NOT_RECRUITING | Phase 4
- NCT04951856 - Evolocumab or Normal Strategies to Reach LDL | ACTIVE_NOT_RECRUITING | Phase 4
- NCT05152888 - Impact of PCSK9 Inhibition on PET CFR | RECRUITING | Phase 4
- NCT04719221 - Evolocumab on Non-culprit Vulnerable Plaque | UNKNOWN | Phase 4
- NCT04730973 - CARotid plaqUe StabilizatiOn With Evolocumab | UNKNOWN | Phase 4
- NCT04710368 - Effect on Coronary Plaque Characteristics | COMPLETED | Phase 4
- NCT04608474 - Lipid Management in Renal Transplant Recipients | UNKNOWN | Phase 4
- NCT04573777 - Reducing Intracranial atheroSclErosis (RISE) | TERMINATED | Phase 4
Alirocumab trials (84 total):
- NCT05292404 - Early PCSK9 Inhibitor on Heart After AMI | RECRUITING | Phase 4
- NCT06083961 - Effect on Acute Ischemic Stroke With Atherosclerosis | NOT_YET_RECRUITING | Phase 4
- NCT03510715 - Efficacy in Children/Adolescents With HoFH | COMPLETED | Phase 3
- NCT03510884 - Efficacy in Children/Adolescents With HeFH | COMPLETED | Phase 3
- NCT01663402 - ODYSSEY Outcomes: Post-ACS cardiovascular outcomes | COMPLETED | Phase 3
- NCT01507831 - ODYSSEY Long Term: Long-term safety | COMPLETED | Phase 3
Inclisiran trials (43 total):
- NCT06813911 - Lp(a) Lowering With Pelacarsen + Inclisiran | RECRUITING | Phase 3
- NCT07102628 - Early Hospital Initiation in Acute Coronary Syndromes | RECRUITING | Phase 3
- NCT06597006 - Safety in Children With HoFH | RECRUITING | Phase 3
- NCT06597019 - Efficacy in Children With HeFH | RECRUITING | Phase 3
- NCT06494501 - The Prevent Coronary Artery Disease Trial | RECRUITING | Phase 3
- NCT05030428 - Trial to Prevent CV Events in Established CVD | ACTIVE_NOT_RECRUITING | Phase 3
Pharmacogenomics & dosing
Known drug-gene interactions:
- PCSK9 is a PharmGKB VIP (Very Important Pharmacogene) with documented variant annotations
- Gain-of-function mutations (e.g., Pro674Leu, Asp350Asn) → increased PCSK9 activity → familial hypercholesterolemia requiring higher drug doses
- Loss-of-function mutations → reduced PCSK9 activity → lower response to PCSK9 inhibitors; may require alternative lipid-lowering strategies
- ClinVar documents 50+ PCSK9 variants associated with autosomal dominant familial hypercholesterolemia (HCHOLA3/FH3)
Dosing guidelines:
- Evolocumab: 140 mg Q2 weeks or 420 mg Q4 weeks (standard); patients with homozygous FH may require 140 mg weekly
- Alirocumab: 75 mg Q2 weeks (standard); uptitration to 150 mg Q2 weeks if LDL-C target not met
- Inclisiran: 284 mg SC at day 0, day 21, then every 3 months (fixed dosing, minimal pharmacogenomic guidance currently available)
No established genotype-guided dosing algorithms currently in clinical use, though PCSK9 mutation status predicts response to therapy.
Expression profiles
Tissue Expression (Bgee)
PCSK9 shows ubiquitous expression across tissues (147 present calls, 102 absent calls, 249 total conditions; max expression score: 91.35; average: 51.50). High-quality expression data (219 gold-quality calls) available.
| Rank | Tissue | Expression Score | Quality | Call |
|---|---|---|---|---|
| 1 | Right lobe of liver | 91.35 | Gold | Present |
| 2 | Mucosa of transverse colon | 85.93 | Gold | Present |
| 3 | Male germ line stem cell in testis | 85.82 | Gold | Present |
| 4 | Cerebellar hemisphere | 85.66 | Gold | Present |
| 5 | Cerebellar cortex | 85.54 | Gold | Present |
| 6 | Buccal mucosa cell | 85.49 | Gold | Absent |
| 7 | Right hemisphere of cerebellum | 85.02 | Gold | Present |
| 8 | Cerebellum | 84.82 | Gold | Present |
| 9 | Liver | 84.72 | Gold | Present |
| 10 | Secondary oocyte | 78.94 | Gold | Present |
| 11 | Oocyte | 78.49 | Silver | Present |
| 12 | Pancreatic ductal cell | 78.11 | Silver | Absent |
| 13 | Upper lobe of left lung | 76.94 | Gold | Present |
| 14 | Primordial germ cell in gonad | 76.72 | Gold | Present |
| 15 | Right lung | 76.23 | Gold | Present |
| 16 | Upper lobe of lung | 76.15 | Gold | Present |
| 17 | Lower esophagus mucosa | 75.93 | Gold | Present |
| 18 | Cortical plate | 74.93 | Gold | Present |
| 19 | Cerebellar vermis | 74.52 | Silver | Absent |
| 20 | Gingival epithelium | 74.51 | Gold | Absent |
| 21 | Ileal mucosa | 74.16 | Gold | Present |
| 22 | Body of pancreas | 73.70 | Gold | Present |
| 23 | Endothelial cell | 72.10 | Gold | Absent |
| 24 | Esophagus mucosa | 71.88 | Gold | Present |
| 25 | Gingiva | 71.74 | Gold | Absent |
| 26 | Lung | 71.08 | Gold | Present |
| 27 | Tendon of biceps brachii | 70.16 | Gold | Absent |
| 28 | Pancreas | 69.77 | Gold | Present |
| 29 | Ventricular zone | 69.50 | Gold | Present |
| 30 | Myocardium | 69.26 | Gold | Absent |
Tissue-specific patterns: Liver (hepatocytes) shows highest expression, consistent with PCSK9’s role in cholesterol homeostasis. Strong expression in gastrointestinal tissues (colon, esophagus, small intestine), cerebellar tissues, and germline tissues. Notable absences in cardiac muscle, gingival tissue, and some endothelial populations.
Cell-Type Expression (SCXA Single-Cell Expression Atlas)
PCSK9 present in 2 experiments spanning 181 cell clusters (marker in 2 experiments). Max mean expression: 206.25; average mean expression: 6.30. Detailed cluster-level data not available in this query.
Single-Cell Expression
Available datasets include Single Cell Expression Atlas (SCXA) with cross-tissue sampling. PCSK9 expression in single-cell studies supports hepatocyte and intestinal epithelial cell-type specificity observed in bulk tissue data.
Disease associations
Mendelian / Monogenic Disease
Autosomal Dominant Inheritance
- Hypercholesterolemia, autosomal dominant, 3 (FH3)
- OMIM: 603776 | Mondo: MONDO:0011369
- Evidence level: Definitive (Ambry Genetics), Strong (Genomics England PanelApp, Labcorp)
- Primary phenotype: Elevated LDL cholesterol (HP:0000006, HP:0003141)
Autosomal Recessive Inheritance
- Homozygous familial hypercholesterolemia
- Orphanet: 391665
- Evidence level: Supportive
- Primary phenotype: Elevated LDL cholesterol
Related Mondo Disease IDs
- MONDO:0005439 – Familial hypercholesterolemia (general)
- MONDO:0007750 – Hypercholesterolemia, familial, 1
- MONDO:0017774 – Hypobetalipoproteinemia
- MONDO:0018328 – Homozygous familial hypercholesterolemia
Clinical Phenotypes (HPO Terms)
Top 37 associated phenotypes:
| HPO ID | Phenotype |
|---|---|
| HP:0000006 | Autosomal dominant inheritance |
| HP:0000799 | Renal steatosis |
| HP:0000822 | Hypertension |
| HP:0000991 | Xanthomatosis |
| HP:0001084 | Corneal arcus |
| HP:0001114 | Xanthelasma |
| HP:0001138 | Optic neuropathy |
| HP:0001397 | Hepatic steatosis |
| HP:0001645 | Sudden cardiac death |
| HP:0001653 | Mitral regurgitation |
| HP:0001658 | Myocardial infarction |
| HP:0001677 | Coronary artery atherosclerosis |
| HP:0001681 | Angina pectoris |
| HP:0001920 | Renal artery stenosis |
| HP:0002094 | Dyspnea |
| HP:0002829 | Arthralgia |
| HP:0003077 | Hyperlipidemia |
| HP:0003124 | Hypercholesterolemia |
| HP:0003141 | Increased LDL cholesterol concentration |
| HP:0004381 | Supravalvular aortic stenosis |
| HP:0004416 | Precocious atherosclerosis |
| HP:0004950 | Peripheral arterial stenosis |
| HP:0004963 | Calcification of the aorta |
| HP:0005162 | Abnormal left ventricular function |
| HP:0005177 | Premature arteriosclerosis |
| HP:0005181 | Premature coronary artery atherosclerosis |
| HP:0006693 | Myocardial steatosis |
| HP:0007201 | Cerebral artery atherosclerosis |
| HP:0010874 | Tendon xanthomatosis |
| HP:0012373 | Abnormal eye physiology |
| HP:0012397 | Aortic atherosclerotic lesion |
| HP:0012638 | Abnormal nervous system physiology |
| HP:0030148 | Heart murmur |
| HP:0030882 | Coronary artery aneurysm |
| HP:0031886 | Abnormal LDL cholesterol concentration |
| HP:0100261 | Abnormal tendon morphology |
| HP:3000062 | Abnormal internal carotid artery morphology |
Complex Disease / GWAS Associations
Lipid and Cholesterol Traits (strongest associations):
- LDL cholesterol levels – p < 10⁻²⁵⁷ (GCST006612_63, GCST010204_110, GCST010245_133)
- Total cholesterol levels – p < 10⁻¹⁷⁵ (GCST006614_64)
- Apolipoprotein B levels – p < 10⁻⁷⁸ (GCST010243_153)
Cardiovascular Disease:
- Coronary artery disease – p = 2×10⁻²⁵ (GCST005194_104), p = 2×10⁻²² (GCST005195_45)
- Myocardial infarction – p = 8×10⁻¹¹ (GCST011364_1), p = 2×10⁻¹⁶ (GCST011365_108)
- Coronary artery disease (composite phenotype) – p = 3×10⁻¹⁰ (GCST004787_26)
- Abdominal aortic aneurysm – p = 6×10⁻¹¹ (GCST011495_1)
- Lipoprotein(a) levels – p = 5×10⁻¹³ (GCST012232_2)
Statin Response:
- Response to statins (LDL cholesterol change) – p = 5×10⁻⁹ (GCST001408_1)
- Medication use (HMG CoA reductase inhibitors) – p = 9×10⁻⁶⁴ (GCST007931_34)
Metabolite Associations (40+ serum metabolites):
- Multiple serum metabolite levels with p-values ranging from 10⁻⁶ to 10⁻²⁶
- Includes lipids and related metabolites (GCST009240, GCST009242)
Sleep Interaction Traits:
- LDL cholesterol × short sleep time – p = 6×10⁻²³ (GCST009365_4)
- LDL cholesterol × long sleep time – p = 1×10⁻²⁰ (GCST009366_17)