Homozygous familial hypercholesterolemia
diseaseOn this page
Also known as HoFH
Summary
Homozygous familial hypercholesterolemia (MONDO:0018328) is a disease with 4 cohort genes and 48 clinical trials. The dominant Reactome pathway is LDL clearance (4 cohort genes). Top therapeutic interventions include lomitapide, evinacumab, and evolocumab.
At a glance
- Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
- Cohort genes: 4
- ClinVar variants: 132
- Phenotypes (HPO): 33
- Clinical trials: 48
Clinical features
Epidemiology
Prevalence records
6 prevalence record(s), Orphanet:
| Type | Class | Value | Geography | Validation |
|---|---|---|---|---|
| Point prevalence | 1-9 / 1 000 000 | 0.3194 | Worldwide | Validated |
| Annual incidence | 1-9 / 1 000 000 | 0.5842 | Japan | Validated |
| Point prevalence | 1-9 / 1 000 000 | 0.22 | Spain | Validated |
| Point prevalence | 1-9 / 1 000 000 | 0.625 | Denmark | Validated |
| Point prevalence | 1-9 / 1 000 000 | 0.33 | Netherlands | Validated |
| Point prevalence | 1-9 / 1 000 000 | 0.125 | Germany | Validated |
Signs & symptoms
Clinical features (HPO)
33 HPO clinical features (Orphanet curated; top 33 by frequency):
| HPO ID | Term | Frequency |
|---|---|---|
| HP:0003077 | Hyperlipidemia | Obligate (100%) |
| HP:0003124 | Hypercholesterolemia | Obligate (100%) |
| HP:0003141 | Increased LDL cholesterol concentration | Obligate (100%) |
| HP:0004416 | Precocious atherosclerosis | Very frequent (80-99%) |
| HP:0005177 | Premature arteriosclerosis | Very frequent (80-99%) |
| HP:0000822 | Hypertension | Frequent (30-79%) |
| HP:0001397 | Hepatic steatosis | Frequent (30-79%) |
| HP:0001645 | Sudden cardiac death | Frequent (30-79%) |
| HP:0001658 | Myocardial infarction | Frequent (30-79%) |
| HP:0001677 | Coronaryartery atherosclerosis | Frequent (30-79%) |
| HP:0001681 | Angina pectoris | Frequent (30-79%) |
| HP:0001920 | Renal artery stenosis | Frequent (30-79%) |
| HP:0002094 | Dyspnea | Frequent (30-79%) |
| HP:0004950 | Peripheral arterial stenosis | Frequent (30-79%) |
| HP:0005162 | Abnormal left ventricular function | Frequent (30-79%) |
| HP:0005181 | Premature coronary artery atherosclerosis | Frequent (30-79%) |
| HP:0006693 | Myocardial steatosis | Frequent (30-79%) |
| HP:0007201 | Cerebral artery atherosclerosis | Frequent (30-79%) |
| HP:0012397 | Aortic atherosclerosis | Frequent (30-79%) |
| HP:0030148 | Heart murmur | Frequent (30-79%) |
| HP:0100261 | Abnormal tendon morphology | Frequent (30-79%) |
| HP:3000062 | Abnormal internal carotid artery morphology | Frequent (30-79%) |
| HP:0000799 | Renal steatosis | Occasional (5-29%) |
| HP:0000991 | Xanthomatosis | Occasional (5-29%) |
| HP:0001653 | Mitral regurgitation | Occasional (5-29%) |
| HP:0002829 | Arthralgia | Occasional (5-29%) |
| HP:0004381 | Supravalvular aortic stenosis | Occasional (5-29%) |
| HP:0004963 | Calcification of the aorta | Occasional (5-29%) |
| HP:0010874 | Tendon xanthomatosis | Occasional (5-29%) |
| HP:0001138 | Optic neuropathy | Very rare (<1-4%) |
| HP:0012373 | Abnormal eye physiology | Very rare (<1-4%) |
| HP:0012638 | Abnormality of nervous system physiology | Very rare (<1-4%) |
| HP:0030882 | Coronary artery aneurysm | Very rare (<1-4%) |
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | homozygous familial hypercholesterolemia |
| Mondo ID | MONDO:0018328 |
| MeSH | D000090542 |
| Orphanet | 391665 |
| SNOMED CT | 238078005 |
| UMLS | C0342881 |
| MedGen | 575266 |
| GARD | 0010416 |
| Is cancer (heuristic) | no |
Also known as: HoFH · homozygous familial hypercholesterolemia
Data availability: 132 ClinVar variants · 4 GenCC gene-disease records · 62 cell lines.
Disease family
Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › familial hyperlipidemia › familial hypercholesterolemia › homozygous familial hypercholesterolemia
Related subtypes (4): hypercholesterolemia, familial, 1, hypercholesterolemia, autosomal dominant, type B, hypercholesterolemia, autosomal dominant, 3, hypercholesterolemia due to cholesterol 7alpha-hydroxylase deficiency
Genetics & variants
GWAS landscape
No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.
Variant details and genetic-evidence tiers
ClinVar germline variants
132 retrieved; paginated sample, class counts are floors:
56 pathogenic/likely pathogenic, 51 pathogenic, 16 likely pathogenic, 6 uncertain significance, 3 conflicting classifications of pathogenicity
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 3737 | FH Aarhus | Pathogenic | criteria provided, multiple submitters, no conflicts | |
| 17890 | NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln) | APOB | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 40223 | NM_000384.3(APOB):c.10579C>T (p.Arg3527Trp) | APOB | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 161266 | NM_000527.5(LDLR):c.301G>A (p.Glu101Lys) | LDLR | Pathogenic | reviewed by expert panel |
| 161268 | NM_000527.5(LDLR):c.862G>A (p.Glu288Lys) | LDLR | Pathogenic | reviewed by expert panel |
| 161271 | NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) | LDLR | Pathogenic | reviewed by expert panel |
| 161277 | NM_000527.5(LDLR):c.1432G>A (p.Gly478Arg) | LDLR | Pathogenic | reviewed by expert panel |
| 161287 | NM_000527.5(LDLR):c.798T>A (p.Asp266Glu) | LDLR | Pathogenic | reviewed by expert panel |
| 162499 | NM_000527.5(LDLR):c.1359-1G>A | LDLR | Pathogenic | reviewed by expert panel |
| 183092 | NM_000527.5(LDLR):c.662A>G (p.Asp221Gly) | LDLR | Pathogenic | reviewed by expert panel |
| 183106 | NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser) | LDLR | Pathogenic | reviewed by expert panel |
| 183110 | NM_000527.5(LDLR):c.1246C>T (p.Arg416Trp) | LDLR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 183116 | NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr) | LDLR | Pathogenic | reviewed by expert panel |
| 183136 | NM_000527.5(LDLR):c.502G>A (p.Asp168Asn) | LDLR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 189296 | NM_000527.5(LDLR):c.313+2T>C | LDLR | Pathogenic | reviewed by expert panel |
| 200918 | NM_000527.5(LDLR):c.501C>A (p.Cys167Ter) | LDLR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 200919 | NM_000527.5(LDLR):c.590G>A (p.Cys197Tyr) | LDLR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 200920 | NM_000527.5(LDLR):c.718G>A (p.Glu240Lys) | LDLR | Pathogenic | reviewed by expert panel |
| 200921 | NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) | LDLR | Pathogenic | reviewed by expert panel |
| 226312 | NM_000527.5(LDLR):c.266G>A (p.Cys89Tyr) | LDLR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 226313 | NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) | LDLR | Pathogenic | reviewed by expert panel |
| 226316 | NM_000527.5(LDLR):c.313_313+1del | LDLR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 226322 | NM_000527.5(LDLR):c.400T>C (p.Cys134Arg) | LDLR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 226329 | NM_000527.5(LDLR):c.651TGG[1] (p.Gly219del) | LDLR | Pathogenic | reviewed by expert panel |
| 226333 | NM_000527.5(LDLR):c.682G>T (p.Glu228Ter) | LDLR | Pathogenic | reviewed by expert panel |
| 226334 | NM_000527.5(LDLR):c.796G>A (p.Asp266Asn) | LDLR | Pathogenic | reviewed by expert panel |
| 226339 | NM_000527.5(LDLR):c.938G>A (p.Cys313Tyr) | LDLR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 226342 | NM_000527.5(LDLR):c.1048C>T (p.Arg350Ter) | LDLR | Pathogenic | reviewed by expert panel |
| 226347 | NM_000527.5(LDLR):c.1118_1121dup (p.Tyr375fs) | LDLR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 226349 | NM_000527.5(LDLR):c.1187-10G>A | LDLR | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 22 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0
GenCC gene–disease validity (cohort genes)
the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.
| Gene | Classification | Inheritance | Disease | Records |
|---|---|---|---|---|
| APOB | Definitive | Autosomal dominant | hypercholesterolemia, autosomal dominant, type B | 9 |
| LDLR | Definitive | Autosomal dominant | hypercholesterolemia, familial, 1 | 4 |
| PCSK9 | Definitive | Autosomal dominant | hypercholesterolemia, autosomal dominant, 3 | 5 |
| LDLRAP1 | Strong | Autosomal recessive | hypercholesterolemia, familial, 4 | 4 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| PCSK9 | Orphanet:391665 | Homozygous familial hypercholesterolemia |
| APOB | Orphanet:391665 | Homozygous familial hypercholesterolemia |
| LDLR | Orphanet:391665 | Homozygous familial hypercholesterolemia |
| LDLRAP1 | Orphanet:391665 | Homozygous familial hypercholesterolemia |
Cohort genes → proteins
4 cohort genes, 4 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 4 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| PCSK9 | HGNC:20001 | ENSG00000169174 | Q8NBP7 | Proprotein convertase subtilisin/kexin type 9 | gencc,clinvar |
| APOB | HGNC:603 | ENSG00000084674 | P04114 | Apolipoprotein B-100 | gencc,clinvar |
| LDLR | HGNC:6547 | ENSG00000130164 | P01130 | Low-density lipoprotein receptor | gencc,clinvar |
| LDLRAP1 | HGNC:18640 | ENSG00000157978 | Q5SW96 | Low density lipoprotein receptor adapter protein 1 | gencc |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| PCSK9 | Proprotein convertase subtilisin/kexin type 9 | Crucial player in the regulation of plasma cholesterol homeostasis. |
| APOB | Apolipoprotein B-100 | Apolipoprotein B is a major protein constituent of chylomicrons (apo B-48), LDL (apo B-100) and VLDL (apo B-100). |
| LDLR | Low-density lipoprotein receptor | Binds low density lipoprotein /LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. |
| LDLRAP1 | Low density lipoprotein receptor adapter protein 1 | Adapter protein (clathrin-associated sorting protein (CLASP)) required for efficient endocytosis of the LDL receptor (LDLR) in polarized cells such as hepatocytes and lymphocytes, but not in non-polarized cells (fibroblasts). |
Protein-family classification
Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25
Family distribution
Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.
| Family | Genes | Fold | FDR |
|---|---|---|---|
| Protease | 1 | 9.2× | 0.210 |
| Other/Unknown | 3 | 1.3× | 0.404 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| PCSK9 | Protease | yes | 3.4.21.61 | Peptidase_S8/S53_dom, S8pro/Inhibitor_I9, Peptidase_S8_subtilisin-rel |
| APOB | Other/Unknown | no | Vitellogenin_N, Lipid_transpt_open_b-sht, Lipovitellin_superhlx_dom | |
| LDLR | Other/Unknown | no | LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF | |
| LDLRAP1 | Other/Unknown | no | PTB/PI_dom, PH-like_dom_sf, Adapter_Engulfment-Domain |
Expression context
Cohort genes with no expression data: 0.
4 cohort genes are a single-cell marker in ≥1 SCXA experiment.
Breadth distribution (Bgee present_calls)
| Bucket | Genes |
|---|---|
| narrow (1-5 tissues) | 0 |
| moderate (6-20) | 0 |
| broad (>20) | 4 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| male germ line stem cell (sensu Vertebrata) in testis | 1 |
| mucosa of transverse colon | 1 |
| right lobe of liver | 1 |
| ileal mucosa | 1 |
| jejunal mucosa | 1 |
| liver | 1 |
| adrenal tissue | 1 |
| lower lobe of lung | 1 |
| right adrenal gland | 1 |
| cerebellar cortex | 1 |
| cerebellar hemisphere | 1 |
| right hemisphere of cerebellum | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| PCSK9 | 147 | broad | marker | right lobe of liver, mucosa of transverse colon, male germ line stem cell (sensu Vertebrata) in testis |
| APOB | 116 | broad | marker | jejunal mucosa, liver, ileal mucosa |
| LDLR | 281 | ubiquitous | marker | adrenal tissue, lower lobe of lung, right adrenal gland |
| LDLRAP1 | 271 | ubiquitous | marker | cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum |
Protein interactions among cohort
Intra-cohort edges: 6.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| APOB | 5,244 |
| PCSK9 | 2,994 |
| LDLR | 1,426 |
| LDLRAP1 | 1,055 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| APOB | LDLR | intact, string_interaction |
| APOB | LDLRAP1 | string_interaction |
| APOB | PCSK9 | string_interaction |
| LDLR | LDLRAP1 | string_interaction |
| LDLR | PCSK9 | biogrid_interaction, intact, string_interaction |
| LDLRAP1 | PCSK9 | string_interaction |
Structural data
PDB: 4 · AlphaFold-only: 0 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| PCSK9 | Q8NBP7 | 65 |
| LDLR | P01130 | 36 |
| APOB | P04114 | 8 |
| LDLRAP1 | Q5SW96 | 1 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 49. Enrichment computed across 4 evidence-associated genes (4 with Reactome annotation).
Pathways by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| LDL clearance | 4 | 543.8× | 4e-10 | PCSK9, APOB, LDLR, LDLRAP1 |
| Chylomicron clearance | 3 | 1713.0× | 4e-09 | APOB, LDLR, LDLRAP1 |
| Plasma lipoprotein clearance | 3 | 356.9× | 5e-07 | APOB, LDLR, LDLRAP1 |
| Plasma lipoprotein assembly, remodeling, and clearance | 3 | 171.3× | 4e-06 | APOB, LDLR, LDLRAP1 |
| Metabolism of vitamins and cofactors | 3 | 87.4× | 2e-05 | APOB, LDLR, LDLRAP1 |
| Cargo recognition for clathrin-mediated endocytosis | 3 | 78.6× | 3e-05 | APOB, LDLR, LDLRAP1 |
| Clathrin-mediated endocytosis | 3 | 63.9× | 4e-05 | APOB, LDLR, LDLRAP1 |
| Metabolism of fat-soluble vitamins | 2 | 190.3× | 2e-04 | APOB, LDLR |
| Visual phototransduction | 2 | 129.8× | 4e-04 | APOB, LDLR |
| Retinoid metabolism and transport | 2 | 124.1× | 4e-04 | APOB, LDLR |
| Membrane Trafficking | 3 | 27.8× | 4e-04 | APOB, LDLR, LDLRAP1 |
| Vesicle-mediated transport | 3 | 26.1× | 4e-04 | APOB, LDLR, LDLRAP1 |
| Transport of small molecules | 3 | 18.9× | 9e-04 | APOB, LDLR, LDLRAP1 |
| Post-translational protein phosphorylation | 2 | 50.1× | 0.002 | PCSK9, APOB |
| Sensory Perception | 2 | 47.6× | 0.002 | APOB, LDLR |
| Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) | 2 | 43.3× | 0.002 | PCSK9, APOB |
| Scavenging by Class H Receptors | 1 | 713.8× | 0.004 | APOB |
| VLDL assembly | 1 | 571.0× | 0.005 | APOB |
| Scavenging by Class F Receptors | 1 | 475.8× | 0.005 | APOB |
| LDL remodeling | 1 | 475.8× | 0.005 | APOB |
| VLDL clearance | 1 | 475.8× | 0.005 | APOB |
| Metabolism | 3 | 8.7× | 0.005 | APOB, LDLR, LDLRAP1 |
| Transport of RCbl within the body | 1 | 356.9× | 0.006 | LDLRAP1 |
| Chylomicron assembly | 1 | 285.5× | 0.007 | APOB |
| Chylomicron remodeling | 1 | 285.5× | 0.007 | APOB |
| Scavenging by Class B Receptors | 1 | 259.6× | 0.007 | APOB |
| Vitamin D (calciferol) metabolism | 1 | 219.6× | 0.008 | LDLRAP1 |
| VLDLR internalisation and degradation | 1 | 178.4× | 0.009 | PCSK9 |
| Plasma lipoprotein assembly | 1 | 178.4× | 0.009 | APOB |
| Platelet sensitization by LDL | 1 | 167.9× | 0.010 | APOB |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| cholesterol metabolic process | 4 | 195.9× | 5e-08 | PCSK9, APOB, LDLR, LDLRAP1 |
| cholesterol homeostasis | 4 | 156.0× | 7e-08 | PCSK9, APOB, LDLR, LDLRAP1 |
| low-density lipoprotein particle clearance | 3 | 743.5× | 1e-07 | APOB, LDLR, LDLRAP1 |
| cholesterol transport | 3 | 549.5× | 2e-07 | APOB, LDLR, LDLRAP1 |
| receptor-mediated endocytosis involved in cholesterol transport | 2 | 4213.0× | 7e-07 | LDLR, LDLRAP1 |
| negative regulation of receptor recycling | 2 | 1685.2× | 6e-06 | PCSK9, LDLR |
| lipoprotein catabolic process | 2 | 1203.7× | 1e-05 | APOB, LDLR |
| negative regulation of low-density lipoprotein particle clearance | 2 | 766.0× | 3e-05 | PCSK9, LDLR |
| artery morphogenesis | 2 | 337.0× | 1e-04 | APOB, LDLR |
| receptor-mediated endocytosis | 2 | 110.9× | 0.001 | LDLR, LDLRAP1 |
| low-density lipoprotein particle receptor catabolic process | 1 | 4213.0× | 0.002 | PCSK9 |
| regulation of phosphatidylcholine catabolic process | 1 | 2106.5× | 0.003 | LDLR |
| regulation of protein binding | 1 | 2106.5× | 0.003 | LDLRAP1 |
| negative regulation of sodium ion import across plasma membrane | 1 | 2106.5× | 0.003 | PCSK9 |
| negative regulation of receptor-mediated endocytosis involved in cholesterol transport | 1 | 2106.5× | 0.003 | PCSK9 |
| positive regulation of receptor-mediated endocytosis involved in cholesterol transport | 1 | 2106.5× | 0.003 | LDLRAP1 |
| positive regulation of low-density lipoprotein particle receptor catabolic process | 1 | 1404.3× | 0.003 | PCSK9 |
| negative regulation of astrocyte activation | 1 | 1404.3× | 0.003 | LDLR |
| triglyceride mobilization | 1 | 1053.2× | 0.004 | APOB |
| plasma lipoprotein particle clearance | 1 | 1053.2× | 0.004 | LDLR |
| positive regulation of low-density lipoprotein particle clearance | 1 | 1053.2× | 0.004 | LDLRAP1 |
| cellular response to lipoprotein particle stimulus | 1 | 842.6× | 0.004 | APOB |
| positive regulation of lysosomal protein catabolic process | 1 | 842.6× | 0.004 | LDLR |
| lipoprotein biosynthetic process | 1 | 702.2× | 0.005 | APOB |
| cholesterol import | 1 | 702.2× | 0.005 | LDLR |
| positive regulation of cholesterol storage | 1 | 601.9× | 0.005 | APOB |
| high-density lipoprotein particle clearance | 1 | 601.9× | 0.005 | LDLR |
| regulation of protein metabolic process | 1 | 526.6× | 0.005 | LDLR |
| negative regulation of protein metabolic process | 1 | 526.6× | 0.005 | LDLR |
| positive regulation of cholesterol metabolic process | 1 | 526.6× | 0.005 | LDLRAP1 |
Therapeutics
Drug target analysis
Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 2
Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Genes with an approved drug
The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.
| Symbol | Example approved molecule |
|---|---|
| PCSK9 | NILOTINIB |
| LDLR | NILOTINIB |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| PCSK9 | 1 | 4 |
| LDLR | 1 | 4 |
| APOB | 0 | 0 |
| LDLRAP1 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| NILOTINIB | 4 | LDLR, PCSK9 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 1.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| PCSK9 | 202 | Binding:201, ADMET:1 |
| LDLR | 55 | Binding:54, Functional:1 |
| APOB | 1 | Binding:1 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| PCSK9 | 3.4.21.61 | Kexin |
Cohort genes with high screening signal
≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.
| Symbol | ChEMBL assays |
|---|---|
| PCSK9 | 202 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Chemical tractability of cohort targets
1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.
| Compound | Max phase | Cohort target (bioactivity) |
|---|---|---|
| NILOTINIB | 4 | LDLR, PCSK9 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 2 | PCSK9, LDLR |
| B | Phased (≥1) drug, not yet approved | 0 | |
| C | Druggable family + PDB, no drug | 0 | |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 2 | APOB, LDLRAP1 |
Undrugged target profiles
2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| LDLRAP1 | 0 | PCSK9 |
| APOB | 1 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 48.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| PHASE3 | 18 |
| Not specified | 14 |
| PHASE2 | 11 |
| PHASE2/PHASE3 | 2 |
| PHASE1/PHASE2 | 1 |
| EARLY_PHASE1 | 1 |
| PHASE1 | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT05682378 | PHASE3 | RECRUITING | Long-term Safety and Tolerability of Inclisiran in Participants With HeFH or HoFH Who Have Completed the Pediatric ORION-16, ORION-13, ORION-20, or ORION-19 Studies |
| NCT06712771 | PHASE3 | ACTIVE_NOT_RECRUITING | A Phase 3 Clinical Trial to Evaluate the Efficacy and Safety of VSA003 in Chinese HoFH Patients |
| NCT07037771 | PHASE3 | RECRUITING | A Phase 3 Study of Zodasiran in Adolescent and Adult Subjects With Homozygous Familial Hypercholesterolemia (YOSEMITE) |
| NCT07473843 | PHASE3 | NOT_YET_RECRUITING | Study of Zodasiran in Adolescent Participants With Homozygous Familial Hypercholesterolemia |
| NCT00730236 | PHASE3 | COMPLETED | A Safety and Efficacy Study of AEGR-733 to Treat Homozygous Familial Hypercholesterolemia (FH) |
| NCT01588496 | PHASE2/PHASE3 | COMPLETED | Trial Evaluating PCSK9 Antibody in Subjects With LDL Receptor Abnormalities |
| NCT01841684 | PHASE3 | TERMINATED | Efficacy and Tolerability of Anacetrapib Added to Ongoing Lipid-Lowering Therapy in Adult Participants With Homozygous Familial Hypercholesterolemia (HoFH) (MK-0859-042) |
| NCT02226198 | PHASE3 | COMPLETED | A Study to Evaluate the Efficacy and Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia |
| NCT02434497 | PHASE3 | COMPLETED | A Study to Evaluate the Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia |
| NCT02765841 | PHASE3 | WITHDRAWN | Evaluate the Efficacy and Safety of Lomitapide in Pediatric Patients With Homozygous Familial Hypercholesterolemia on Stable Lipid-lowering Therapy |
| NCT03156621 | PHASE3 | COMPLETED | Study in Participants With Homozygous Familial Hypercholesterolemia (HoFH) |
| NCT03399786 | PHASE3 | COMPLETED | Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia |
| NCT03409744 | PHASE3 | COMPLETED | Evaluate the Long-Term Safety and Efficacy of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia |
| NCT03814187 | PHASE3 | COMPLETED | Trial to Assess the Effect of Long Term Dosing of Inclisiran in Subjects With High CV Risk and Elevated LDL-C |
| NCT03851705 | PHASE3 | COMPLETED | A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia (HoFH) |
| NCT04031742 | PHASE2/PHASE3 | COMPLETED | A Study to Evaluate Safety and Efficacy of IBI306, a PCSK9 Monoclonal Antibody in Chinese Subjects With Homozygous Familial Hypercholesterolemia |
| NCT04034485 | PHASE3 | COMPLETED | Phase 3 Study to Evaluate the Efficacy and Safety of LIB003 With Evolocumab in HoFH |
| NCT04233918 | PHASE3 | COMPLETED | Evaluate the Efficacy and Safety of Evinacumab in Pediatric Patients With Homozygous Familial Hypercholesterolemia |
| NCT05611528 | PHASE3 | COMPLETED | Safety and Effectiveness of Evinacumab for the Treatment of Homozygous Familial Hypercholesterolemia |
| NCT06723652 | PHASE3 | COMPLETED | A Multicenter, Randomized, Double-blind, Placebo-controlled Phase III Clinical Study Evaluating the Efficacy and Safety of SHR-1918 in Patients With Homozygous Familial Hypercholesterolemia |
| NCT07133815 | PHASE2 | NOT_YET_RECRUITING | Evaluate the Long-term Efficacy and Safety of SHR-1918 in Patients With Homozygous Familial Hypercholesterolemia |
| NCT07489209 | PHASE2 | RECRUITING | A Dose-exploration Study of EDP167 in HoFH |
| NCT01412034 | PHASE2 | COMPLETED | Effect of CER-001 on Plaque Volume in Homozygous Familial Hypercholesterolemia (HoFH) Subjects |
| NCT01556906 | PHASE2 | COMPLETED | Safety, Tolerability and Efficacy of Microsomal Triglyceride Protein (MTP) Inhibitor |
| NCT02265952 | PHASE2 | COMPLETED | Study of REGN1500 in Participants With Homozygous Familial Hypercholesterolemia (HoFH) |
| NCT02472535 | PHASE2 | COMPLETED | Study to Evaluate the Effects of MBX-8025 in Patients With HoFH |
| NCT02651675 | PHASE1/PHASE2 | TERMINATED | A Gene Therapy Study for Homozygous Familial Hypercholesterolemia (HoFH) |
| NCT02963311 | PHASE2 | COMPLETED | A Study of ALN-PCSSC in Participants With Homozygous Familial Hypercholesterolemia (HoFH) |
| NCT03455777 | PHASE2 | WITHDRAWN | Study of AKCEA-ANGPTL3-LRX (ISIS 703802) in Patients With Homozygous Familial Hypercholesterolemia (HoFH) |
| NCT03933293 | PHASE2 | COMPLETED | A Study to Evaluate the Safety and Efficacy of the PCSK9 Inhibitor AK102 in Patients With HoFH |
| NCT05217667 | PHASE2 | TERMINATED | Study of ARO-ANG3 in Participants With Homozygous Familial Hypercholesterolemia (HOFH) |
| NCT06009393 | PHASE2 | COMPLETED | Evaluate the Efficacy and Safety of SHR-1918 in Patients With Homozygous Familial Hypercholesterolemia |
| NCT07491172 | PHASE1 | RECRUITING | A Safety and Tolerability Trial Evaluating CTX310 in Participants With Refractory Dyslipidemias |
| NCT06125847 | EARLY_PHASE1 | RECRUITING | NGGT006 Gene Therapy for Homozygous Familial Hypercholesterolemia |
| NCT01109368 | Not specified | RECRUITING | The Rogosin Institute Homozygous Familial Hypercholesterolemia Repository |
| NCT04815005 | Not specified | RECRUITING | HoFH, the International Clinical Collaborators Registry |
| NCT06832371 | Not specified | ACTIVE_NOT_RECRUITING | Evaluation of the Effect of Lomitapide Treatment on Major Adverse Cardiovascular Events (MACE) in Patients With Homozygous Familial Hypercholesterolemia |
| NCT07447648 | Not specified | RECRUITING | Assessing the Impact of Intensification of Lipid Lowering Therapy With Guidelines-based Evinacumab Administration on Coronary Plaque Volumes Measured by Coronary Computed Tomography Angiography (CCTA) in Patients With Homozygous Familial Hypercholesterolemia (HoFH) |
| NCT07470723 | Not specified | RECRUITING | The ORIGIN-FH Study |
| NCT00704535 | Not specified | COMPLETED | Evaluation of the Safety, Tolerability and Efficacy of Ezetimibe on a Select Population of Filipinos With Hypercholesterolemia (Study P04748)(COMPLETED) |
Drugs tested across these trials (top 30)
| Molecule | Max phase | Trials referencing |
|---|---|---|
| LOMITAPIDE | 4 | 15 |
| EVINACUMAB | 4 | 4 |
| EVOLOCUMAB | 4 | 2 |
| INCLISIRAN SODIUM | 4 | 2 |
| ALIROCUMAB | 4 | 1 |
| INCLISIRAN | 3 | 2 |
| ANACETRAPIB | 3 | 1 |
| DEXTRAN | 3 | 1 |
| LERODALCIBEP | 3 | 1 |
| TAFOLECIMAB | 3 | 1 |
| ZODASIRAN | 2 | 2 |
| DEXTRAN 1 | 2 | 1 |
| VUPANORSEN | 2 | 1 |
| CHEMBL3787505 | 0 | 1 |
Related Atlas pages
- Cohort genes: PCSK9, APOB, LDLR, LDLRAP1
- Drugs: Lomitapide, Evinacumab, Evolocumab, Inclisiran, Alirocumab, Inclisiran, Anacetrapib, Dextran, Lerodalcibep, Tafolecimab