Familial hypercholesterolemia

disease

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Also known as hyperlipoproteinemia type II

Summary

Familial hypercholesterolemia (MONDO:0005439) is a disease (an umbrella term covering 5 Mondo subtypes) with 20 cohort genes and 110 clinical trials. The dominant Reactome pathway is Chylomicron clearance (4 cohort genes). Top therapeutic interventions include mipomersen, evolocumab, and lomitapide.

At a glance

Umbrella term: 5 Mondo subtypes
Cohort genes: 20
ClinVar variants: 4,321
Clinical trials: 110

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hypercholesterolemia
Mondo ID	MONDO:0005439
EFO	EFO:0004911
OMIM	143890
DOID	DOID:13810
ICD-10-CM	E78.01
NCIT	C34704
SNOMED CT	190773008
UMLS	C0020445
MedGen	5688
Is cancer (heuristic)	no

Also known as: hyperlipoproteinemia type II

Data availability: 4,321 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 5 Mondo subtypes.

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

Subtypes (5): hypercholesterolemia, familial, 1, hypercholesterolemia, autosomal dominant, type B, hypercholesterolemia, autosomal dominant, 3, hypercholesterolemia due to cholesterol 7alpha-hydroxylase deficiency, homozygous familial hypercholesterolemia

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

600 retrieved; paginated sample, class counts are floors:

277 likely benign, 142 uncertain significance, 61 pathogenic, 49 conflicting classifications of pathogenicity, 32 likely pathogenic, 19 pathogenic/likely pathogenic, 9 benign, 9 benign/likely benign, 1 association, 1 conflicting classifications of pathogenicity; other; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
17887	NM_000384.3(APOB):c.6253C>T (p.Arg2085Ter)	APOB	Pathogenic/Likely 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
126456	NM_000041.4(APOE):c.497TCC[1] (p.Leu167del)	APOE	Pathogenic	criteria provided, multiple submitters, no conflicts
1052293	NM_000527.5(LDLR):c.1706A>T (p.Asp569Val)	LDLR	Pathogenic	criteria provided, single submitter
1068547	NM_000527.5(LDLR):c.1187-1_1187delinsTA	LDLR	Pathogenic	criteria provided, single submitter
1069255	NM_000527.5(LDLR):c.1503_1504dup (p.Asp502fs)	LDLR	Pathogenic	criteria provided, single submitter
1069978	NM_000527.5(LDLR):c.2469_2470insTTTTTTTTTTTTTTTTTNNNNNNNNNNTTAGCCAGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAAGCGTGAGCCACCGCGCCCGGCCAACAGCATCAACTTT (p.Asp824delinsPhePhePhePhePheXaaXaaXaaXaaLeuAlaArgMetValSerIleSerTer)	LDLR	Pathogenic	criteria provided, single submitter
1070723	NC_000019.9:g.(?11213320)(11216296_?)del	LDLR	Pathogenic	criteria provided, single submitter
1070724	NC_000019.9:g.(?11213330)(11222326_?)del	LDLR	Pathogenic	criteria provided, single submitter
1070725	NC_000019.9:g.(?11217231)(11224448_?)del	LDLR	Pathogenic	criteria provided, single submitter
1071946	NM_000527.5(LDLR):c.1411del (p.Arg471fs)	LDLR	Pathogenic	criteria provided, single submitter
1072924	NM_000527.5(LDLR):c.1356C>A (p.Cys452Ter)	LDLR	Pathogenic	criteria provided, single submitter
1073028	NM_000527.5(LDLR):c.1516dup (p.Val506fs)	LDLR	Pathogenic	criteria provided, single submitter
1073362	NM_000527.5(LDLR):c.1824del (p.Phe609fs)	LDLR	Pathogenic	criteria provided, single submitter
1074663	NC_000019.9:g.(?11240179)(11241992_?)del	LDLR	Pathogenic	criteria provided, single submitter
1074682	NM_000527.5(LDLR):c.2462_2463insTGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGTGGATCATGAGGTCAGGAGATCGAGACCATCCTGGCTAACAAGGTGAAACCCCGTCTCTACTAAAAATACAAAAAAAATTAGCCGGGCGCGGTGGCGGGCGCCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATGGCGTGAACCCGGGAAGCGGAGCTTGCAGTGAGCCGAGATTGCGCCACTGCAGTCCGCAGTCCCGCCTGGGCGACAGAGCGAGACTCCATCTCAAAAAAAAAATAATAATAAAAGAACATCAACAGCAT (p.Ile821_Asn822insGlyArgAlaArgTrpLeuThrProValIleProAlaLeuTrpGluAlaGluAlaGlyGlySerTer)	LDLR	Pathogenic	criteria provided, single submitter
1074804	NC_000019.9:g.(?11223944)(11227689_?)del	LDLR	Pathogenic	criteria provided, single submitter
1074805	NC_000019.9:g.(?11223948)(11241997_?)del	LDLR	Pathogenic	criteria provided, single submitter
1075416	NM_000527.5(LDLR):c.678_681dup (p.Glu228Ter)	LDLR	Pathogenic	criteria provided, multiple submitters, no conflicts
1075455	NM_000527.5(LDLR):c.2530_2542del (p.Gly844fs)	LDLR	Pathogenic	criteria provided, single submitter
1076614	NC_000019.9:g.(?11217231)(11218204_?)del	LDLR	Pathogenic	criteria provided, single submitter
1076616	NC_000019.9:g.(?11221289)(11221471_?)del	LDLR	Pathogenic	criteria provided, single submitter
1076861	NM_000527.5(LDLR):c.1531_1532dup (p.Leu511fs)	LDLR	Pathogenic	criteria provided, single submitter
1076971	NM_000527.5(LDLR):c.2449_2453del (p.Asn817fs)	LDLR	Pathogenic	criteria provided, single submitter
1120259	NM_000527.5(LDLR):c.1070_1071dup (p.Cys358fs)	LDLR	Pathogenic	criteria provided, multiple submitters, no conflicts
1180494	NM_000527.5(LDLR):c.227_233del (p.Gly76fs)	LDLR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1192228	NM_000527.5(LDLR):c.777T>G (p.Tyr259Ter)	LDLR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343370	NM_000527.5(LDLR):c.667_681del (p.Lys223_Asp227del)	LDLR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1362872	NC_000019.9:g.(?11230748)(11231218_?)del	LDLR	Pathogenic	criteria provided, single submitter
1371905	NM_000527.5(LDLR):c.1222G>T (p.Glu408Ter)	LDLR	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 11 · 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
RAB35	Limited	Autosomal dominant	familial hypercholesterolemia	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LDLRAP1	Orphanet:391665	Homozygous familial hypercholesterolemia
PCSK9	Orphanet:391665	Homozygous familial hypercholesterolemia
PIBF1	Orphanet:475	Isolated Joubert syndrome
ABCA1	Orphanet:31150	Tangier disease
ABCA1	Orphanet:425	Apolipoprotein A-I deficiency
APOB	Orphanet:391665	Homozygous familial hypercholesterolemia
APOE	Orphanet:329481	Lipoprotein glomerulopathy
APOE	Orphanet:412	Dysbetalipoproteinemia
ITPR2	Orphanet:468666	Isolated generalized anhidrosis with normal sweat glands
LDLR	Orphanet:391665	Homozygous familial hypercholesterolemia
PLCB4	Orphanet:137888	Auriculocondylar syndrome

Cohort genes → proteins

20 cohort genes, 18 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	20

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RAB35	HGNC:9774	ENSG00000111737	Q15286	Ras-related protein Rab-35	gencc
SLC27A2	HGNC:10996	ENSG00000140284	O14975	Long-chain fatty acid transport protein 2	clinvar
MRPL4	HGNC:14276	ENSG00000105364	Q9BYD3	Large ribosomal subunit protein uL4m	clinvar
INPP5F	HGNC:17054	ENSG00000198825	Q9Y2H2	Phosphatidylinositide 4-phosphatase SAC2	clinvar
PLA1A	HGNC:17661	ENSG00000144837	Q53H76	Phospholipase A1 member A	clinvar
HACL1	HGNC:17856	ENSG00000131373	Q9UJ83	2-hydroxyacyl-CoA lyase 1	clinvar
LDLRAP1	HGNC:18640	ENSG00000157978	Q5SW96	Low density lipoprotein receptor adapter protein 1	clinvar
PCSK9	HGNC:20001	ENSG00000169174	Q8NBP7	Proprotein convertase subtilisin/kexin type 9	clinvar
PIBF1	HGNC:23352	ENSG00000083535	Q8WXW3	Progesterone-induced-blocking factor 1	clinvar
CARM1	HGNC:23393	ENSG00000142453	Q86X55	Histone-arginine methyltransferase CARM1	clinvar
CYP3A4	HGNC:2637	ENSG00000160868	P08684	Cytochrome P450 3A4	clinvar
ABCA1	HGNC:29	ENSG00000165029	O95477	Phospholipid-transporting ATPase ABCA1	clinvar
MIR6886	HGNC:50121	ENSG00000284553		microRNA 6886	clinvar
LDLR-AS1	HGNC:54407			LDLR antisense RNA 1	clinvar
APOB	HGNC:603	ENSG00000084674	P04114	Apolipoprotein B-100	clinvar
APOE	HGNC:613	ENSG00000130203	P02649	Apolipoprotein E	clinvar
ITPR2	HGNC:6181	ENSG00000123104	Q14571	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2	clinvar
LDLR	HGNC:6547	ENSG00000130164	P01130	Low-density lipoprotein receptor	clinvar
PIP5K1B	HGNC:8995	ENSG00000107242	O14986	Phosphatidylinositol 4-phosphate 5-kinase type-1 beta	clinvar
PLCB4	HGNC:9059	ENSG00000101333	Q15147	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAB35	Ras-related protein Rab-35	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.
SLC27A2	Long-chain fatty acid transport protein 2	Mediates the import of long-chain fatty acids (LCFA) into the cell by facilitating their transport across cell membranes, playing an important role in hepatic fatty acid uptake.
INPP5F	Phosphatidylinositide 4-phosphatase SAC2	Phosphoinositide phosphatase which catalyzes the hydrolysis of phosphatidylinositol 4-phosphate (1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate), PtdIns(4)P).
PLA1A	Phospholipase A1 member A	Hydrolyzes the ester bond of the acyl group attached at the sn-1 position of phosphatidylserines (phospholipase A1 activity) and 1-acyl-2-lysophosphatidylserines (lysophospholipase activity) in the pathway of phosphatidylserines acyl chain…
HACL1	2-hydroxyacyl-CoA lyase 1	Peroxisomal 2-OH acyl-CoA lyase involved in the cleavage (C1 removal) reaction in the fatty acid alpha-oxydation in a thiamine pyrophosphate (TPP)-dependent manner.
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).
PCSK9	Proprotein convertase subtilisin/kexin type 9	Crucial player in the regulation of plasma cholesterol homeostasis.
PIBF1	Progesterone-induced-blocking factor 1	Plays a role in ciliogenesis.
CARM1	Histone-arginine methyltransferase CARM1	Methylates (mono- and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in several proteins involved in DNA packaging, transcription regulation, pre-mRNA splicing, and mRNA stability.
CYP3A4	Cytochrome P450 3A4	A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids.
ABCA1	Phospholipid-transporting ATPase ABCA1	Catalyzes the translocation of specific phospholipids from the cytoplasmic to the extracellular/lumenal leaflet of membrane coupled to the hydrolysis of ATP.
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).
APOE	Apolipoprotein E	APOE is an apolipoprotein, a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids.
ITPR2	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2	Inositol 1,4,5-trisphosphate-gated calcium channel that upon inositol 1,4,5-trisphosphate binding transports calcium from the endoplasmic reticulum lumen to cytoplasm.
LDLR	Low-density lipoprotein receptor	Binds low density lipoprotein /LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis.
PIP5K1B	Phosphatidylinositol 4-phosphate 5-kinase type-1 beta	Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2/PIP2), a lipid second messenger that regulates several cellular processes such as signal trans…
PLCB4	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4	Activated phosphatidylinositol-specific phospholipase C enzymes catalyze the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) involved in G-protein coupled receptor signaling pathways.

Protein-family classification

Druggable: 10 · Difficult: 0 · Unknown: 10 · Druggable fraction: 0.5

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
Enzyme (other)	5	3.0×	0.151
Ion channel	1	5.6×	0.399
Phosphatase	1	4.2×	0.399
Transporter	1	3.9×	0.399
Protease	1	1.8×	0.596
Kinase	1	1.4×	0.607
Other/Unknown	10	0.9×	0.774

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAB35	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
SLC27A2	Other/Unknown	no		AMP-dep_synth/lig_dom, AMP-binding_CS, AMP-bd_C
MRPL4	Other/Unknown	no		Ribosomal_uL4, Ribosomal_uL4-like, Ribosomal_uL4_dom_sf
INPP5F	Phosphatase	yes		SAC_dom, Inositol_phosphatase, hSac2
PLA1A	Enzyme (other)	yes	3.1.1.111	TAG_lipase, Lipase, Lipase_LIPH
HACL1	Enzyme (other)	yes	4.1.2.63	TPP_enzyme_TPP-bd, Thiamin_PyroP_enz_cen_dom, Thiamin_PyroP_enz_TPP-bd_dom
LDLRAP1	Other/Unknown	no		PTB/PI_dom, PH-like_dom_sf, Adapter_Engulfment-Domain
PCSK9	Protease	yes	3.4.21.61	Peptidase_S8/S53_dom, S8pro/Inhibitor_I9, Peptidase_S8_subtilisin-rel
PIBF1	Other/Unknown	no		PIBF1
CARM1	Enzyme (other)	yes	2.1.1.319	PH-like_dom_sf, Arg_MeTrfase, SAM-dependent_MTases_sf
CYP3A4	Enzyme (other)	yes	1.14.14.55	Cyt_P450, Cyt_P450_E_grp-II, Cyt_P450_E_CYP3A
ABCA1	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
MIR6886	Other/Unknown	no
LDLR-AS1	Other/Unknown	no
APOB	Other/Unknown	no		Vitellogenin_N, Lipid_transpt_open_b-sht, Lipovitellin_superhlx_dom
APOE	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E
ITPR2	Ion channel	yes		InsP3_rcpt, RIH_dom, Ion_trans_dom
LDLR	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF
PIP5K1B	Kinase	yes	2.7.1.68	PInositol-4-P-4/5-kinase_core, PInositol-4/5-P-5/4-kinase, PInositol-4-P-4/5-kinase_C_sf
PLCB4	Enzyme (other)	yes	3.1.4.11	C2_dom, PLipase_C_PInositol-sp_X_dom, PI-PLC_fam

Expression context

Cohort genes with no expression data: 1.

16 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)	19
unknown	1

Top tissues across cohort

Tissue	Cohort genes
liver	4
jejunal mucosa	4
adrenal tissue	4
sural nerve	3
ileal mucosa	3
mucosa of transverse colon	2
lateral nuclear group of thalamus	2
right lobe of liver	2
calcaneal tendon	2
left adrenal gland	2
cortical plate	1
granulocyte	1
stromal cell of endometrium	1
bronchial epithelial cell	1
epithelium of bronchus	1
apex of heart	1
lower esophagus mucosa	1
pons	1
superior vestibular nucleus	1
caput epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAB35	266	ubiquitous	yes	cortical plate, granulocyte, stromal cell of endometrium
SLC27A2	231	broad	marker	bronchial epithelial cell, epithelium of bronchus, liver
MRPL4	271	ubiquitous	marker	apex of heart, mucosa of transverse colon, lower esophagus mucosa
INPP5F	282	ubiquitous	marker	pons, superior vestibular nucleus, lateral nuclear group of thalamus
PLA1A	208	broad	marker	corpus epididymis, seminal vesicle, caput epididymis
HACL1	245	ubiquitous	marker	jejunal mucosa, duodenum, right lobe of liver
LDLRAP1	271	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
PCSK9	147	broad	marker	right lobe of liver, mucosa of transverse colon, male germ line stem cell (sensu Vertebrata) in testis
PIBF1	273	ubiquitous	marker	calcaneal tendon, ventricular zone, sural nerve
CARM1	279	ubiquitous	yes	hindlimb stylopod muscle, gastrocnemius, endometrium epithelium
CYP3A4	194	tissue_specific	marker	jejunal mucosa, ileal mucosa, liver
ABCA1	272	ubiquitous	marker	adrenal tissue, skin of hip, left adrenal gland
MIR6886	29		yes	sural nerve, liver, adrenal tissue
LDLR-AS1
APOB	116	broad	marker	jejunal mucosa, liver, ileal mucosa
APOE	267	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, right adrenal gland cortex
ITPR2	273	ubiquitous	marker	calcaneal tendon, adrenal tissue, germinal epithelium of ovary
LDLR	281	ubiquitous	marker	adrenal tissue, lower lobe of lung, right adrenal gland
PIP5K1B	248	broad	marker	choroid plexus epithelium, jejunal mucosa, ileal mucosa
PLCB4	273	ubiquitous	marker	parotid gland, lateral nuclear group of thalamus, sural nerve

Protein interactions among cohort

Intra-cohort edges: 12.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOE	6,793
APOB	5,244
MRPL4	5,173
CARM1	3,580
ABCA1	3,551
PCSK9	2,994
RAB35	2,763
SLC27A2	2,406
HACL1	2,251
ITPR2	1,815

Intra-cohort edges

A	B	Sources
ABCA1	APOB	string_interaction
ABCA1	APOE	string_interaction
APOB	APOE	string_interaction
APOB	LDLR	intact, string_interaction
APOB	LDLRAP1	string_interaction
APOB	PCSK9	string_interaction
APOE	CARM1	string_interaction
APOE	LDLR	intact
APOE	LDLRAP1	string_interaction
LDLR	LDLRAP1	string_interaction
LDLR	PCSK9	biogrid_interaction, intact, string_interaction
LDLRAP1	PCSK9	string_interaction

Structural data

PDB: 11 · AlphaFold-only: 7 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYP3A4	P08684	122
MRPL4	Q9BYD3	87
PCSK9	Q8NBP7	65
LDLR	P01130	36
CARM1	Q86X55	33
APOE	P02649	29
APOB	P04114	8
ABCA1	O95477	7
RAB35	Q15286	4
INPP5F	Q9Y2H2	1
LDLRAP1	Q5SW96	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HACL1	Q9UJ83	95.09
SLC27A2	O14975	92.43
PLA1A	Q53H76	89.55
PLCB4	Q15147	86.03
PIBF1	Q8WXW3	77.70
PIP5K1B	O14986	70.02
ITPR2	Q14571

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 169. Enrichment computed across 20 evidence-associated genes (17 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 17 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Chylomicron clearance	4	537.4×	3e-09	LDLRAP1, APOB, APOE, LDLR
Plasma lipoprotein assembly, remodeling, and clearance	5	67.2×	7e-07	LDLRAP1, ABCA1, APOB, APOE, LDLR
LDL clearance	4	128.0×	1e-06	LDLRAP1, PCSK9, APOB, LDLR
Plasma lipoprotein clearance	4	112.0×	1e-06	LDLRAP1, APOB, APOE, LDLR
Plasma lipoprotein assembly	3	126.0×	5e-05	ABCA1, APOB, APOE
Metabolism	9	6.2×	9e-05	SLC27A2, INPP5F, LDLRAP1, CARM1, ABCA1, APOB, APOE, ITPR2 (+1 more)
Metabolism of fat-soluble vitamins	3	67.2×	2e-04	APOB, APOE, LDLR
Metabolism of vitamins and cofactors	4	27.4×	2e-04	LDLRAP1, APOB, APOE, LDLR
Alpha-oxidation of phytanate	2	223.9×	6e-04	SLC27A2, HACL1
Visual phototransduction	3	45.8×	6e-04	APOB, APOE, LDLR
Retinoid metabolism and transport	3	43.8×	6e-04	APOB, APOE, LDLR
Chylomicron assembly	2	134.3×	0.001	APOB, APOE
Chylomicron remodeling	2	134.3×	0.001	APOB, APOE
Metabolism of lipids	5	9.3×	0.002	SLC27A2, INPP5F, LDLRAP1, CARM1, ABCA1
Metabolism of steroids	3	24.3×	0.003	SLC27A2, LDLRAP1, CARM1
Scavenging by Class A Receptors	2	70.7×	0.004	APOB, APOE
Transport of small molecules	5	7.4×	0.004	LDLRAP1, ABCA1, APOB, APOE, LDLR
Binding and Uptake of Ligands by Scavenger Receptors	2	64.0×	0.004	APOB, APOE
Plasma lipoprotein remodeling	2	56.0×	0.005	APOB, APOE
Cargo recognition for clathrin-mediated endocytosis	3	18.5×	0.005	LDLRAP1, APOB, LDLR
Signaling by Nuclear Receptors	3	18.0×	0.005	CARM1, ABCA1, APOE
Post-translational protein phosphorylation	3	17.7×	0.005	PCSK9, APOB, APOE
Sensory Perception	3	16.8×	0.005	APOB, APOE, LDLR
NR1H2 and NR1H3-mediated signaling	2	46.3×	0.006	ABCA1, APOE
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	3	15.3×	0.006	PCSK9, APOB, APOE
Clathrin-mediated endocytosis	3	15.0×	0.006	LDLRAP1, APOB, LDLR
Vesicle-mediated transport	4	8.2×	0.007	LDLRAP1, APOB, APOE, LDLR
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	2	36.3×	0.008	ABCA1, APOE
Platelet homeostasis	2	32.8×	0.010	APOB, ITPR2
PLC beta mediated events	2	31.2×	0.010	ITPR2, PLCB4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 18 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	7	76.2×	6e-10	LDLRAP1, PCSK9, CYP3A4, ABCA1, APOB, APOE, LDLR
cholesterol homeostasis	6	52.0×	1e-07	LDLRAP1, PCSK9, ABCA1, APOB, APOE, LDLR
lipoprotein biosynthetic process	3	468.1×	2e-06	ABCA1, APOB, APOE
lipoprotein catabolic process	3	401.2×	2e-06	APOB, APOE, LDLR
low-density lipoprotein particle clearance	3	165.2×	4e-05	LDLRAP1, APOB, LDLR
receptor-mediated endocytosis involved in cholesterol transport	2	936.2×	5e-05	LDLRAP1, LDLR
cholesterol transport	3	122.1×	7e-05	LDLRAP1, APOB, LDLR
artery morphogenesis	3	112.3×	8e-05	APOB, APOE, LDLR
positive regulation of low-density lipoprotein particle receptor catabolic process	2	624.1×	9e-05	PCSK9, APOE
methyl-branched fatty acid metabolic process	2	624.1×	9e-05	SLC27A2, HACL1
cholesterol efflux	3	87.8×	1e-04	ABCA1, APOB, APOE
negative regulation of receptor recycling	2	374.5×	2e-04	PCSK9, LDLR
cellular response to lipoprotein particle stimulus	2	374.5×	2e-04	APOB, APOE
fatty acid alpha-oxidation	2	267.5×	4e-04	SLC27A2, HACL1
high-density lipoprotein particle clearance	2	267.5×	4e-04	APOE, LDLR
regulation of protein metabolic process	2	234.1×	5e-04	APOE, LDLR
negative regulation of protein metabolic process	2	234.1×	5e-04	APOE, LDLR
positive regulation of cholesterol metabolic process	2	234.1×	5e-04	LDLRAP1, APOE
high-density lipoprotein particle assembly	2	187.2×	7e-04	ABCA1, APOE
negative regulation of low-density lipoprotein particle clearance	2	170.2×	8e-04	PCSK9, LDLR
response to caloric restriction	2	170.2×	8e-04	APOE, LDLR
regulation of Cdc42 protein signal transduction	2	156.0×	8e-04	ABCA1, APOE
receptor-mediated endocytosis	3	37.0×	8e-04	LDLRAP1, APOE, LDLR
amyloid precursor protein metabolic process	2	144.0×	9e-04	LDLRAP1, APOE
negative regulation of amyloid fibril formation	2	144.0×	9e-04	APOE, LDLR
phospholipid efflux	2	124.8×	0.001	ABCA1, APOE
regulation of cholesterol metabolic process	2	124.8×	0.001	APOE, LDLR
low-density lipoprotein particle remodeling	2	117.0×	0.001	APOB, APOE
reverse cholesterol transport	2	104.0×	0.002	ABCA1, APOE
cellular response to low-density lipoprotein particle stimulus	2	98.5×	0.002	ABCA1, LDLR

Therapeutics

Drugs indicated for this disease

7 approved, 15 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Alirocumab	Approved (phase 4)
Bempedoic Acid	Approved (phase 4)
Evinacumab	Approved (phase 4)
Evolocumab	Approved (phase 4)
Ezetimibe	Approved (phase 4)
Inclisiran Sodium	Approved (phase 4)
Simvastatin	Approved (phase 4)
Anacetrapib	Phase 3 (in late-stage trials)
Atorvastatin	Phase 3 (in late-stage trials)
Bococizumab	Phase 3 (in late-stage trials)
Cholestyramine	Phase 3 (in late-stage trials)
Eprotirome	Phase 3 (in late-stage trials)
Inclisiran	Phase 3 (in late-stage trials)
Laropiprant	Phase 3 (in late-stage trials)
Lerodalcibep	Phase 3 (in late-stage trials)
Lomitapide	Phase 3 (in late-stage trials)
Niacin	Phase 3 (in late-stage trials)
OMEGA-3-ACID ETHYL ESTERS	Phase 3 (in late-stage trials)
Ongericimab	Phase 3 (in late-stage trials)
Rosuvastatin	Phase 3 (in late-stage trials)
Tafolecimab	Phase 3 (in late-stage trials)
Torcetrapib	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Resmetirom.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 4 · Phased (≥1): 4 · Undrugged: 16

Druggability breadth: 10 of 20 evidence-associated genes (50%) 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
CYP3A4	KETOCONAZOLE
LDLR	NILOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP3A4	695	4
CARM1	4	3
PCSK9	1	4
LDLR	1	4
RAB35	0	0
SLC27A2	0	0
MRPL4	0	0
INPP5F	0	0
PLA1A	0	0
HACL1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NILOTINIB	4	CYP3A4, LDLR, PCSK9
KETOCONAZOLE	4	CYP3A4
TELITHROMYCIN	4	CYP3A4
CYCLOSPORINE	4	CYP3A4
RITONAVIR	4	CYP3A4
TACROLIMUS ANHYDROUS	4	CYP3A4
CARFILZOMIB	4	CYP3A4
VORICONAZOLE	4	CYP3A4
BEPRIDIL	4	CYP3A4
PHENYLBUTAZONE	4	CYP3A4
CANDESARTAN CILEXETIL	4	CYP3A4
TELMISARTAN	4	CYP3A4
DIENESTROL	4	CYP3A4
PROGESTERONE	4	CYP3A4
DICLOFENAC SODIUM	4	CYP3A4
CLOTRIMAZOLE	4	CYP3A4
CHOLECALCIFEROL	4	CYP3A4
DAPSONE	4	CYP3A4
FLUCONAZOLE	4	CYP3A4
OXCARBAZEPINE	4	CYP3A4
COLCHICINE	4	CYP3A4
NABUMETONE	4	CYP3A4
OXAPROZIN	4	CYP3A4
GLIPIZIDE	4	CYP3A4
MORICIZINE	4	CYP3A4
SALMETEROL XINAFOATE	4	CYP3A4
AMIODARONE HYDROCHLORIDE	4	CYP3A4
PHENELZINE	4	CYP3A4
BRETYLIUM TOSYLATE	4	CYP3A4
BENZNIDAZOLE	4	CYP3A4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CYP3A4	5,927	ADMET:5828, Binding:97, Functional:1, Toxicity:1
CARM1	371	Binding:363, Functional:8
PCSK9	202	Binding:201, ADMET:1
LDLR	55	Binding:54, Functional:1
ITPR2	8	Binding:7, Functional:1
PIP5K1B	4	Binding:4
SLC27A2	2	Binding:2
ABCA1	2	Binding:2
RAB35	1	Binding:1
APOB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLA1A	3.1.1.111, 3.1.1.32	phosphatidylserine sn-1 acylhydrolase, phospholipase A1
HACL1	4.1.2.63	2-hydroxyacyl-CoA lyase
PCSK9	3.4.21.61	Kexin
CARM1	2.1.1.319	type I protein arginine methyltransferase
CYP3A4	1.14.14.55, 1.14.14.73, 1.14.99.38	quinine 3-monooxygenase, albendazole monooxygenase (sulfoxide-forming), cholesterol 25-monooxygenase
PIP5K1B	2.7.1.68	1-phosphatidylinositol-4-phosphate 5-kinase
PLCB4	3.1.4.11	phosphoinositide phospholipase C

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PCSK9	202
CARM1	371
CYP3A4	5,927

Pharmacogenomics

Cohort genes with a PharmGKB record: 18; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
CYP3A4	1

Chemical tractability of cohort targets

30 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	CYP3A4, LDLR, PCSK9
KETOCONAZOLE	4	CYP3A4
TELITHROMYCIN	4	CYP3A4
CYCLOSPORINE	4	CYP3A4
RITONAVIR	4	CYP3A4
TACROLIMUS ANHYDROUS	4	CYP3A4
CARFILZOMIB	4	CYP3A4
VORICONAZOLE	4	CYP3A4
BEPRIDIL	4	CYP3A4
PHENYLBUTAZONE	4	CYP3A4
CANDESARTAN CILEXETIL	4	CYP3A4
TELMISARTAN	4	CYP3A4
DIENESTROL	4	CYP3A4
PROGESTERONE	4	CYP3A4
DICLOFENAC SODIUM	4	CYP3A4
CLOTRIMAZOLE	4	CYP3A4
CHOLECALCIFEROL	4	CYP3A4
DAPSONE	4	CYP3A4
FLUCONAZOLE	4	CYP3A4
OXCARBAZEPINE	4	CYP3A4
COLCHICINE	4	CYP3A4
NABUMETONE	4	CYP3A4
OXAPROZIN	4	CYP3A4
GLIPIZIDE	4	CYP3A4
MORICIZINE	4	CYP3A4
SALMETEROL XINAFOATE	4	CYP3A4
AMIODARONE HYDROCHLORIDE	4	CYP3A4
PHENELZINE	4	CYP3A4
BRETYLIUM TOSYLATE	4	CYP3A4
BENZNIDAZOLE	4	CYP3A4

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	PCSK9, CYP3A4, LDLR
B	Phased (≥1) drug, not yet approved	1	CARM1
C	Druggable family + PDB, no drug	2	INPP5F, ABCA1
D	Druggable family + AlphaFold only, no drug	5	PLA1A, HACL1, ITPR2, PIP5K1B, PLCB4
E	Difficult family or no structure, no drug	9	RAB35, SLC27A2, MRPL4, LDLRAP1, PIBF1, MIR6886, LDLR-AS1, APOB, APOE

Undrugged target profiles

16 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
LDLRAP1	0	PCSK9
RAB35	1	—
SLC27A2	2	—
MRPL4	0	—
INPP5F	0	—
PLA1A	0	—
HACL1	0	—
PIBF1	0	—
ABCA1	2	—
MIR6886	0	—
LDLR-AS1	0	—
APOB	1	—
APOE	0	—
ITPR2	8	—
PIP5K1B	4	—
PLCB4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 110.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	67
PHASE3	19
PHASE2	9
PHASE1	5
PHASE4	4
EARLY_PHASE1	4
PHASE1/PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00655265	PHASE4	COMPLETED	A Study of the Safety and Efficacy of Patients With Familial Hypercholesterolaemia Taking Colesevelam as add-on Therapy to Their Existing Medication
NCT00916643	PHASE4	COMPLETED	Low-Density Lipoprotein (LDL) Apheresis Using H.E.L.P. Therapy
NCT03331666	PHASE4	TERMINATED	Impact of LDL-cholesterol Lowering on Platelet Activation
NCT05465278	PHASE4	COMPLETED	Alirocumab and Plaque Burden In Familial Hypercholesterolaemia
NCT04798430	PHASE3	ENROLLING_BY_INVITATION	Long-term Efficacy and Safety of OLE LIB003 in HoFH, HeFH, and High-risk CVD Patients Requiring Further LDL-C Reduction
NCT05238519	PHASE3	ACTIVE_NOT_RECRUITING	Improved Diagnosis of Familial Hypercholesterolemia Across the Northland (ID-FH)
NCT00355615	PHASE3	COMPLETED	PLUTO: Pediatric Lipid-redUction Trial of rOsuvastatin
NCT00552097	PHASE3	COMPLETED	Effect of Ezetimibe Plus Simvastatin Versus Simvastatin Alone on Atherosclerosis in the Carotid Artery (ENHANCE)(P02578)
NCT00607373	PHASE3	COMPLETED	Study to Assess the Safety and Efficacy of ISIS 301012 (Mipomersen) in Homozygous Familial Hypercholesterolemia
NCT00694109	PHASE3	COMPLETED	An Open-label Extension Study to Assess the Long-term Safety and Efficacy of ISIS 301012 (Mipomersen) in Patients With Familial Hypercholesterolemia or Severe-Hypercholesterolemia
NCT00827606	PHASE3	COMPLETED	Atorvastatin Three Year Pediatric Study
NCT00943306	PHASE3	COMPLETED	Long Term, Follow-on Study of Lomitapide in Patients With Homozygous Familial Hypercholesterolemia
NCT01524289	PHASE3	COMPLETED	Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020)
NCT01813006	PHASE3	COMPLETED	Effect of Omega-3 Fatty Acid on Endothelial Function
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)
NCT02624869	PHASE3	COMPLETED	Safety, Tolerability and Efficacy of Evolocumab (AMG 145) in Children With Inherited Elevated Low-density Lipoprotein Cholesterol (Familial Hypercholesterolemia)
NCT02748057	PHASE3	COMPLETED	A Clinical Trial to Assess the Long Term Safety and Tolerability of MK-0653H in Japanese Participants With Hypercholesterolemia (MK-0653H-833)
NCT03884452	PHASE3	COMPLETED	Ezetimibe (SCH 58235) Taken With Either Atorvastatin or Simvastatin in Participants With Familial Hypercholesterolemia (MK-0653-018)
NCT05142722	PHASE3	COMPLETED	Randomized Study to Evaluate the Effect of Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies
NCT05425745	PHASE3	COMPLETED	Evaluate the Effect of Obicetrapib in Patients With HeFH on Top of Maximum Tolerated Lipid-Modifying Therapies.
NCT05952856	PHASE3	COMPLETED	A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-013) CORALreef Lipids
NCT05952869	PHASE3	COMPLETED	A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Heterozygous Familial Hypercholesterolemia (MK-0616-017/CORALreef HeFH)
NCT06005597	PHASE3	COMPLETED	Study of Obicetrapib & Ezetimibe Fixed Dose Combination on Top of Maximum Tolerated Lipid-Modifying Therapies
NCT04941599	PHASE2	RECRUITING	2-Hydroxybenzylamine (2-HOBA) to Reduce HDL Modification and Improve HDL Function in Familial Hypercholesterolemia (FH)
NCT00079846	PHASE2	TERMINATED	Implitapide in Patients With Homozygous Familial Hypercholesterolemia (HoFH) on Maximal Concurrent Lipid-Lowering Therapy
NCT00079859	PHASE2	TERMINATED	Implitapide in Patients With Heterozygous Familial Hypercholesterolemia (HeFH) on Maximal Concurrent Lipid-Lowering Therapy
NCT00477594	PHASE2	COMPLETED	Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia
NCT00751608	PHASE2	WITHDRAWN	Effect of APL180 on Endothelial Function in Familial Hypercholesterolemia Patients
NCT02048410	PHASE1/PHASE2	COMPLETED	Efficacy of a New Symbiotic Formulation in Children With Familial Hypercholesterolemia
NCT02100839	PHASE1/PHASE2	COMPLETED	Safety Study of AEM-28 to Treat Refractory Hypercholesterolemia
NCT02597127	PHASE2	COMPLETED	Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol (LDL-C)
NCT03060577	PHASE2	COMPLETED	An Extension Trial of Inclisiran in Participants With Cardiovascular Disease and High Cholesterol
NCT04455581	PHASE2	UNKNOWN	A Study to Determine the Safety, Tolerability, and Efficacy of SHR-1209 in Patients With Familial Hypercholesterolemia
NCT05261126	PHASE2	COMPLETED	A Study of the Efficacy and Safety of Enclitide Chloride (MK-0616 Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-008)
NCT05043181	PHASE1	NOT_YET_RECRUITING	Exosome-based Nanoplatform for Ldlr mRNA Delivery in FH
NCT00004809	PHASE1	COMPLETED	Phase I Study of Ex Vivo Liver-Directed Gene Therapy for Familial Hypercholesterolemia
NCT02709850	PHASE1	COMPLETED	Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS ANGPTL3-LRx in Healthy Volunteers With Elevated Triglycerides and Participants With Familial Hypercholesterolemia
NCT03747224	PHASE1	COMPLETED	Study of ARO-ANG3 in Healthy Volunteers and in Dyslipidemic Patients
NCT05851066	PHASE1	COMPLETED	A VSA003 Phase 1 Study in Chinese Adult Healthy Volunteers
NCT06293729	EARLY_PHASE1	NOT_YET_RECRUITING	Safety and Efficacy Study of NGGT006 in Refractory Hypercholesterolemia Patients

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MIPOMERSEN	4	4
EVOLOCUMAB	4	3
LOMITAPIDE	4	3
ALIROCUMAB	4	1
COLESEVELAM	4	1
OBICETRAPIB	3	3
ANACETRAPIB	3	2
ENLICITIDE DECANOATE	3	2
INCLISIRAN	3	2
LERODALCIBEP	3	1
OMEGA-3 FATTY ACIDS	3	1
RECATICIMAB	3	1
IMPLITAPIDE	2	2
2-(AMINOMETHYL)PHENOL	2	1
AEM-28	1	1
CHEMBL3787505	0	2
CHEMBL4752650	0	2
CHEMBL1201677	0	1
HYDROCHLORIC ACID	-1	1

Cohort genes: RAB35, SLC27A2, MRPL4, INPP5F, PLA1A, HACL1, LDLRAP1, PCSK9, PIBF1, CARM1, CYP3A4, ABCA1, MIR6886, LDLR-AS1, APOB, APOE, ITPR2, LDLR, PIP5K1B, PLCB4
Drugs: Mipomersen, Evolocumab, Lomitapide, Alirocumab, Colesevelam, Obicetrapib, Anacetrapib, Enlicitide Decanoate, Inclisiran, Lerodalcibep, OMEGA-3 FATTY ACIDS, Recaticimab