Hypercholesterolemia, familial, 1

Summary

Hypercholesterolemia, familial, 1 (MONDO:0007750) is a disease caused by LDLR (GenCC Definitive), with 46 cohort genes and 28 clinical trials. The dominant Reactome pathway is Plasma lipoprotein assembly, remodeling, and clearance (6 cohort genes). Top therapeutic interventions include evolocumab, cholestyramine, and edotreotide gallium ga-68.

At a glance

• Causal gene: LDLR (GenCC Definitive)
• Cohort genes: 46
• ClinVar variants: 3,590
• Clinical trials: 28

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypercholesterolemia, familial, 1
Mondo ID	MONDO:0007750
OMIM	143890
SNOMED CT	398036000
UMLS	C0745103
MedGen	152875
GARD	0024574
Is cancer (heuristic)	no

Also known as: FHC · FHCL1 · hypercholesterolemia, familial · hypercholesterolemia, familial, 1 · hypercholesterolemia, familial, due to ldlr defect, modifier of · hypercholesterolemia, familial, modifier of · hypercholesterolemic xanthomatosis, familial · hyperlipoproteinemia, type 2 · hyperlipoproteinemia, type 2A · LDL cholesterol level QTL2 · LDL receptor disorder

Data availability: 3,590 ClinVar variants · 561 ClinGen variant curations · 5 GenCC gene-disease records.

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 › hypercholesterolemia, familial, 1

Related subtypes (4): 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:

160 pathogenic, 111 uncertain significance, 95 conflicting classifications of pathogenicity, 72 pathogenic/likely pathogenic, 66 likely pathogenic, 57 likely benign, 20 benign/likely benign, 18 benign, 1 risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
250921	NG_009060.1(LDLR):g.[27134_32618del5485;4982_15965del10984]		Pathogenic	criteria provided, single submitter
250922	NG_009060.1(LDLR):g.[18284_22307del4024;27134_45290dup18157]		Pathogenic	criteria provided, single submitter
250923	NM_000527.4(LDLR):c.[649_654dupGATGGT;657_661delCCCCG]		Pathogenic	criteria provided, single submitter
17890	NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln)	APOB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10403	NM_000402.4(G6PD):c.185A>G (p.His62Arg)	G6PD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1120145	Single allele	LDLR	Pathogenic	criteria provided, single submitter
1120147	Single allele	LDLR	Pathogenic	criteria provided, single submitter
1120148	Single allele	LDLR	Pathogenic	criteria provided, single submitter
1120149	Single allele	LDLR	Pathogenic	criteria provided, single submitter
1120150	Single allele	LDLR	Pathogenic	criteria provided, single submitter
1120249	NM_000527.5(LDLR):c.1943_1944delinsG (p.Ser648fs)	LDLR	Pathogenic	criteria provided, single submitter
1120250	NM_000527.4(LDLR):c.(1845+1_1846-1)_(2140+1_2141-1)del	LDLR	Pathogenic	criteria provided, single submitter
1120251	NM_000527.4(LDLR):c.(1586+1_1587-1)_(1845+1_1846-1)del	LDLR	Pathogenic	criteria provided, single submitter
1120252	NM_000527.4:c.(1845+1_1846-1)_(2311+1_2312-1)del	LDLR	Pathogenic	criteria provided, single submitter
1120253	NM_000527.4:c.(2140+1_2141-1)_(2389+1_2390-1)del	LDLR	Pathogenic	criteria provided, single submitter
1120254	NM_000527.4:c.(67+1_68-1)_(1845+1_1846-1)del	LDLR	Pathogenic	criteria provided, single submitter
1120255	NM_000527.4:c.(1705+1_1706-1)_(1845+1_1846-1)del	LDLR	Pathogenic	criteria provided, single submitter
1120256	NM_000527.5(LDLR):c.2547+2T>G	LDLR	Pathogenic	criteria provided, single submitter
1120258	NM_000527.5(LDLR):c.1061-1G>T	LDLR	Pathogenic	criteria provided, multiple submitters, no conflicts
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
1220548	NM_000527.5(LDLR):c.181G>T (p.Glu61Ter)	LDLR	Pathogenic	no assertion criteria provided
1321217	NM_000527.5(LDLR):c.103del (p.Gln35fs)	LDLR	Pathogenic	no assertion criteria provided
1321218	NM_000527.5(LDLR):c.1550C>T (p.Ser517Phe)	LDLR	Pathogenic	no assertion criteria provided
1321221	NM_000527.5(LDLR):c.2487G>C (p.Gln829His)	LDLR	Pathogenic	no assertion criteria provided
1321223	NM_000527.5(LDLR):c.607del (p.His203fs)	LDLR	Pathogenic	no assertion criteria provided
1321224	NM_000527.5(LDLR):c.618T>A (p.Ser206Arg)	LDLR	Pathogenic	no assertion criteria provided
1321225	NM_000527.5(LDLR):c.619G>T (p.Gly207Cys)	LDLR	Pathogenic	no assertion criteria provided
1321227	NM_000527.5(LDLR):c.764G>T (p.Cys255Phe)	LDLR	Pathogenic	no assertion criteria provided
1321228	NM_000527.5(LDLR):c.1178A>C (p.Lys393Thr)	LDLR	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 29 · 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
LDLR	Definitive	Autosomal dominant	hypercholesterolemia, familial, 1	4
APOA2	Limited	Autosomal recessive	hypercholesterolemia, familial, 1	2
EPHX2	No Known Disease Relationship	Autosomal dominant	hypercholesterolemia, familial, 1

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APOA2	Orphanet:238269	AApoAII amyloidosis
LDLR	Orphanet:391665	Homozygous familial hypercholesterolemia
SPTLC2	Orphanet:36386	Hereditary sensory and autonomic neuropathy type 1
MBTPS2	Orphanet:216796	Osteogenesis imperfecta type 1
MBTPS2	Orphanet:216812	Osteogenesis imperfecta type 3
MBTPS2	Orphanet:216820	Osteogenesis imperfecta type 4
MBTPS2	Orphanet:2273	Ichthyosis follicularis-alopecia-photophobia syndrome
MBTPS2	Orphanet:2340	Keratosis follicularis spinulosa decalvans
MBTPS2	Orphanet:659	Mutilating palmoplantar keratoderma with periorificial keratotic plaques
MBTPS2	Orphanet:85284	BRESEK syndrome
LDLRAP1	Orphanet:391665	Homozygous familial hypercholesterolemia
DOCK6	Orphanet:974	Adams-Oliver syndrome
PCSK9	Orphanet:391665	Homozygous familial hypercholesterolemia
MIB1	Orphanet:54260	Left ventricular noncompaction
AGK	Orphanet:1369	Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome
AGK	Orphanet:98994	Total early-onset cataract
ESCO2	Orphanet:2319	Juberg-Hayward syndrome
ESCO2	Orphanet:3103	Roberts syndrome
ABCA1	Orphanet:31150	Tangier disease
ABCA1	Orphanet:425	Apolipoprotein A-I deficiency
ABCA5	Orphanet:2026	Gingival fibromatosis-hypertrichosis syndrome
G6PD	Orphanet:466026	Class I glucose-6-phosphate dehydrogenase deficiency
GHR	Orphanet:314802	Short stature due to partial GHR deficiency
GHR	Orphanet:633	Laron syndrome
APOB	Orphanet:391665	Homozygous familial hypercholesterolemia
OCRL	Orphanet:534	Oculocerebrorenal syndrome of Lowe
OCRL	Orphanet:93623	Dent disease type 2
PDE1C	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
RBP3	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

46 cohort genes, 44 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	46

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EPHX2	HGNC:3402	ENSG00000120915	P34913	Bifunctional epoxide hydrolase 2	gencc,clinvar
APOA2	HGNC:601	ENSG00000158874	P02652	Apolipoprotein A-II	gencc,clinvar
LDLR	HGNC:6547	ENSG00000130164	P01130	Low-density lipoprotein receptor	gencc,clinvar
BPNT1	HGNC:1096	ENSG00000162813	O95861	3’(2’),5’-bisphosphate nucleotidase 1	clinvar
SPTLC2	HGNC:11278	ENSG00000100596	O15270	Serine palmitoyltransferase 2	clinvar
SQLE	HGNC:11279	ENSG00000104549	Q14534	Squalene monooxygenase	clinvar
ATP8A1	HGNC:13531	ENSG00000124406	Q9Y2Q0	Phospholipid-transporting ATPase IA	clinvar
PLEKHA3	HGNC:14338	ENSG00000116095	Q9HB20	Pleckstrin homology domain-containing family A member 3	clinvar
MBTPS2	HGNC:15455	ENSG00000012174	O43462	Membrane-bound transcription factor site-2 protease	clinvar
UGGT1	HGNC:15663	ENSG00000136731	Q9NYU2	UDP-glucose:glycoprotein glucosyltransferase 1	clinvar
CCKBR	HGNC:1571	ENSG00000110148	P32239	Gastrin/cholecystokinin type B receptor	clinvar
LACTB	HGNC:16468	ENSG00000103642	P83111	Serine beta-lactamase-like protein LACTB, mitochondrial	clinvar
RCHY1	HGNC:17479	ENSG00000163743	Q96PM5	RING finger and CHY zinc finger domain-containing protein 1	clinvar
LDLRAP1	HGNC:18640	ENSG00000157978	Q5SW96	Low density lipoprotein receptor adapter protein 1	clinvar
DOCK6	HGNC:19189	ENSG00000130158	Q96HP0	Dedicator of cytokinesis protein 6	clinvar
ST6GALNAC5	HGNC:19342	ENSG00000117069	Q9BVH7	Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 5	clinvar
PCSK9	HGNC:20001	ENSG00000169174	Q8NBP7	Proprotein convertase subtilisin/kexin type 9	clinvar
AGPAT5	HGNC:20886	ENSG00000155189	Q9NUQ2	1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon	clinvar
MIB1	HGNC:21086	ENSG00000101752	Q86YT6	E3 ubiquitin-protein ligase MIB1	clinvar
NAPEPLD	HGNC:21683	ENSG00000161048	Q6IQ20	N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D	clinvar
AGK	HGNC:21869	ENSG00000006530	Q53H12	Acylglycerol kinase, mitochondrial	clinvar
PHYHD1	HGNC:23396	ENSG00000175287	Q5SRE7	Phytanoyl-CoA dioxygenase domain-containing protein 1	clinvar
STAP1	HGNC:24133	ENSG00000035720	Q9ULZ2	Signal-transducing adaptor protein 1	clinvar
OXSM	HGNC:26063	ENSG00000151093	Q9NWU1	3-oxoacyl-[acyl-carrier-protein] synthase, mitochondrial	clinvar
SAMD8	HGNC:26320	ENSG00000156671	Q96LT4	Sphingomyelin synthase-related protein 1	clinvar
SPTY2D1	HGNC:26818	ENSG00000179119	Q68D10	Protein SPT2 homolog	clinvar
ESCO2	HGNC:27230	ENSG00000171320	Q56NI9	N-acetyltransferase ESCO2	clinvar
DGKG	HGNC:2853	ENSG00000058866	P49619	Diacylglycerol kinase gamma	clinvar
DGKH	HGNC:2854	ENSG00000102780	Q86XP1	Diacylglycerol kinase eta	clinvar
ABCA1	HGNC:29	ENSG00000165029	O95477	Phospholipid-transporting ATPase ABCA1	clinvar
PLEKHA5	HGNC:30036	ENSG00000052126	Q9HAU0	Pleckstrin homology domain-containing family A member 5	clinvar
AGMO	HGNC:33784	ENSG00000187546	Q6ZNB7	Alkylglycerol monooxygenase	clinvar
ABCA5	HGNC:35	ENSG00000154265	Q8WWZ7	Cholesterol transporter ABCA5	clinvar
FNTA	HGNC:3782	ENSG00000168522	P49354	Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha	clinvar
ABCA8	HGNC:38	ENSG00000141338	O94911	ABC-type organic anion transporter ABCA8	clinvar
G6PD	HGNC:4057	ENSG00000160211	P11413	Glucose-6-phosphate 1-dehydrogenase	clinvar
GHR	HGNC:4263	ENSG00000112964	P10912	Growth hormone receptor	clinvar
FFAR1	HGNC:4498	ENSG00000126266	O14842	Free fatty acid receptor 1	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
INPP4B	HGNC:6075	ENSG00000109452	O15327	Inositol polyphosphate 4-phosphatase type II	clinvar
OCRL	HGNC:8108	ENSG00000122126	Q01968	Inositol polyphosphate 5-phosphatase OCRL	clinvar
PDE1C	HGNC:8776	ENSG00000154678	Q14123	Dual specificity calcium/calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1C	clinvar
B3GALT1	HGNC:916	ENSG00000172318	Q9Y5Z6	Beta-1,3-galactosyltransferase 1	clinvar
RBP3	HGNC:9921	ENSG00000265203	P10745	Retinol-binding protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EPHX2	Bifunctional epoxide hydrolase 2	Bifunctional enzyme.
APOA2	Apolipoprotein A-II	May stabilize HDL (high density lipoprotein) structure by its association with lipids, and affect the HDL metabolism.
LDLR	Low-density lipoprotein receptor	Binds low density lipoprotein /LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis.
BPNT1	3’(2’),5’-bisphosphate nucleotidase 1	Phosphatase that converts 3’(2’)-phosphoadenosine 5’-phosphate (PAP) to AMP and inositol 1,4-bisphosphate (Ins(1,4)P2) to inositol 4-phosphate.
SPTLC2	Serine palmitoyltransferase 2	Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-…
SQLE	Squalene monooxygenase	Catalyzes the stereospecific oxidation of squalene to (S)-2,3-epoxysqualene, and is considered to be a rate-limiting enzyme in steroid biosynthesis.
ATP8A1	Phospholipid-transporting ATPase IA	Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric dis…
PLEKHA3	Pleckstrin homology domain-containing family A member 3	Plays a role in regulation of vesicular cargo transport from the trans-Golgi network (TGN) to the plasma membrane.
MBTPS2	Membrane-bound transcription factor site-2 protease	Zinc metalloprotease that mediates intramembrane proteolysis of proteins such as ATF6, ATF6B, SREBF1/SREBP1 and SREBF2/SREBP2.
UGGT1	UDP-glucose:glycoprotein glucosyltransferase 1	Recognizes glycoproteins with minor folding defects.
CCKBR	Gastrin/cholecystokinin type B receptor	Receptor for the peptide hormones gastrin and cholecystokinin (CCK).
LACTB	Serine beta-lactamase-like protein LACTB, mitochondrial	Mitochondrial serine protease that acts as a regulator of mitochondrial lipid metabolism.
RCHY1	RING finger and CHY zinc finger domain-containing protein 1	E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins, including p53/TP53, TP73, HDAC1 and CDKN1B.
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).
DOCK6	Dedicator of cytokinesis protein 6	Acts as a guanine nucleotide exchange factor (GEF) for CDC42 and RAC1 small GTPases.
ST6GALNAC5	Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 5	Predominantly catalyzes the biosynthesis of ganglioside GD1alpha from GM1b in the brain, by transferring the sialyl group (N-acetyl-alpha-neuraminyl or NeuAc) from CMP-NeuAc to the GalNAc residue on the NeuAc-alpha-2,3-Gal-beta-1,3-GalNAc…
PCSK9	Proprotein convertase subtilisin/kexin type 9	Crucial player in the regulation of plasma cholesterol homeostasis.
AGPAT5	1-acyl-sn-glycerol-3-phosphate acyltransferase epsilon	Converts 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone.
MIB1	E3 ubiquitin-protein ligase MIB1	E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins.
NAPEPLD	N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D	D-type phospholipase that hydrolyzes N-acyl-phosphatidylethanolamines (NAPEs) to produce bioactive N-acylethanolamines/fatty acid ethanolamides (NAEs/FAEs) and phosphatidic acid.
AGK	Acylglycerol kinase, mitochondrial	Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively.
PHYHD1	Phytanoyl-CoA dioxygenase domain-containing protein 1	2-oxoglutarate(2OG)-dependent dioxygenase that catalyzes the conversion of 2-oxoglutarate to succinate and CO(2) in an iron-dependent manner.
STAP1	Signal-transducing adaptor protein 1	In BCR signaling, appears to function as a docking protein acting downstream of TEC and participates in a positive feedback loop by increasing the activity of TEC.
OXSM	3-oxoacyl-[acyl-carrier-protein] synthase, mitochondrial	May play a role in the biosynthesis of lipoic acid as well as longer chain fatty acids required for optimal mitochondrial function.
SAMD8	Sphingomyelin synthase-related protein 1	Has phospholipase C (PLC) activity.
SPTY2D1	Protein SPT2 homolog	Histone chaperone that stabilizes pre-existing histone tetramers and regulates replication-independent histone exchange on chromatin.
ESCO2	N-acetyltransferase ESCO2	Acetyltransferase required for the establishment of sister chromatid cohesion.
DGKG	Diacylglycerol kinase gamma	Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids.
DGKH	Diacylglycerol kinase eta	Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids.
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.
AGMO	Alkylglycerol monooxygenase	Glyceryl-ether monooxygenase that cleaves the O-alkyl bond of ether lipids.
ABCA5	Cholesterol transporter ABCA5	Cholesterol efflux transporter in macrophages that is responsible for APOAI/high-density lipoproteins (HDL) formation at the plasma membrane under high cholesterol levels and participates in reverse cholesterol transport.
FNTA	Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha	Essential subunit of both the farnesyltransferase and the geranylgeranyltransferase complex.
ABCA8	ABC-type organic anion transporter ABCA8	Catalyzes ATP-dependent import of organic anions such as taurocholate and estrone sulfate.
G6PD	Glucose-6-phosphate 1-dehydrogenase	Catalyzes the rate-limiting step of the oxidative pentose-phosphate pathway, which represents a route for the dissimilation of carbohydrates besides glycolysis.
GHR	Growth hormone receptor	Receptor for pituitary gland growth hormone (GH1) involved in regulating postnatal body growth.
FFAR1	Free fatty acid receptor 1	G-protein coupled receptor for medium and long chain saturated and unsaturated fatty acids that plays an important role in glucose 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).
INPP4B	Inositol polyphosphate 4-phosphatase type II	Catalyzes the hydrolysis of the 4-position phosphate of phosphatidylinositol 3,4-bisphosphate, inositol 1,3,4-trisphosphate and inositol 3,4-trisphosphate.
OCRL	Inositol polyphosphate 5-phosphatase OCRL	Catalyzes the hydrolysis of the 5-position phosphate of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol-3,4,5-bisphosphate (PtdIns(3,4,5)P3), with the greatest catalytic activity towards PtdIns(4,5)P2.
PDE1C	Dual specificity calcium/calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1C	Calmodulin-dependent cyclic nucleotide phosphodiesterase with a dual specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.
B3GALT1	Beta-1,3-galactosyltransferase 1	Beta-1,3-galactosyltransferase that transfers galactose from UDP-alpha-D-galactose to substrates with a terminal beta-N-acetylglucosamine (beta-GlcNAc) residue.
RBP3	Retinol-binding protein 3	IRBP shuttles 11-cis and all trans retinoids between the retinol isomerase in the pigment epithelium and the visual pigments in the photoreceptor cells of the retina.

Protein-family classification

Druggable: 27 · Difficult: 8 · Unknown: 11 · Druggable fraction: 0.59

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)	12	3.1×	0.003
Transporter	3	5.1×	0.106
Protease	4	3.2×	0.121
Kinase	3	1.8×	0.576
Phosphatase	1	1.8×	0.717
Antibody/Immunoglobulin	2	1.3×	0.717
Scaffold/PPI	3	1.1×	0.717
GPCR	2	1.0×	0.723
Transcription factor	5	0.9×	0.744
Other/Unknown	11	0.4×	1.000

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EPHX2	Enzyme (other)	yes	3.1.3.106	AB_hydrolase_1, Epox_hydrolase-like, HAD-SF_hydro_IA
APOA2	Other/Unknown	no		ApoA-II, ApoA-II_sf
LDLR	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF
BPNT1	Phosphatase	yes	3.1.3.7	Inositol_monophosphatase-like, Inositol_monophosphatase_CS, Inositol_monoP_metal-BS
SPTLC2	Enzyme (other)	yes	2.3.1.50	Aminotrans_II_pyridoxalP_BS, Aminotransferase_I/II_large, PyrdxlP-dep_Trfase_major
SQLE	Enzyme (other)	yes	1.14.14.17	Squalene_epoxidase, FAD/NAD-bd_sf, Squalene_monox
ATP8A1	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf
PLEKHA3	Scaffold/PPI	no		PH_domain, PH-like_dom_sf, Boi1/Boi2-like
MBTPS2	Protease	yes	3.4.24.85	MBTPS2, Peptidase_M50, PDZ_sf
UGGT1	Other/Unknown	no		UDP-g_GGtrans, Nucleotide-diphossugar_trans, Glyco_transf_24
CCKBR	GPCR	yes		GPCR_Rhodpsn, Gastrin_rcpt, Cholcskin_rcpt
LACTB	Protease	yes		Beta-lactam-related, Beta-lactam/transpept-like, Mito_Ser_Protease_LACTB
RCHY1	Transcription factor	no	2.3.2.27	Znf_RING, Znf_CHY, Znf_RING/FYVE/PHD
LDLRAP1	Other/Unknown	no		PTB/PI_dom, PH-like_dom_sf, Adapter_Engulfment-Domain
DOCK6	Other/Unknown	no		DOCK_C/D_N, DOCK, C2_DOCK-type_domain
ST6GALNAC5	Enzyme (other)	yes	2.4.99.7	Glyco_trans_29, Sialyl_trans, GT29-like_sf
PCSK9	Protease	yes	3.4.21.61	Peptidase_S8/S53_dom, S8pro/Inhibitor_I9, Peptidase_S8_subtilisin-rel
AGPAT5	Enzyme (other)	yes	2.3.1.51	Plipid/glycerol_acylTrfase, Acyltransf_C
MIB1	Transcription factor	no		Znf_ZZ, Znf_RING, Ankyrin_rpt
NAPEPLD	Enzyme (other)	yes	3.1.4.54	Metallo-B-lactamas, NAPE-PLD, RibonucZ/Hydroxyglut_hydro
AGK	Kinase	yes	2.7.1.94	Diacylglycerol_kinase_cat_dom, NAD/diacylglycerol_kinase_sf, ATP-NAD_kinase_N
PHYHD1	Other/Unknown	no		Phytyl_CoA_dOase-like
STAP1	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
OXSM	Enzyme (other)	yes	2.3.1.41	Beta-ketoacyl_synthase, KAS_N, KAS_C
SAMD8	Other/Unknown	no		SAM, SAM/pointed_sf, Sphingomyelin_synth-like_dom
SPTY2D1	Other/Unknown	no		Chromatin_SPT2, SPT2_N
ESCO2	Transcription factor	no		AcTrfase_ESCO_Znf_dom, ESCO_Acetyltransf_dom
DGKG	Kinase	yes	2.7.1.107	Diacylglycerol_kin_accessory, Diacylglycerol_kinase_cat_dom, EF_hand_dom
DGKH	Kinase	yes	2.7.1.107	Diacylglycerol_kin_accessory, Diacylglycerol_kinase_cat_dom, SAM
ABCA1	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
PLEKHA5	Scaffold/PPI	no		WW_dom, PH_domain, PH-like_dom_sf
AGMO	Enzyme (other)	yes	1.14.16.5	Fatty_acid_hydroxylase, Sterol_desaturase/TMEM195, AGMP_C
ABCA5	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
FNTA	Enzyme (other)	yes	2.5.1.58	Prenyl_trans_a
ABCA8	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
G6PD	Enzyme (other)	yes	1.1.1.49	G6P_DH, G6P_DH_AS, G6P_DH_NAD-bd
GHR	Antibody/Immunoglobulin	yes		Long_hematopoietin_rcpt_CS, FN3_dom, Ig-like_fold
FFAR1	GPCR	yes		GPCR_Rhodpsn, GPR40-rel_orph, GPR40_recept_FA
MIR6886	Other/Unknown	no
LDLR-AS1	Other/Unknown	no
APOB	Other/Unknown	no		Vitellogenin_N, Lipid_transpt_open_b-sht, Lipovitellin_superhlx_dom
INPP4B	Enzyme (other)	yes	3.1.3.66	C2_dom, C2_domain_sf, INPP4
OCRL	Antibody/Immunoglobulin	yes	3.1.3.36	RhoGAP_dom, IPPc, Rho_GTPase_activation_prot
PDE1C	Transcription factor	no	3.1.4.17	PDEase_catalytic_dom, HD/PDEase_dom, PDE1_N
B3GALT1	Enzyme (other)	yes	2.4.1.134	Glyco_trans_31, Nucleotide-diphossugar_trans
RBP3	Protease	yes		Tail-specific_protease, ClpP/crotonase-like_dom_sf

Expression context

Cohort genes with no expression data: 1.

44 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)	45
unknown	1

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	6
adrenal tissue	6
corpus callosum	6
endothelial cell	6
male germ line stem cell (sensu Vertebrata) in testis	5
liver	4
calcaneal tendon	4
mucosa of transverse colon	3
ventricular zone	3
stromal cell of endometrium	3
cerebellar cortex	3
cerebellar hemisphere	3
right adrenal gland	2
colonic epithelium	2
islet of Langerhans	2
medial globus pallidus	2
epithelial cell of pancreas	2
parietal pleura	2
tibia	2
epithelium of nasopharynx	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EPHX2	206	ubiquitous	marker	right lobe of liver, mucosa of transverse colon, right adrenal gland
APOA2	160	tissue_specific	marker	right lobe of liver, liver, colonic epithelium
LDLR	281	ubiquitous	marker	adrenal tissue, lower lobe of lung, right adrenal gland
BPNT1	232	ubiquitous	marker	islet of Langerhans, mucosa of transverse colon, rectum
SPTLC2	274	ubiquitous	marker	corpus callosum, inferior vagus X ganglion, medial globus pallidus
SQLE	287	ubiquitous	marker	adrenal tissue, ventricular zone, ganglionic eminence
ATP8A1	292	ubiquitous	marker	Brodmann (1909) area 23, corpus callosum, endothelial cell
PLEKHA3	259	ubiquitous	marker	epithelial cell of pancreas, oviduct epithelium, endothelial cell
MBTPS2	264	ubiquitous	marker	endothelial cell, tibia, parietal pleura
UGGT1	270	ubiquitous	marker	calcaneal tendon, stromal cell of endometrium, epithelium of nasopharynx
CCKBR	148	broad	marker	Brodmann (1909) area 10, frontal pole, prefrontal cortex
LACTB	259	ubiquitous	marker	left ventricle myocardium, monocyte, deltoid
RCHY1	295	ubiquitous	marker	sperm, secondary oocyte, endothelial cell
LDLRAP1	271	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
DOCK6	254	ubiquitous	marker	colonic epithelium, right lung, apex of heart
ST6GALNAC5	188	broad	marker	CA1 field of hippocampus, stromal cell of endometrium, right coronary artery
PCSK9	147	broad	marker	right lobe of liver, mucosa of transverse colon, male germ line stem cell (sensu Vertebrata) in testis
AGPAT5	137	ubiquitous	marker	corpus callosum, ventricular zone, cortical plate
MIB1	262	ubiquitous	marker	corpus epididymis, kidney epithelium, tibia
NAPEPLD	134	ubiquitous	marker	corpus callosum, ventricular zone, superior frontal gyrus
AGK	161	ubiquitous	marker	adrenal tissue, cerebellar hemisphere, cerebellar cortex
PHYHD1	222	ubiquitous	marker	body of pancreas, olfactory segment of nasal mucosa, right lobe of liver
STAP1	150	broad	marker	lymph node, epithelium of nasopharynx, spleen
OXSM	271	ubiquitous	marker	right lobe of liver, tongue squamous epithelium, left testis
SAMD8	253	ubiquitous	marker	medial globus pallidus, globus pallidus, corpus callosum
SPTY2D1	250	ubiquitous	marker	amniotic fluid, calcaneal tendon, germinal epithelium of ovary
ESCO2	157	ubiquitous	marker	oocyte, buccal mucosa cell, secondary oocyte
DGKG	177	broad	marker	cerebellar cortex, cerebellar hemisphere, right hemisphere of cerebellum
DGKH	237	ubiquitous	marker	endothelial cell, dorsal root ganglion, epithelial cell of pancreas
ABCA1	272	ubiquitous	marker	adrenal tissue, skin of hip, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 17.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOB	5,244
EPHX2	4,455
G6PD	4,226
SQLE	3,874
ABCA1	3,551
OXSM	3,123
PCSK9	2,994
ESCO2	2,514
AGK	2,341
SPTLC2	2,335

Intra-cohort edges

A	B	Sources
ABCA1	ABCA8	string_interaction
ABCA1	APOA2	string_interaction
ABCA1	APOB	string_interaction
AGK	PCSK9	biogrid_interaction
APOA2	APOB	string_interaction
APOB	LDLR	intact, string_interaction
APOB	LDLRAP1	string_interaction
APOB	PCSK9	string_interaction
APOB	STAP1	string_interaction
DGKG	DGKH	biogrid_interaction
LDLR	LDLRAP1	string_interaction
LDLR	PCSK9	biogrid_interaction, intact, string_interaction
LDLRAP1	PCSK9	string_interaction
LDLRAP1	STAP1	string_interaction
PCSK9	STAP1	string_interaction
PCSK9	UGGT1	biogrid_interaction
SAMD8	SPTLC2	string_interaction

Structural data

PDB: 29 · AlphaFold-only: 15 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EPHX2	P34913	139
PCSK9	Q8NBP7	65
LDLR	P01130	36
G6PD	P11413	25
SPTLC2	O15270	17
FNTA	P49354	14
GHR	P10912	11
FFAR1	O14842	9
ATP8A1	Q9Y2Q0	8
APOB	P04114	8
DOCK6	Q96HP0	7
ABCA1	O95477	7
MIB1	Q86YT6	6
CCKBR	P32239	5
OXSM	Q9NWU1	5
OCRL	Q01968	5
LACTB	P83111	4
RCHY1	Q96PM5	4
NAPEPLD	Q6IQ20	4
SAMD8	Q96LT4	4
SQLE	Q14534	3
PLEKHA3	Q9HB20	3
PHYHD1	Q5SRE7	2
STAP1	Q9ULZ2	2
SPTY2D1	Q68D10	2
BPNT1	O95861	1
LDLRAP1	Q5SW96	1
AGK	Q53H12	1
PLEKHA5	Q9HAU0	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AGPAT5	Q9NUQ2	94.23
AGMO	Q6ZNB7	93.90
B3GALT1	Q9Y5Z6	89.11
MBTPS2	O43462	87.78
RBP3	P10745	85.10
UGGT1	Q9NYU2	83.97
INPP4B	O15327	82.85
ST6GALNAC5	Q9BVH7	81.83
ABCA8	O94911	78.67
DGKG	P49619	77.53
ABCA5	Q8WWZ7	77.12
APOA2	P02652	75.92
PDE1C	Q14123	71.53
DGKH	Q86XP1	71.33
ESCO2	Q56NI9	58.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 156. Enrichment computed across 46 evidence-associated genes (40 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 40 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Plasma lipoprotein assembly, remodeling, and clearance	6	34.3×	3e-06	APOA2, LDLR, MBTPS2, LDLRAP1, ABCA1, APOB
Chylomicron clearance	3	171.3×	2e-05	LDLR, LDLRAP1, APOB
Metabolism of lipids	10	7.9×	2e-05	APOA2, SPTLC2, MBTPS2, LDLRAP1, ST6GALNAC5, AGK, SAMD8, ABCA1 (+2 more)
LDL clearance	4	54.4×	3e-05	LDLR, LDLRAP1, PCSK9, APOB
Metabolism	14	4.1×	1e-04	APOA2, LDLR, BPNT1, SPTLC2, MBTPS2, LDLRAP1, ST6GALNAC5, AGK (+6 more)
Plasma lipoprotein assembly	3	53.5×	5e-04	APOA2, ABCA1, APOB
Transport of small molecules	9	5.7×	5e-04	APOA2, LDLR, ATP8A1, MBTPS2, LDLRAP1, ABCA1, ABCA5, ABCA8 (+1 more)
Synthesis of PIPs at the plasma membrane	4	21.1×	7e-04	PLEKHA3, PLEKHA5, INPP4B, OCRL
Plasma lipoprotein remodeling	3	35.7×	0.001	APOA2, MBTPS2, APOB
Plasma lipoprotein clearance	3	35.7×	0.001	LDLR, LDLRAP1, APOB
Metabolism of fat-soluble vitamins	3	28.6×	0.002	APOA2, LDLR, APOB
Metabolism of vitamins and cofactors	4	11.7×	0.005	APOA2, LDLR, LDLRAP1, APOB
Chylomicron assembly	2	57.1×	0.005	APOA2, APOB
Chylomicron remodeling	2	57.1×	0.005	APOA2, APOB
Visual phototransduction	3	19.5×	0.005	APOA2, LDLR, APOB
Retinoid metabolism and transport	3	18.6×	0.005	APOA2, LDLR, APOB
Synthesis of IP2, IP, and Ins in the cytosol	2	38.1×	0.011	INPP4B, OCRL
Clathrin-mediated endocytosis	4	8.5×	0.011	LDLR, LDLRAP1, APOB, OCRL
Sphingolipid metabolism	3	12.6×	0.014	SPTLC2, ST6GALNAC5, SAMD8
Biosynthesis of A2E, implicated in retinal degradation	1	285.5×	0.026	NAPEPLD
Effects of PIP2 hydrolysis	2	22.8×	0.026	DGKG, DGKH
Defective ABCA1 causes TGD	1	142.8×	0.045	ABCA1
Biosynthesis of maresins	1	142.8×	0.045	EPHX2
Cargo recognition for clathrin-mediated endocytosis	3	7.9×	0.045	LDLR, LDLRAP1, APOB
Post-translational protein phosphorylation	3	7.5×	0.046	APOA2, PCSK9, APOB
Sphingolipid de novo biosynthesis	2	14.3×	0.050	SPTLC2, SAMD8
Sensory Perception	3	7.1×	0.050	APOA2, LDLR, APOB
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	3	6.5×	0.061	APOA2, PCSK9, APOB
Cam-PDE 1 activation	1	71.4×	0.064	PDE1C
Retinoid cycle disease events	1	71.4×	0.064	NAPEPLD

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 43 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	8	36.5×	1e-08	APOA2, LDLR, MBTPS2, LDLRAP1, PCSK9, ABCA1, ABCA5, APOB
cholesterol homeostasis	8	29.0×	4e-08	EPHX2, APOA2, LDLR, LDLRAP1, PCSK9, ABCA1, ABCA5, APOB
cholesterol transport	5	85.2×	3e-07	APOA2, LDLR, LDLRAP1, ABCA8, APOB
cholesterol efflux	5	61.2×	1e-06	APOA2, ABCA1, ABCA5, ABCA8, APOB
lipid phosphorylation	3	117.6×	1e-04	AGK, DGKG, DGKH
sphingomyelin biosynthetic process	3	98.0×	2e-04	SPTLC2, SAMD8, ABCA8
receptor-mediated endocytosis involved in cholesterol transport	2	391.9×	3e-04	LDLR, LDLRAP1
low-density lipoprotein particle clearance	3	69.2×	4e-04	LDLR, LDLRAP1, APOB
reverse cholesterol transport	3	65.3×	5e-04	APOA2, ABCA1, ABCA5
negative regulation of receptor recycling	2	156.8×	0.002	LDLR, PCSK9
cellular response to lipoprotein particle stimulus	2	156.8×	0.002	APOA2, APOB
phosphatidic acid biosynthetic process	3	35.6×	0.002	AGPAT5, DGKG, DGKH
lipoprotein biosynthetic process	2	130.6×	0.002	ABCA1, APOB
lipid metabolic process	5	10.7×	0.002	LDLR, LACTB, G6PD, OCRL, RBP3
regulation of cholesterol efflux	2	112.0×	0.003	ABCA5, ABCA8
high-density lipoprotein particle clearance	2	112.0×	0.003	APOA2, LDLR
lipoprotein catabolic process	2	112.0×	0.003	LDLR, APOB
ceramide biosynthetic process	3	29.4×	0.003	SPTLC2, AGK, SAMD8
glycerolipid metabolic process	2	98.0×	0.003	AGK, DGKG
high-density lipoprotein particle assembly	2	78.4×	0.005	APOA2, ABCA1
phospholipase C-activating G protein-coupled receptor signaling pathway	4	12.2×	0.005	CCKBR, DGKG, DGKH, FFAR1
negative regulation of low-density lipoprotein particle clearance	2	71.3×	0.005	LDLR, PCSK9
regulation of cholesterol biosynthetic process	2	71.3×	0.005	MBTPS2, APOB
negative regulation of macrophage derived foam cell differentiation	2	60.3×	0.007	ABCA1, ABCA5
phospholipid catabolic process	2	56.0×	0.007	APOA2, NAPEPLD
diacylglycerol metabolic process	2	56.0×	0.007	DGKG, DGKH
phospholipid efflux	2	52.2×	0.008	APOA2, ABCA1
regulation of cholesterol metabolic process	2	52.2×	0.008	EPHX2, LDLR
low-density lipoprotein particle remodeling	2	49.0×	0.008	APOA2, APOB
sphingosine biosynthetic process	2	49.0×	0.008	SPTLC2, AGK

Therapeutics

Drug target analysis

Approved (phase 4): 10 · Phase ≥3: 10 · Phased (≥1): 10 · Undrugged: 36

Druggability breadth: 21 of 46 evidence-associated genes (46%) 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
EPHX2	OXAPROZIN
LDLR	NILOTINIB
SQLE	AMIODARONE
CCKBR	SINCALIDE
PCSK9	NILOTINIB
NAPEPLD	HEXACHLOROPHENE
FNTA	CORTISONE ACETATE
G6PD	BREXANOLONE
FFAR1	ROSIGLITAZONE
PDE1C	VARDENAFIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CCKBR	33	4
EPHX2	19	4
PDE1C	15	4
G6PD	8	4
FFAR1	8	4
FNTA	6	4
SQLE	2	4
LDLR	1	4
PCSK9	1	4
NAPEPLD	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OXAPROZIN	4	EPHX2
SORAFENIB	4	EPHX2
FULVESTRANT	4	EPHX2
REGORAFENIB	4	EPHX2
ZAFIRLUKAST	4	EPHX2
ZILEUTON	4	EPHX2
NILOTINIB	4	LDLR, PCSK9
AMIODARONE	4	SQLE
TERBINAFINE	4	SQLE
SINCALIDE	4	CCKBR
CHLORDIAZEPOXIDE	4	CCKBR
CANDESARTAN CILEXETIL	4	CCKBR
CLOTRIMAZOLE	4	CCKBR
RIMONABANT	4	CCKBR
INDOCYANINE GREEN ACID FORM	4	CCKBR
FIDAXOMICIN	4	CCKBR
PENTAGASTRIN	4	CCKBR
FLUNITRAZEPAM	4	CCKBR
NITAZOXANIDE	4	CCKBR
ILOPERIDONE	4	CCKBR
DESOGESTREL	4	CCKBR
AZLOCILLIN	4	CCKBR
RIFAXIMIN	4	CCKBR
ISRADIPINE	4	CCKBR
FLUTRIMAZOLE	4	CCKBR
EFAVIRENZ	4	CCKBR
ENCORAFENIB	4	CCKBR
FLUOXETINE	4	CCKBR
LANSOPRAZOLE	4	CCKBR
APOMORPHINE	4	CCKBR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 22.

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

Symbol	Assays	Type breakdown
FNTA	513	Binding:438, Functional:75
FFAR1	444	Functional:320, Binding:124
CCKBR	374	Binding:322, Functional:51, Toxicity:1
EPHX2	314	Binding:311, ADMET:3
PCSK9	202	Binding:201, ADMET:1
PDE1C	185	Binding:175, ADMET:5, Functional:5
LDLR	55	Binding:54, Functional:1
G6PD	49	Binding:46, ADMET:2, Functional:1
SQLE	23	Binding:21, Functional:2
AGK	19	Binding:19
DGKH	10	Binding:10
UGGT1	7	Binding:7
DGKG	5	Binding:5
SPTLC2	4	Binding:4
NAPEPLD	3	Binding:3
B3GALT1	3	Binding:3
ABCA1	2	Binding:2
GHR	2	Binding:2
BPNT1	1	Binding:1
AGPAT5	1	Binding:1
APOB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EPHX2	3.1.3.106, 3.3.2.10	2-lysophosphatidate phosphatase, soluble epoxide hydrolase
BPNT1	3.1.3.7	3’(2’),5’-bisphosphate nucleotidase
SPTLC2	2.3.1.50	serine C-palmitoyltransferase
SQLE	1.14.14.17	squalene monooxygenase
ATP8A1	7.6.2.1	P-type phospholipid transporter
MBTPS2	3.4.24.85	S2P endopeptidase
RCHY1	2.3.2.27	RING-type E3 ubiquitin transferase
ST6GALNAC5	2.4.99.7	alpha-N-acetylneuraminyl-2,3-beta-galactosyl-1,3-N-acetylgalactosaminide 6-alpha-sialyltransferase
PCSK9	3.4.21.61	Kexin
AGPAT5	2.3.1.51	1-acylglycerol-3-phosphate O-acyltransferase
NAPEPLD	3.1.4.54	N-acetylphosphatidylethanolamine-hydrolysing phospholipase D
AGK	2.7.1.94	acylglycerol kinase
OXSM	2.3.1.41	beta-ketoacyl-[acyl-carrier-protein] synthase I
DGKG	2.7.1.107	diacylglycerol kinase (ATP)
DGKH	2.7.1.107	diacylglycerol kinase (ATP)
AGMO	1.14.16.5	alkylglycerol monooxygenase
FNTA	2.5.1.58, 2.5.1.59	protein farnesyltransferase, protein geranylgeranyltransferase type I
G6PD	1.1.1.49	glucose-6-phosphate dehydrogenase (NADP+)
INPP4B	3.1.3.66	phosphatidylinositol-3,4-bisphosphate 4-phosphatase
OCRL	3.1.3.36	phosphoinositide 5-phosphatase
PDE1C	3.1.4.17	3’,5’-cyclic-nucleotide phosphodiesterase
B3GALT1	2.4.1.134	galactosylxylosylprotein 3-beta-galactosyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EPHX2	314
CCKBR	374
PCSK9	202
FNTA	513
FFAR1	444
PDE1C	185

Pharmacogenomics

Cohort genes with a PharmGKB record: 44; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
G6PD	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)
OXAPROZIN	4	EPHX2
SORAFENIB	4	EPHX2
FULVESTRANT	4	EPHX2
REGORAFENIB	4	EPHX2
ZAFIRLUKAST	4	EPHX2
ZILEUTON	4	EPHX2
NILOTINIB	4	LDLR, PCSK9
AMIODARONE	4	SQLE
TERBINAFINE	4	SQLE
SINCALIDE	4	CCKBR
CHLORDIAZEPOXIDE	4	CCKBR
CANDESARTAN CILEXETIL	4	CCKBR
CLOTRIMAZOLE	4	CCKBR
RIMONABANT	4	CCKBR
INDOCYANINE GREEN ACID FORM	4	CCKBR
FIDAXOMICIN	4	CCKBR
PENTAGASTRIN	4	CCKBR
FLUNITRAZEPAM	4	CCKBR
NITAZOXANIDE	4	CCKBR
ILOPERIDONE	4	CCKBR
DESOGESTREL	4	CCKBR
AZLOCILLIN	4	CCKBR
RIFAXIMIN	4	CCKBR
ISRADIPINE	4	CCKBR
FLUTRIMAZOLE	4	CCKBR
EFAVIRENZ	4	CCKBR
ENCORAFENIB	4	CCKBR
FLUOXETINE	4	CCKBR
LANSOPRAZOLE	4	CCKBR
APOMORPHINE	4	CCKBR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	10	EPHX2, LDLR, SQLE, CCKBR, PCSK9, NAPEPLD, FNTA, G6PD, FFAR1, PDE1C
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	8	BPNT1, SPTLC2, LACTB, AGK, OXSM, ABCA1, GHR, OCRL
D	Druggable family + AlphaFold only, no drug	11	MBTPS2, ST6GALNAC5, AGPAT5, DGKG, DGKH, AGMO, ABCA5, ABCA8, INPP4B, B3GALT1 (+1 more)
E	Difficult family or no structure, no drug	17	APOA2, ATP8A1, PLEKHA3, UGGT1, RCHY1, LDLRAP1, DOCK6, MIB1, PHYHD1, STAP1 (+7 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LDLRAP1	0	PCSK9
APOA2	0	—
BPNT1	1	—
SPTLC2	4	—
ATP8A1	0	—
PLEKHA3	0	—
MBTPS2	0	—
UGGT1	7	—
LACTB	0	—
RCHY1	0	—
DOCK6	0	—
ST6GALNAC5	0	—
AGPAT5	1	—
MIB1	0	—
AGK	19	—
PHYHD1	0	—
STAP1	0	—
OXSM	0	—
SAMD8	0	—
SPTY2D1	0	—
ESCO2	0	—
DGKG	5	—
DGKH	10	—
ABCA1	2	—
PLEKHA5	0	—
AGMO	0	—
ABCA5	0	—
ABCA8	0	—
GHR	2	—
MIR6886	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 28.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	15
PHASE3	7
PHASE2	3
PHASE1	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06231459	PHASE4	COMPLETED	Expression of Pro- and Anti-inflammatory Cytokines During Anti-PCSK9 in Familial Hypercholesterolemia
NCT00000594	PHASE3	COMPLETED	NHLBI Type II Coronary Intervention Study
NCT00092833	PHASE3	TERMINATED	Investigational Drug in Patients With Hypercholesterolemia or in Patients With Sitosterolemia (0653-026)(COMPLETED)
NCT00134485	PHASE3	COMPLETED	Study To Evaluate The Safety And Efficacy Of Torcetrapib/Atorvastatin In Subjects With Familial Hypercholerolemia
NCT00134511	PHASE3	COMPLETED	Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Patients With Genetic High Cholesterol Disorder
NCT00136981	PHASE3	COMPLETED	Carotid B-Mode Ultrasound Study to Compare Anti-Atherosclerotic Effect of Torcetrpib/Atorvastatin to Atorvastatin Alone.
NCT00384293	PHASE3	TERMINATED	Carotid IMT (Intima Media Thickening) Study (0524A-041)(TERMINATED)
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)
NCT00280995	PHASE2	COMPLETED	Dose-escalating Safety Study of ISIS 301012 in Homozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT00281008	PHASE2	COMPLETED	Study of ISIS 301012 (Mipomersen) in Heterozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT01375751	PHASE2	COMPLETED	Reduction of Low-Density Lipoprotein Cholesterol (LDL-C) With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study
NCT00515307	PHASE1	COMPLETED	Bone Marrow Stem Cells as a Source of Allogenic Hepatocyte Transplantation in Homozygous Familial Hypercholesterolemia
NCT01583647	PHASE1	TERMINATED	A Study of Extended-release (ER) Niacin/Laropiprant in Adolescents With Heterozygous Familial Hypercholesterolemia (MK-0524A-158)
NCT03989167	Not specified	RECRUITING	Clinical Decision Support for Familial Hypercholesterolemia
NCT04073797	Not specified	RECRUITING	PET Imaging of Inflammation and Lipid Lowering Study
NCT04656028	Not specified	ACTIVE_NOT_RECRUITING	Genetic Testing and Motivational Counseling for FH
NCT06555120	Not specified	RECRUITING	Screening for Familial Hypercholesterolemia in Children
NCT07543731	Not specified	NOT_YET_RECRUITING	A Real-World Study of Long-Term Adherence and Persistence to Inclisiran, Evolocumab, and Alirocumab
NCT00005168	Not specified	COMPLETED	Hyperapo B and Coronary Heart Disease
NCT01753232	Not specified	COMPLETED	Safety and Efficacy of the DALI LDL-adsorber and MONET Lipoprotein Filter
NCT03018678	Not specified	COMPLETED	Screening Protocol for a Gene Therapy Trial in Subjects With Homozygous Familial Hypercholesterolemia
NCT03110432	Not specified	COMPLETED	Prospective German Very High Cardiovascular Risk Patients Dyslipidemia Treatment Indication Registry
NCT03795038	Not specified	COMPLETED	Comparison of the Plasma Lipoprotein Apheresis Systems DIAMED and MONET vs. the Whole Blood Apheresis System DALI
NCT04118348	Not specified	COMPLETED	Evaluating the Efficacy of Pediatric Lipid Screening Alerts
NCT04313270	Not specified	UNKNOWN	Subclinical Atherosclerosis in Patients With Familial Hypercholesterolemia Treated With Evolocumab®
NCT04526457	Not specified	COMPLETED	Is Family Screening Improved by Genetic Testing of Familial Hypercholesterolemia
NCT04722068	Not specified	COMPLETED	Regeneron 1331 Kinetics Sub-Study HoFH
NCT04837638	Not specified	UNKNOWN	Diet Quality and Coronary Artery Calcification in Adults With Heterozygous Familial Hypercholesterolemia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EVOLOCUMAB	4	3
CHOLESTYRAMINE	4	1
EDOTREOTIDE GALLIUM GA-68	4	1
EZETIMIBE	4	1
MIPOMERSEN SODIUM	4	1
TORCETRAPIB	3	3
ANACETRAPIB	3	1
INCLISIRAN	3	1
CHEMBL3787505	0	1