Metabolic dysfunction-associated steatotic liver disease

Summary

Metabolic dysfunction-associated steatotic liver disease (MONDO:0013209) is a disease with 45 cohort genes (496 GWAS associations across 40 studies) and 1,067 clinical trials. Top therapeutic interventions include empagliflozin, exenatide, and omega-3-acid ethyl esters.

At a glance

• Cohort genes: 45
• GWAS associations: 496
• Clinical trials: 1,067

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	metabolic dysfunction-associated steatotic liver disease
Mondo ID	MONDO:0013209
EFO	EFO:0003095
MeSH	D065626
Orphanet	33271
DOID	DOID:0080208, DOID:0080546
ICD-11	1912806631
NCIT	C84444
SNOMED CT	197315008
UMLS	C0400966
MedGen	96033
MedDRA	10029530
Is cancer (heuristic)	no

Also known as: fatty liver disease, nonalcoholic · fatty liver disease, nonalcoholic, susceptibility to, 1 · MASLD · NAFLD · NAFLD - nonalcoholic fatty liver disease · NAFLD1 · non-alcoholic fatty liver · non-alcoholic fatty liver disease · nonalcoholic fatty liver disease

Data availability: 496 GWAS associations (40 studies) · 1 GenCC gene-disease record · 39 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hepatobiliary disorder › liver disorder › fatty liver disease › metabolic dysfunction-associated steatotic liver disease

Related subtypes (3): visceral steatosis, congenital, alcoholic fatty liver disease, metabolic dysfunction and alcohol associated liver disease

Subtypes (2): metabolic dysfunction-associated steatohepatitis, NAFLD1

Genetics & variants

GWAS landscape

496 GWAS associations across 40 studies. Top hits map to 36 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs738408	2e-271	PNPLA3	T	35.21
rs3747207	5e-128	PNPLA3	G	0.23
rs58542926	1e-114	TM6SF2	T	22.76
rs1372344	8e-88	LPL - RPL30P9	A	0.09
rs964184	1e-76	ZPR1	G	0.11
rs1558902	1e-75	FTO	T	0.08
rs738409	3e-73	PNPLA3	G	0.52
rs268	9e-65	LPL	A	0.25
rs2006092	1e-63	GGT1	?	0.02
rs2980871	2e-57	TRIB1AL	A	0.07
rs1042034	6e-54	APOB	C	0.08
rs9939224	1e-41	CETP	T	0.07
rs10489615	6e-41	GALNT2	A	0.06
rs174536	1e-35	MYRF, TMEM258	A	0.05
rs429358	4e-34	APOE	T	12.18
rs2896019	2e-31	PNPLA3	G	1.85
rs1260326	3e-31	GCKR	T	11.62
rs7811265	9e-31	BAZ1B	A	0.06
rs73001065	8e-30	MAU2	C	1.41
rs4465830	6e-27	ZNF335	A	0.06
rs3758673	1e-26	NR1H3	C	0.05
rs2943650	1e-26	NYAP2 - MIR5702	C	0.05
rs3749147	2e-25	GPN1	G	0.05
rs1457489	2e-24	RNU4-17P - MC4R	G	0.05
rs231492	7e-24	MPP2	G	0.07
rs4783961	7e-24	HERPUD1 - CETP	G	0.04
rs188247550	1e-23	SUGP1	C	0.33
rs2895432	2e-23	NUP93	G	0.07
rs1128249	4e-23	COBLL1	G	0.04
rs12446198	9e-23	NFATC3	G	0.06

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90094908	Miao Z	2021	28,396	108,652	Identification of 90 NAFLD GWAS loci and establishment of NAFLD PRS and causal role of NAFLD in coronary artery disease.
GCST90091033	Ghodsian N	2021	8,434	770,180	Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease.
GCST90275041	Sun Z	2023	6,623	26,318	Genetic variants in HFE are associated with non-alcoholic fatty liver disease in lean individuals.
GCST90651149	Liu TY	2025	6,479	217,650	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90054782	Fairfield CJ	2021	4,761	373,227	Genome-Wide Association Study of NAFLD Using Electronic Health Records.
GCST90104598	Li J	2022	3,711	426,252	Mendelian Randomization Analysis Reveals No Causal Relationship Between Nonalcoholic Fatty Liver Disease and Severe COVID-19.
GCST90081501	Backman JD	2021	3,220	376,493	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90085487	Backman JD	2021	3,220	376,493	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90275047	Sun Z	2023	3,069	10,641	Genetic variants in HFE are associated with non-alcoholic fatty liver disease in lean individuals.
GCST90271929	Zhang Z	2023	2,757	460,161	Non-Alcoholic Fatty Liver Disease and Vitamin D in the UK Biobank: A Two-Sample Bidirectional Mendelian Randomisation Study.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	6
Tier 2: splice/UTR	3
Tier 3: regulatory	3
Tier 4: intronic/intergenic	38

MAF distribution

Bucket	Variants
common (>=0.05)	46
low_freq (0.01-0.05)	4
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	27
intergenic_variant	8
missense_variant	5
regulatory_region_variant	3
non_coding_transcript_exon_variant	2
synonymous_variant	1
stop_gained	1
3_prime_UTR_variant	1
5_prime_UTR_variant	1
splice_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs738408	22	43928850	C>A,G,T	0.22	synonymous_variant	PNPLA3	2e-271	Tier 4: intronic/intergenic
rs3747207	22	43928975	G>A,C,T	0.223	intron_variant	PNPLA3	5e-128	Tier 4: intronic/intergenic
rs58542926	19	19268740	C>A,T	0.07	stop_gained	TM6SF2	1e-114	Tier 1: coding
rs1372344	8	19995428	A>G,T	0.284	intergenic_variant	LPL - RPL30P9	8e-88	Tier 4: intronic/intergenic
rs964184	11	116778201	G>C	0.162	3_prime_UTR_variant	ZPR1	1e-76	Tier 2: splice/UTR
rs1558902	16	53769662	T>A	0.432	intron_variant	FTO	1e-75	Tier 4: intronic/intergenic
rs738409	22	43928847	C>A,G,T	0.05	missense_variant	PNPLA3	3e-73	Tier 1: coding
rs268	8	19956018	A>G	0.014	missense_variant	LPL	9e-65	Tier 1: coding
rs2006092	22	24599701	A>G	0.05	intron_variant	GGT1	1e-63	Tier 4: intronic/intergenic
rs2980871	8	125476688	A>C,G	0.43	intron_variant	TRIB1AL	2e-57	Tier 4: intronic/intergenic
rs1042034	2	21002409	C>A,G,T	0.218	missense_variant	APOB	6e-54	Tier 1: coding
rs9939224	16	56968820	T>A,C,G	0.233	intron_variant	CETP	1e-41	Tier 4: intronic/intergenic
rs10489615	1	230169242	A>C,G	0.391	intron_variant	GALNT2	6e-41	Tier 4: intronic/intergenic
rs174536	11	61784455	A>C	0.35	intron_variant	MYRF, TMEM258	1e-35	Tier 4: intronic/intergenic
rs429358	19	44908684	T>C	0.15	missense_variant	APOE	4e-34	Tier 1: coding
rs2896019	22	43937814	T>G	0.46	intron_variant	PNPLA3	2e-31	Tier 4: intronic/intergenic
rs1260326	2	27508073	T>A,C,G	0.38	missense_variant	GCKR	3e-31	Tier 1: coding
rs7811265	7	73520180	A>C,G	0.189	intron_variant	BAZ1B	9e-31	Tier 4: intronic/intergenic
rs73001065	19	19349732	G>C	0.071	intron_variant	MAU2	8e-30	Tier 4: intronic/intergenic
rs4465830	20	45956781	A>G	0.204	intron_variant	ZNF335	6e-27	Tier 4: intronic/intergenic
rs3758673	11	47257366	C>A,G,T	0.297	intron_variant	NR1H3	1e-26	Tier 4: intronic/intergenic
rs2943650	2	226241205	C>A,G,T	0.374	intergenic_variant	NYAP2 - MIR5702	1e-26	Tier 4: intronic/intergenic
rs3749147	2	27629051	G>A,C,T	0.253	5_prime_UTR_variant	GPN1	2e-25	Tier 2: splice/UTR
rs1457489	18	60194728	G>A,C	0.268	intergenic_variant	RNU4-17P - MC4R	2e-24	Tier 4: intronic/intergenic
rs231492	17	43901388	G>T	0.088	intron_variant	MPP2	7e-24	Tier 4: intronic/intergenic
rs4783961	16	56960982	G>A	0.469	intergenic_variant	HERPUD1 - CETP	7e-24	Tier 4: intronic/intergenic
rs188247550	19	19285807	C>T	0.013	intron_variant	SUGP1	1e-23	Tier 4: intronic/intergenic
rs2895432	16	56823043	G>A,C	0.097	intron_variant	NUP93	2e-23	Tier 4: intronic/intergenic
rs1128249	2	164672114	G>A,C,T	0.434	regulatory_region_variant	COBLL1	4e-23	Tier 3: regulatory
rs12446198	16	68092069	G>A,C,T	0.14	intron_variant	NFATC3	9e-23	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
PNPLA3	PNPLA3	GWAS, GenCC

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
PNPLA3	Limited	Autosomal dominant	metabolic dysfunction-associated steatotic liver disease

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNA2D1	Orphanet:130	Brugada syndrome
CACNA2D1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA2D1	Orphanet:51083	Congenital short QT syndrome
PALLD	Orphanet:1333	Familial pancreatic carcinoma
COL13A1	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
COL13A1	Orphanet:98914	Presynaptic congenital myasthenic syndromes
FTO	Orphanet:210144	Lethal polymalformative syndrome, Boissel type
IRF4	Orphanet:3452	Whipple disease
APOE	Orphanet:329481	Lipoprotein glomerulopathy
APOE	Orphanet:412	Dysbetalipoproteinemia
LPL	Orphanet:309015	Familial lipoprotein lipase deficiency
LTBP2	Orphanet:238763	Glaucoma secondary to spherophakia/ectopia lentis and megalocornea
LTBP2	Orphanet:3449	Weill-Marchesani syndrome
LTBP2	Orphanet:98976	Congenital glaucoma
NGF	Orphanet:64752	Hereditary sensory and autonomic neuropathy type 5

Cohort genes → proteins

45 cohort genes, 45 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	44
gwas_and_gencc	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PNPLA3	HGNC:18590	ENSG00000100344	Q9NST1	1-acylglycerol-3-phosphate O-acyltransferase PNPLA3	gwas,gencc
ST8SIA1	HGNC:10869	ENSG00000111728	Q92185	Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase	gwas
TM6SF2	HGNC:11861	ENSG00000213996	Q9BZW4	Transmembrane 6 superfamily member 2	gwas
ZNF101	HGNC:12881	ENSG00000181896	Q8IZC7	Zinc finger protein 101	gwas
CACNA2D1	HGNC:1399	ENSG00000153956	P54289	Voltage-dependent calcium channel subunit alpha-2/delta-1	gwas
PARVB	HGNC:14653	ENSG00000188677	Q9HBI1	Beta-parvin	gwas
ZP4	HGNC:15770	ENSG00000116996	Q12836	Zona pellucida sperm-binding protein 4	gwas
MACROD2	HGNC:16126	ENSG00000172264	A1Z1Q3	ADP-ribose glycohydrolase MACROD2	gwas
TRIB1	HGNC:16891	ENSG00000173334	Q96RU8	Tribbles homolog 1	gwas
GPN1	HGNC:17030	ENSG00000198522	Q9HCN4	GPN-loop GTPase 1	gwas
PALLD	HGNC:17068	ENSG00000129116	Q8WX93	Palladin	gwas
SUGP1	HGNC:18643	ENSG00000105705	Q8IWZ8	SURP and G-patch domain-containing protein 1	gwas
TOX4	HGNC:20161	ENSG00000092203	O94842	TOX high mobility group box family member 4	gwas
SLC9A9	HGNC:20653	ENSG00000181804	Q8IVB4	Sodium/hydrogen exchanger 9	gwas
COL13A1	HGNC:2190	ENSG00000197467	Q5TAT6	Collagen alpha-1(XIII) chain	gwas
COMMD1	HGNC:23024	ENSG00000173163	Q8N668	COMM domain-containing protein 1	gwas
PLPPR4	HGNC:23496	ENSG00000117600	Q7Z2D5	Phospholipid phosphatase-related protein type 4	gwas
FAM171A1	HGNC:23522	ENSG00000148468	Q5VUB5	Protein FAM171A1	gwas
FAM107B	HGNC:23726	ENSG00000065809	Q9H098	Protein FAM107B	gwas
SAMM50	HGNC:24276	ENSG00000100347	Q9Y512	Sorting and assembly machinery component 50 homolog	gwas
NCAN	HGNC:2465	ENSG00000130287	O14594	Neurocan core protein	gwas
FTO	HGNC:24678	ENSG00000140718	Q9C0B1	Alpha-ketoglutarate-dependent dioxygenase FTO	gwas
YIPF1	HGNC:25231	ENSG00000058799	Q9Y548	Protein YIPF1	gwas
SPATA31H1	HGNC:25275	ENSG00000221843	Q68DN1	Spermatogenesis-associated protein 31H1	gwas
MTARC1	HGNC:26189	ENSG00000186205	Q5VT66	Mitochondrial amidoxime-reducing component 1	gwas
DDX60L	HGNC:26429	ENSG00000181381	Q5H9U9	Probable ATP-dependent RNA helicase DDX60-like	gwas
DCLK1	HGNC:2700	ENSG00000133083	O15075	Serine/threonine-protein kinase DCLK1	gwas
SLC46A3	HGNC:27501	ENSG00000139508	Q7Z3Q1	Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3	gwas
CRACR2A	HGNC:28657	ENSG00000130038	Q9BSW2	EF-hand calcium-binding domain-containing protein 4B	gwas
ZNF512	HGNC:29380	ENSG00000243943	Q96ME7	Zinc finger protein 512	gwas
GATAD2A	HGNC:29989	ENSG00000167491	Q86YP4	Transcriptional repressor p66-alpha	gwas
EHBP1L1	HGNC:30682	ENSG00000173442	Q8N3D4	EH domain-binding protein 1-like protein 1	gwas
TEX36	HGNC:31653	ENSG00000175018	Q5VZQ5	Testis-expressed protein 36	gwas
FARP1	HGNC:3591	ENSG00000152767	Q9Y4F1	FERM, ARHGEF and pleckstrin domain-containing protein 1	gwas
FDFT1	HGNC:3629	ENSG00000079459	P37268	Squalene synthase	gwas
GC	HGNC:4187	ENSG00000145321	P02774	Vitamin D-binding protein	gwas
HS3ST1	HGNC:5194	ENSG00000002587	O14792	Heparan sulfate glucosamine 3-O-sulfotransferase 1	gwas
IRF4	HGNC:6119	ENSG00000137265	Q15306	Interferon regulatory factor 4	gwas
APOE	HGNC:613	ENSG00000130203	P02649	Apolipoprotein E	gwas
LPL	HGNC:6677	ENSG00000175445	P06858	Lipoprotein lipase	gwas
LTBP2	HGNC:6715	ENSG00000119681	Q14767	Latent-transforming growth factor beta-binding protein 2	gwas
MAP4K5	HGNC:6867	ENSG00000012983	Q9Y4K4	Mitogen-activated protein kinase kinase kinase kinase 5	gwas
NGF	HGNC:7808	ENSG00000134259	P01138	Beta-nerve growth factor	gwas
PTPRU	HGNC:9683	ENSG00000060656	Q92729	Receptor-type tyrosine-protein phosphatase U	gwas
PZP	HGNC:9750	ENSG00000126838	P20742	Pregnancy zone protein	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PNPLA3	1-acylglycerol-3-phosphate O-acyltransferase PNPLA3	Specifically catalyzes coenzyme A (CoA)-dependent acylation of 1-acyl-sn-glycerol 3-phosphate (2-lysophosphatidic acid/LPA) to generate phosphatidic acid (PA), an important metabolic intermediate and precursor for both triglycerides and gl…
ST8SIA1	Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase	Catalyzes the addition of sialic acid in alpha 2,8-linkage to the sialic acid moiety of the ganglioside GM3 to form ganglioside GD3; gangliosides are a subfamily of complex glycosphingolipds that contain one or more residues of sialic acid.
TM6SF2	Transmembrane 6 superfamily member 2	Regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content.
ZNF101	Zinc finger protein 101	May be involved in transcriptional regulation.
CACNA2D1	Voltage-dependent calcium channel subunit alpha-2/delta-1	The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel.
PARVB	Beta-parvin	Adapter protein that plays a role in integrin signaling via ILK and in activation of the GTPases CDC42 and RAC1 by guanine exchange factors, such as ARHGEF6.
ZP4	Zona pellucida sperm-binding protein 4	Component of the zona pellucida, an extracellular matrix surrounding oocytes which mediates sperm binding, induction of the acrosome reaction and prevents post-fertilization polyspermy.
MACROD2	ADP-ribose glycohydrolase MACROD2	Removes ADP-ribose from aspartate and glutamate residues in proteins bearing a single ADP-ribose moiety.
TRIB1	Tribbles homolog 1	Adapter protein involved in protein degradation by interacting with COP1 ubiquitin ligase.
GPN1	GPN-loop GTPase 1	Small GTPase involved in the correct assembly of RNA polymerase II (RNAPII) complex, ensuring proper nuclear import of RNAPII.
PALLD	Palladin	Cytoskeletal protein required for organization of normal actin cytoskeleton.
SUGP1	SURP and G-patch domain-containing protein 1	Plays a role in pre-mRNA splicing.
TOX4	TOX high mobility group box family member 4	Transcription factor that modulates cell fate reprogramming from the somatic state to the pluripotent and neuronal fate.
SLC9A9	Sodium/hydrogen exchanger 9	Endosomal Na(+), K(+)/H(+) antiporter.
COL13A1	Collagen alpha-1(XIII) chain	Involved in cell-matrix and cell-cell adhesion interactions that are required for normal development.
COMMD1	COMM domain-containing protein 1	Scaffold protein in the commander complex that is essential for endosomal recycling of transmembrane cargos; the commander complex is composed of the CCC subcomplex and the retriever subcomplex.
PLPPR4	Phospholipid phosphatase-related protein type 4	Postsynaptic density membrane protein that indirectly regulates glutamatergic synaptic transmission through lysophosphatidic acid (LPA)-mediated signaling pathways.
FAM171A1	Protein FAM171A1	Involved in the regulation of the cytoskeletal dynamics, plays a role in actin stress fiber formation.
SAMM50	Sorting and assembly machinery component 50 homolog	Plays a crucial role in the maintenance of the structure of mitochondrial cristae and the proper assembly of the mitochondrial respiratory chain complexes.
NCAN	Neurocan core protein	May modulate neuronal adhesion and neurite growth during development by binding to neural cell adhesion molecules (NG-CAM and N-CAM).
FTO	Alpha-ketoglutarate-dependent dioxygenase FTO	RNA demethylase that mediates oxidative demethylation of different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a regulator of fat mass, adipogenesis and energy homeostasis.
MTARC1	Mitochondrial amidoxime-reducing component 1	Catalyzes the reduction of N-oxygenated molecules, acting as a counterpart of cytochrome P450 and flavin-containing monooxygenases in metabolic cycles.
DCLK1	Serine/threonine-protein kinase DCLK1	Probable kinase that may be involved in a calcium-signaling pathway controlling neuronal migration in the developing brain.
SLC46A3	Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3	Lysosomal proton-coupled steroid conjugate and bile acid transporter.
CRACR2A	EF-hand calcium-binding domain-containing protein 4B	Ca(2+)-binding protein that plays a key role in store-operated Ca(2+) entry (SOCE) in T-cells by regulating CRAC channel activation.
ZNF512	Zinc finger protein 512	Sequence-specific DNA-binding protein that recognizes repetitive and non-consecutive TTC sequences in pericentric repeat and initiates heterochromatin formation through interaction with SUV39H1/2 methyltransferases which catalyze histone H…
GATAD2A	Transcriptional repressor p66-alpha	Transcriptional repressor.
EHBP1L1	EH domain-binding protein 1-like protein 1	May act as Rab effector protein and play a role in vesicle trafficking.
FARP1	FERM, ARHGEF and pleckstrin domain-containing protein 1	Functions as a guanine nucleotide exchange factor for RAC1.
FDFT1	Squalene synthase	Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP) moieties to form squalene.
GC	Vitamin D-binding protein	Involved in vitamin D transport and storage, scavenging of extracellular G-actin, enhancement of the chemotactic activity of C5 alpha for neutrophils in inflammation and macrophage activation.
HS3ST1	Heparan sulfate glucosamine 3-O-sulfotransferase 1	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to position 3 of glucosamine residues in heparan.
IRF4	Interferon regulatory factor 4	Transcriptional activator.
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.
LPL	Lipoprotein lipase	Key enzyme in triglyceride metabolism.
LTBP2	Latent-transforming growth factor beta-binding protein 2	May play an integral structural role in elastic-fiber architectural organization and/or assembly.
MAP4K5	Mitogen-activated protein kinase kinase kinase kinase 5	May play a role in the response to environmental stress.
NGF	Beta-nerve growth factor	Nerve growth factor is important for the development and maintenance of the sympathetic and sensory nervous systems.
PTPRU	Receptor-type tyrosine-protein phosphatase U	Tyrosine-protein phosphatase which dephosphorylates CTNNB1.
PZP	Pregnancy zone protein	Is able to inhibit all four classes of proteinases by a unique ’trapping’ mechanism.

Protein-family classification

Druggable: 17 · Difficult: 4 · Unknown: 24 · Druggable fraction: 0.38

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
Complement	2	11.9×	0.110
Enzyme (other)	8	2.1×	0.139
Kinase	3	1.9×	0.662
Phosphatase	1	1.9×	0.689
Transporter	1	1.7×	0.689
Antibody/Immunoglobulin	2	1.3×	0.689
Other/Unknown	24	1.0×	0.884
Transcription factor	3	0.6×	0.932
Scaffold/PPI	1	0.4×	0.932

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PNPLA3	Other/Unknown	no		PNPLA_dom, Acyl_Trfase/lysoPLipase, PLPL
ST8SIA1	Enzyme (other)	yes	2.4.99.8	Glyco_trans_29, Sialyl_trans, GT29-like_sf
TM6SF2	Other/Unknown	no		EXPERA, TM6SF1-like, TM_Tm6sf1/2
ZNF101	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
CACNA2D1	Other/Unknown	no		VWF_A, VWA_N, VDCC_a2/dsu
PARVB	Other/Unknown	no		CH_dom, Parvin, CH_dom_sf
ZP4	Antibody/Immunoglobulin	yes		P_trefoil_dom, ZP_dom, P_trefoil_CS
MACROD2	Enzyme (other)	yes	3.1.1.106	Macro_dom, Macro_dom-like
TRIB1	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, Tribbles/Ser_Thr_kinase_40
GPN1	Other/Unknown	no		AAA+_ATPase, Gpn, P-loop_NTPase
PALLD	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
SUGP1	Other/Unknown	no		Surp, G_patch_dom, SWAP/Surp_sf
TOX4	Other/Unknown	no		HMG_box_dom, HMG_box_dom_sf, TOX_HMG-box_domain
SLC9A9	Other/Unknown	no		NHE-6/7/9, NaH_exchanger, Cation/H_exchanger_TM
COL13A1	Other/Unknown	no		Collagen, Collagen_Structural_Proteins
COMMD1	Other/Unknown	no		COMM, COMMD1_N, Murr1
PLPPR4	Enzyme (other)	yes	3.1.3.4	PAP2/HPO, PAP2/HPO_sf, PAP-like
FAM171A1	Other/Unknown	no		FAM171, FAM171_N, FAM171_C
FAM107B	Other/Unknown	no		FAM107
SAMM50	Other/Unknown	no		Bac_surfAg_D15, POTRA, D15-like
NCAN	Complement	yes		EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, Link_dom
FTO	Enzyme (other)	yes	1.14.11.53	FTO_C, FTO_cat_dom, FTO
YIPF1	Other/Unknown	no		Yip1_dom, Yip5/YIPF1/YIPF2
SPATA31H1	Other/Unknown	no
MTARC1	Enzyme (other)	yes	1.16.98.B1	MoCF_Sase_C, MOCOS_middle, Pyrv_Knase-like_insert_dom_sf
DDX60L	Other/Unknown	no		Helicase_C-like, DEAD/DEAH_box_helicase_dom, Helicase_ATP-bd
DCLK1	Kinase	yes	2.7.11.1	Prot_kinase_dom, Doublecortin_dom, Ser/Thr_kinase_AS
SLC46A3	Transporter	yes		MFS, MFS_trans_sf
CRACR2A	Other/Unknown	no		Small_GTPase, EF_hand_dom, Small_GTP-bd
ZNF512	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, ZNF512_znf-C2H2
GATAD2A	Transcription factor	no		Znf_GATA, P66_CC, P66
EHBP1L1	Other/Unknown	no		CH_dom, NT-C2, bMERB_dom
TEX36	Other/Unknown	no		HDNR
FARP1	Scaffold/PPI	no		DH_dom, FERM_domain, Ez/rad/moesin-like
FDFT1	Enzyme (other)	yes	2.5.1.21	Squ/phyt_synthse, Squal_synth-like, Isoprenoid_synthase_dom_sf
GC	Other/Unknown	no		VitD-bd, ALB/AFP/VDB, Serum_albumin_N
HS3ST1	Enzyme (other)	yes	2.8.2.23	Sulfotransferase_dom, P-loop_NTPase, NST/OST
IRF4	Other/Unknown	no		Interferon_reg_fact_DNA-bd_dom, SMAD_FHA_dom_sf, SMAD-like_dom_sf
APOE	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E
LPL	Enzyme (other)	yes	3.1.1.34	TAG_lipase, PLAT/LH2_dom, Lipo_Lipase
LTBP2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
MAP4K5	Kinase	yes		Prot_kinase_dom, CNH_dom, Kinase-like_dom_sf
NGF	Other/Unknown	no		Nerve_growth_factor-rel, Nerve_growth_factor_CS, Nerve_growth_factor-like
PTPRU	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, MAM_dom
PZP	Complement	yes		Macroglobln_a2, MG2, Terpenoid_cyclase/PrenylTrfase

Expression context

Cohort genes with no expression data: 0.

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)	1
broad (>20)	44
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	5
ganglionic eminence	5
buccal mucosa cell	4
ventricular zone	4
ileal mucosa	4
jejunal mucosa	3
endothelial cell	3
islet of Langerhans	3
bronchial epithelial cell	3
adrenal tissue	3
right lobe of liver	2
oocyte	2
secondary oocyte	2
skeletal muscle tissue of rectus abdominis	2
mucosa of sigmoid colon	2
right testis	2
olfactory bulb	2
calcaneal tendon	2
monocyte	2
cardiac muscle of right atrium	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PNPLA3	178	ubiquitous	marker	pigmented layer of retina, buccal mucosa cell, right lobe of liver
ST8SIA1	224	broad	marker	ventricular zone, ganglionic eminence, cortical plate
TM6SF2	151	broad	marker	ileal mucosa, jejunal mucosa, duodenum
ZNF101	228	ubiquitous	marker	buccal mucosa cell, secondary oocyte, oocyte
CACNA2D1	261	ubiquitous	marker	biceps brachii, skeletal muscle tissue of biceps brachii, skeletal muscle tissue of rectus abdominis
PARVB	235	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, muscle of leg
ZP4	18		marker	oocyte, secondary oocyte, pancreatic ductal cell
MACROD2	214	ubiquitous	marker	endothelial cell, buccal mucosa cell, epithelial cell of pancreas
TRIB1	280	ubiquitous	marker	mucosa of urinary bladder, mucosa of sigmoid colon, visceral pleura
GPN1	297	ubiquitous	marker	islet of Langerhans, ganglionic eminence, ventricular zone
PALLD	302	ubiquitous	marker	saphenous vein, heart right ventricle, blood vessel layer
SUGP1	262	ubiquitous	marker	lower esophagus mucosa, right testis, right hemisphere of cerebellum
TOX4	290	ubiquitous	marker	colonic epithelium, olfactory bulb, islet of Langerhans
SLC9A9	240	ubiquitous	marker	calcaneal tendon, tendon, monocyte
COL13A1	209	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, cerebellum
COMMD1	261	ubiquitous	marker	left ventricle myocardium, tibialis anterior, cardiac muscle of right atrium
PLPPR4	213	broad	yes	CA1 field of hippocampus, orbitofrontal cortex, entorhinal cortex
FAM171A1	282	ubiquitous	marker	inferior vagus X ganglion, middle temporal gyrus, subthalamic nucleus
FAM107B	260	ubiquitous	marker	corpus callosum, nasal cavity epithelium, inferior vagus X ganglion
SAMM50	292	ubiquitous	marker	endothelial cell, vastus lateralis, skeletal muscle tissue of rectus abdominis
NCAN	126	broad	marker	ventricular zone, ganglionic eminence, cortical plate
FTO	294	ubiquitous	marker	cortical plate, bronchial epithelial cell, Brodmann (1909) area 10
YIPF1	281	ubiquitous	marker	islet of Langerhans, right lobe of thyroid gland, left lobe of thyroid gland
SPATA31H1	138	tissue_specific	marker	cardiac muscle of right atrium, left ventricle myocardium, sperm
MTARC1	209	ubiquitous	marker	adipose tissue, adipose tissue of abdominal region, omental fat pad
DDX60L	229	ubiquitous	marker	monocyte, leukocyte, jejunal mucosa
DCLK1	264	ubiquitous	marker	endothelial cell, frontal pole, cortical plate
SLC46A3	254	ubiquitous	marker	ileal mucosa, adrenal tissue, jejunal mucosa
CRACR2A	210	broad	marker	parotid gland, ileal mucosa, mucosa of sigmoid colon
ZNF512	248	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 17.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOE	6,793
NGF	3,968
DCLK1	3,597
IRF4	3,450
FDFT1	3,249
SAMM50	2,977
LTBP2	2,658
GATAD2A	2,526
FTO	2,496
PALLD	2,362

Intra-cohort edges

A	B	Sources
APOE	LPL	string_interaction
FDFT1	PNPLA3	string_interaction
FDFT1	TM6SF2	string_interaction
GATAD2A	SUGP1	intact
GPN1	SPATA31H1	string_interaction
GPN1	ZNF512	string_interaction
LTBP2	ZNF101	biogrid_interaction
MTARC1	PNPLA3	string_interaction
MTARC1	TM6SF2	string_interaction
MTARC1	TRIB1	string_interaction
NCAN	PNPLA3	string_interaction
NCAN	TM6SF2	string_interaction
PNPLA3	SAMM50	string_interaction
PNPLA3	TM6SF2	string_interaction
SPATA31H1	TRIB1	string_interaction
SPATA31H1	ZNF512	string_interaction
SUGP1	TM6SF2	string_interaction

Structural data

PDB: 24 · AlphaFold-only: 21 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FDFT1	P37268	32
CACNA2D1	P54289	30
APOE	P02649	29
FTO	Q9C0B1	28
IRF4	Q15306	19
DCLK1	O15075	11
NGF	P01138	10
GC	P02774	6
TRIB1	Q96RU8	5
LPL	P06858	5
MACROD2	A1Z1Q3	4
COMMD1	Q8N668	4
PARVB	Q9HBI1	3
SUGP1	Q8IWZ8	3
MTARC1	Q5VT66	3
PALLD	Q8WX93	2
SAMM50	Q9Y512	2
PTPRU	Q92729	2
TOX4	O94842	1
CRACR2A	Q9BSW2	1
ZNF512	Q96ME7	1
GATAD2A	Q86YP4	1
FARP1	Q9Y4F1	1
HS3ST1	O14792	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TM6SF2	Q9BZW4	91.03
ST8SIA1	Q92185	88.71
SLC46A3	Q7Z3Q1	86.84
FAM107B	Q9H098	82.72
PZP	P20742	81.87
GPN1	Q9HCN4	79.83
DDX60L	Q5H9U9	79.77
YIPF1	Q9Y548	77.85
ZP4	Q12836	74.90
MAP4K5	Q9Y4K4	74.15
SLC9A9	Q8IVB4	73.46
PNPLA3	Q9NST1	71.70
ZNF101	Q8IZC7	66.56
TEX36	Q5VZQ5	60.88
NCAN	O14594	58.75
LTBP2	Q14767	58.33
FAM171A1	Q5VUB5	57.15
PLPPR4	Q7Z2D5	56.09
COL13A1	Q5TAT6	55.67
EHBP1L1	Q8N3D4	49.98
SPATA31H1	Q68DN1	34.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 171. Enrichment computed across 45 evidence-associated genes (28 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 28 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Chylomicron remodeling	2	81.6×	0.044	APOE, LPL
Defective SLC9A9 causes autism 16 (AUTS16)	1	407.9×	0.105	SLC9A9
TRKA activation by NGF	1	203.9×	0.105	NGF
NFG and proNGF binds to p75NTR	1	203.9×	0.105	NGF
PLC-gamma1 signalling	1	135.9×	0.105	NGF
Ceramide signalling	1	135.9×	0.105	NGF
Signalling to STAT3	1	135.9×	0.105	NGF
Plasma lipoprotein remodeling	2	34.0×	0.105	APOE, LPL
Metabolism of fat-soluble vitamins	2	27.2×	0.105	APOE, LPL
Visual phototransduction	2	18.5×	0.105	APOE, LPL
Retinoid metabolism and transport	2	17.7×	0.105	APOE, LPL
Plasma lipoprotein assembly, remodeling, and clearance	2	16.3×	0.105	APOE, LPL
NGF processing	1	102.0×	0.119	NGF
Axonal growth stimulation	1	102.0×	0.119	NGF
Signalling to p38 via RIT and RIN	1	81.6×	0.128	NGF
Chylomicron clearance	1	81.6×	0.128	APOE
p75NTR negatively regulates cell cycle via SC1	1	68.0×	0.128	NGF
NADE modulates death signalling	1	68.0×	0.128	NGF
Acyl chain remodeling of DAG and TAG	1	58.3×	0.128	PNPLA3
ARMS-mediated activation	1	58.3×	0.128	NGF
Reversal of alkylation damage by DNA dioxygenases	1	58.3×	0.128	FTO
Defective CHST3 causes SEDCJD	1	51.0×	0.128	NCAN
Defective CHST14 causes EDS, musculocontractural type	1	51.0×	0.128	NCAN
Defective CHSY1 causes TPBS	1	51.0×	0.128	NCAN
Regulation of cytoskeletal remodeling and cell spreading by IPP complex components	1	51.0×	0.128	PARVB
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	2	10.5×	0.128	GATAD2A, IRF4
PI3K/AKT activation	1	45.3×	0.133	NGF
Sodium/Proton exchangers	1	45.3×	0.133	SLC9A9
Chylomicron assembly	1	40.8×	0.134	APOE
HDL remodeling	1	40.8×	0.134	APOE

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 41 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
very-low-density lipoprotein particle clearance	2	164.4×	0.019	APOE, LPL
very-low-density lipoprotein particle remodeling	2	102.8×	0.027	APOE, LPL
lipid transport involved in lipid storage	1	411.0×	0.051	APOE
vacuolar transmembrane transport	1	411.0×	0.051	SLC46A3
triglyceride acyl-chain remodeling	1	411.0×	0.051	PNPLA3
farnesyl diphosphate metabolic process	1	411.0×	0.051	FDFT1
maintenance of location in cell	1	411.0×	0.051	APOE
regulation of white fat cell proliferation	1	411.0×	0.051	FTO
intermediate-density lipoprotein particle clearance	1	411.0×	0.051	APOE
positive regulation of lipid transport across blood-brain barrier	1	411.0×	0.051	APOE
positive regulation of cholesterol import	1	411.0×	0.051	COMMD1
regulation of cellular response to very-low-density lipoprotein particle stimulus	1	411.0×	0.051	APOE
triglyceride catabolic process	2	39.1×	0.051	PNPLA3, LPL
high-density lipoprotein particle remodeling	2	39.1×	0.051	APOE, LPL
negative regulation of smooth muscle cell proliferation	2	30.4×	0.051	TRIB1, APOE
cholesterol homeostasis	3	11.4×	0.051	COMMD1, APOE, LPL
positive regulation of eosinophil differentiation	1	205.5×	0.055	TRIB1
negative regulation of neutrophil differentiation	1	205.5×	0.055	TRIB1
detoxification of nitrogen compound	1	205.5×	0.055	MTARC1
triglyceride-rich lipoprotein particle clearance	1	205.5×	0.055	APOE
lipid import into cell	1	205.5×	0.055	PLPPR4
regulation of amyloid-beta clearance	1	205.5×	0.055	APOE
negative regulation of hypoxia-inducible factor-1alpha signaling pathway	1	205.5×	0.055	COMMD1
cellular response to 3,3’,5-triiodo-L-thyronine	1	205.5×	0.055	PNPLA3
regulation of amyloid fibril formation	1	205.5×	0.055	APOE
positive regulation of neuron maturation	1	137.0×	0.055	NGF
positive regulation of low-density lipoprotein particle receptor catabolic process	1	137.0×	0.055	APOE
nitrate metabolic process	1	137.0×	0.055	MTARC1
RNA repair	1	137.0×	0.055	FTO
purine nucleoside metabolic process	1	137.0×	0.055	MACROD2

Therapeutics

Drugs indicated for this disease

1 approved, 20 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Resmetirom	Approved (phase 4)
Ademetionine	Phase 3 (in late-stage trials)
Cenicriviroc	Phase 3 (in late-stage trials)
Cholecalciferol	Phase 3 (in late-stage trials)
Diosmin	Phase 3 (in late-stage trials)
Empagliflozin	Phase 3 (in late-stage trials)
Ergocalciferol	Phase 3 (in late-stage trials)
Icomidocholic Acid	Phase 3 (in late-stage trials)
Lactose, Anhydrous	Phase 3 (in late-stage trials)
Lanifibranor	Phase 3 (in late-stage trials)
Losartan	Phase 3 (in late-stage trials)
Metformin	Phase 3 (in late-stage trials)
OMEGA-3-ACID ETHYL ESTERS	Phase 3 (in late-stage trials)
Obeticholic Acid	Phase 3 (in late-stage trials)
Oltipraz	Phase 3 (in late-stage trials)
Pioglitazone	Phase 3 (in late-stage trials)
Pyridoxine	Phase 3 (in late-stage trials)
Rosuvastatin	Phase 3 (in late-stage trials)
Selonsertib	Phase 3 (in late-stage trials)
Semaglutide	Phase 3 (in late-stage trials)
Vitamin E	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acarbose, Atorvastatin, Berberine, Cilofexor, Elafibranor, Exenatide, Ezetimibe, Febuxostat, Fenofibrate, Fish Oil, Furosemide, Icosapent, Icosapent Ethyl, Insulin Human, K-877, Levocarnitine, Maltodextrin, Metreleptin, Milk Thistle, Namodenoson, Niacin, Olesoxime, Pegozafermin, Pradigastat, Resveratrol, Roflumilast, Rosiglitazone, Saroglitazar, Silybin A, Sitagliptin, Somatropin, Sorbitol, Trehalose, Trimetazidine, Urea, Ursodiol.

Drug target analysis

Approved (phase 4): 7 · Phase ≥3: 7 · Phased (≥1): 7 · Undrugged: 38

Druggability breadth: 17 of 45 evidence-associated genes (38%) 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
CACNA2D1	PREGABALIN
FTO	FLUORESCEIN
DCLK1	FEDRATINIB
FDFT1	AMIODARONE
GC	CALCITRIOL
LPL	ORLISTAT
MAP4K5	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP4K5	67	4
FTO	18	4
DCLK1	15	4
CACNA2D1	5	4
FDFT1	3	4
GC	1	4
LPL	1	4
PNPLA3	0	0
ST8SIA1	0	0
TM6SF2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PREGABALIN	4	CACNA2D1
GABAPENTIN	4	CACNA2D1
NIMODIPINE	4	CACNA2D1
TACRINE	4	CACNA2D1, FTO
FLUORESCEIN	4	FTO
DEMECLOCYCLINE	4	FTO
ROXADUSTAT	4	FTO
MECLOFENAMIC ACID	4	FTO
AMILORIDE	4	FTO
ENTACAPONE	4	FTO
FEDRATINIB	4	DCLK1
RUXOLITINIB	4	DCLK1
TOFACITINIB CITRATE	4	DCLK1
TOFACITINIB	4	DCLK1
NINTEDANIB	4	DCLK1, MAP4K5
SUNITINIB	4	DCLK1, MAP4K5
CRIZOTINIB	4	DCLK1, MAP4K5
AMIODARONE	4	FDFT1
CALCITRIOL	4	GC
ORLISTAT	4	LPL
VEMURAFENIB	4	MAP4K5
LENVATINIB	4	MAP4K5
AXITINIB	4	MAP4K5
SORAFENIB	4	MAP4K5
NERATINIB	4	MAP4K5
PALBOCICLIB	4	MAP4K5
ENTRECTINIB	4	MAP4K5
VANDETANIB	4	MAP4K5
BOSUTINIB	4	MAP4K5
GILTERITINIB	4	MAP4K5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 10.

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

Symbol	Assays	Type breakdown
MAP4K5	262	Binding:261, Functional:1
FTO	153	Binding:153
DCLK1	150	Binding:149, Functional:1
CACNA2D1	47	Binding:45, ADMET:1, Toxicity:1
FDFT1	40	Binding:40
MTARC1	25	Binding:12, ADMET:11, Unclassified:2
LPL	16	Binding:16
GC	13	Binding:13
GATAD2A	7	Binding:7
TOX4	6	Binding:6
MACROD2	4	Binding:2, Toxicity:2
NGF	4	Binding:4
IRF4	3	Binding:3
TRIB1	1	Binding:1
SAMM50	1	Binding:1
CRACR2A	1	Binding:1
PTPRU	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ST8SIA1	2.4.99.8	alpha-N-acetylneuraminate alpha-2,8-sialyltransferase
MACROD2	3.1.1.106	O-acetyl-ADP-ribose deacetylase
PLPPR4	3.1.3.4	phosphatidate phosphatase
FTO	1.14.11.53	mRNA N6-methyladenine demethylase
MTARC1	1.16.98.B1, 1.7.2.1	, nitrite reductase (NO-forming)
DCLK1	2.7.11.1	non-specific serine/threonine protein kinase
FDFT1	2.5.1.21	squalene synthase
HS3ST1	2.8.2.23	[heparan sulfate]-glucosamine 3-sulfotransferase 1
LPL	3.1.1.34	lipoprotein lipase
PTPRU	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
FTO	153
DCLK1	150
MAP4K5	262

Pharmacogenomics

Cohort genes with a PharmGKB record: 45; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

29 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)
PREGABALIN	4	CACNA2D1
GABAPENTIN	4	CACNA2D1
NIMODIPINE	4	CACNA2D1
TACRINE	4	CACNA2D1, FTO
FLUORESCEIN	4	FTO
DEMECLOCYCLINE	4	FTO
ROXADUSTAT	4	FTO
MECLOFENAMIC ACID	4	FTO
AMILORIDE	4	FTO
ENTACAPONE	4	FTO
FEDRATINIB	4	DCLK1
RUXOLITINIB	4	DCLK1
TOFACITINIB CITRATE	4	DCLK1
TOFACITINIB	4	DCLK1
NINTEDANIB	4	DCLK1, MAP4K5
SUNITINIB	4	DCLK1, MAP4K5
CRIZOTINIB	4	DCLK1, MAP4K5
AMIODARONE	4	FDFT1
ORLISTAT	4	LPL
VEMURAFENIB	4	MAP4K5
LENVATINIB	4	MAP4K5
AXITINIB	4	MAP4K5
SORAFENIB	4	MAP4K5
NERATINIB	4	MAP4K5
PALBOCICLIB	4	MAP4K5
ENTRECTINIB	4	MAP4K5
VANDETANIB	4	MAP4K5
BOSUTINIB	4	MAP4K5
GILTERITINIB	4	MAP4K5

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	7	CACNA2D1, FTO, DCLK1, FDFT1, GC, LPL, MAP4K5
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	6	MACROD2, TRIB1, PALLD, MTARC1, HS3ST1, PTPRU
D	Druggable family + AlphaFold only, no drug	6	ST8SIA1, ZP4, PLPPR4, NCAN, SLC46A3, PZP
E	Difficult family or no structure, no drug	26	PNPLA3, TM6SF2, ZNF101, PARVB, GPN1, SUGP1, TOX4, SLC9A9, COL13A1, COMMD1 (+16 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PNPLA3	0	—
ST8SIA1	0	—
TM6SF2	0	—
ZNF101	0	—
PARVB	0	—
ZP4	0	—
MACROD2	4	—
TRIB1	1	—
GPN1	0	—
PALLD	0	—
SUGP1	0	—
TOX4	6	—
SLC9A9	0	—
COL13A1	0	—
COMMD1	0	—
PLPPR4	0	—
FAM171A1	0	—
FAM107B	0	—
SAMM50	1	—
NCAN	0	—
YIPF1	0	—
SPATA31H1	0	—
MTARC1	25	—
DDX60L	0	—
SLC46A3	0	—
CRACR2A	1	—
ZNF512	0	—
GATAD2A	7	—
EHBP1L1	0	—
TEX36	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1,067.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	746
PHASE2	136
PHASE4	60
PHASE1	60
PHASE3	29
PHASE1/PHASE2	15
EARLY_PHASE1	13
PHASE2/PHASE3	8

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04639414	PHASE4	ACTIVE_NOT_RECRUITING	Combined Active Treatment in Type 2 Diabetes with NASH
NCT05147090	PHASE4	ACTIVE_NOT_RECRUITING	Effects of Empagliflozin on Fibrosis and Cirrhosis in Chronic Hepatitis B Patients
NCT05195944	PHASE4	ENROLLING_BY_INVITATION	Semaglutide vs Sitagliptin
NCT05305287	PHASE4	RECRUITING	Quantifying Hepatic Mitochondrial Fluxes in Humans
NCT06368882	PHASE4	RECRUITING	Efficacy and Safety of Antiviral Therapy With Peg-interferon for Chronic Hepatitis B Complicated With Nonalcoholic Fatty Liver Disease（OCEAN PROJECT）
NCT06374875	PHASE4	RECRUITING	Fibrosis Lessens After Metabolic Surgery
NCT06449833	PHASE4	RECRUITING	Effect of Henagliflozein on Hepatic Fat Content in Patients With T2DM and NAFLD
NCT06523530	PHASE4	RECRUITING	Effect of a GnRH Analog on Hepatic Steatosis
NCT06762223	PHASE4	NOT_YET_RECRUITING	Henagliflozin on Liver Fibrosis in Patients with MASLD and T2DM
NCT06845345	PHASE4	ENROLLING_BY_INVITATION	Effect of an Early Time Restricted Eating Mediterranean Diet Compared to Naltrexone/Bupropion on Liver Fibrosis in People With Cardiometabolic Risk Factors in a Hospital Outpatient Clinic (MEDFAST-study)
NCT06920316	PHASE4	NOT_YET_RECRUITING	Digital Diet and Exercise Intervention to Reduce Liver Fibrosis in Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD)
NCT07071636	PHASE4	NOT_YET_RECRUITING	Clinical Efficacy of Pegylated Interferon Alpha-2b Combined With Nucleos(t)Ide Analogues in the Treatment of Chronic Hepatitis B Patients
NCT07274644	PHASE4	ENROLLING_BY_INVITATION	Effects of iGlarLixi Versus iGlar on Liver Fat Content in Patients With Type 2 Diabetes Mellitus Combined With Metabolic Dysfunction-associated Steatotic Liver Disease
NCT00760513	PHASE4	COMPLETED	Treatment of Non Alcoholic Fatty Liver Disease With n-3 Fatty Acids
NCT00941642	PHASE4	UNKNOWN	Placebo Controlled Study Using Lovaza as Treatment for Non-Alcoholic Fatty Liver Disease
NCT00994682	PHASE4	COMPLETED	University of Texas H.S.C. San Antonio Pioglitazone in Non-Alcoholic Steatohepatitis Trial (UTHSCSA NASH Trial)
NCT01006889	PHASE4	COMPLETED	Adding Exenatide to Insulin Therapy for Patients With Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease
NCT01208649	PHASE4	COMPLETED	Effects of Exenatide (Byetta®) on Liver Function in Patients With Nonalcoholic Steatohepatitis (NASH)
NCT01355575	PHASE4	TERMINATED	Rifaximin in Fatty Liver Disease
NCT01956825	PHASE4	UNKNOWN	The Effect Of Dual Treatment With L-Carnitine And Magnesium On Fatty Liver
NCT02051842	PHASE4	UNKNOWN	Effect of Metadoxine on Oxidative Stress in Non-alcoholic Hepatic Steatosis
NCT02147925	PHASE4	COMPLETED	Efficacy Study of Liraglutide vs.Sitagliptin vs. Glargine on Liver Fat in T2DM Subjects
NCT02213224	PHASE4	UNKNOWN	Perindopril and Telmisartan for the Treatment of Nonalcoholic Fatty Liver Disease
NCT02263677	PHASE4	WITHDRAWN	Evaluation of the DPP-4 Inhibitor Sitagliptin in the Treatment of Non-Alcoholic Fatty Liver Disease Using MRI
NCT02285205	PHASE4	COMPLETED	A 24 Week, Multicenter, Prospective, Open-labeled, Single-arm, Exploratory Phase 4 Clinical Trial to Evaluate the Safety and Efficacy of Lobeglitazone in Decreasing Intrahepatic Fat Contents in Type 2 Diabetes With NAFLD
NCT02303730	PHASE4	COMPLETED	Exenatide Compared With Insulin Glargine to Change Liver Fat Content in Type 2 Diabetes
NCT02329405	PHASE4	COMPLETED	The Effects of PXR Activation on Hepatic Fat Content
NCT02500147	PHASE4	TERMINATED	Metformin for Ectopic Fat Deposition and Metabolic Markers in Polycystic Ovary Syndrome (PCOS)
NCT02637973	PHASE4	COMPLETED	Effects of Empagliflozin on Liver Fat Content, Energy Metabolism and Body Composition in Patients With Type 2 Diabetes
NCT02649465	PHASE4	COMPLETED	SGLT2 Inhibitor Versus Sulfonylurea on Type 2 Diabetes With NAFLD
NCT02964715	PHASE4	UNKNOWN	The Effect of Empagliflozin on NAFLD in Asian Patients With Type 2 Diabetes
NCT02973295	PHASE4	WITHDRAWN	Silymarin in NAFLD
NCT03068065	PHASE4	COMPLETED	Antidiabetic Effects on Intrahepatic Fat
NCT03222206	PHASE4	COMPLETED	The Comparison of Effect Between Salsalate and Placebo in Osteoarthritis With Nonalcoholic Fatty Liver Disease
NCT03434613	PHASE4	COMPLETED	Phase IV Study to Evaluate the Effects of Statin Monotherapy or Statin / Ezetimibe Combination Therapy on Hepatic Steatosis in Patients With Hyperlipidemia and Nonalcoholic Fatty Liver Disease
NCT03444233	PHASE4	COMPLETED	Impact of Short-term Fructose-enriched Diet on Serum Metabolome by Normal- and Over-weighed Women.
NCT03646292	PHASE4	COMPLETED	Antidiabetic Drugs for Steatotic Liver Disease
NCT03796975	PHASE4	COMPLETED	Efficacy of Pioglitazone Hydrochloride and Metformin Hydrochloride Tablets on the Patients With Newly Diagnosed Type 2 Diabetes Mellitus Combined With Non-alcoholic Fatty Liver Disease
NCT03849729	PHASE4	COMPLETED	Effectiveness and Tolerability of Phentermine in Patients Under Bariatric Surgery
NCT03910361	PHASE4	COMPLETED	Efficacy and Safety of Evoglitin in Patients With Type 2 Diabetes and Non-alcoholic Fatty Liver Diseases

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EMPAGLIFLOZIN	4	8
EXENATIDE	4	4
OMEGA-3-ACID ETHYL ESTERS	4	4
PIOGLITAZONE	4	4
PERINDOPRIL	4	3
PHENTERMINE	4	3
SEMAGLUTIDE	4	3
TOFOGLIFLOZIN ANHYDROUS	4	3
LIRAGLUTIDE	4	2
METFORMIN	4	2
ROSUVASTATIN	4	2
AMLODIPINE	4	1
CALCITRIOL	4	1
EVOGLIPTIN	4	1
GLICLAZIDE	4	1
GLIMEPIRIDE	4	1
PANTOPRAZOLE	4	1
PYRIDOXINE	4	1
RIFAMPIN	4	1
RIFAXIMIN	4	1
SITAGLIPTIN	4	1
TELMISARTAN	4	1
WATER	4	1
SILIBININ	3	5
SILYBIN A	3	5
LOBEGLITAZONE	3	1
SALSALATE	2	1
CHEMBL443232	0	8
CHEMBL5177502	0	8
SILYBIN B	0	5