Monogenic diabetes

Summary

Monogenic diabetes (MONDO:0015967) is a disease caused by variants in HNF1A and NKX2-2, with 47 cohort genes and 9 clinical trials. The dominant Reactome pathway is Regulation of gene expression in beta cells (9 cohort genes). Top therapeutic interventions include sitagliptin, avexitide, and dorzagliatin.

At a glance

• Causal genes: HNF1A (GenCC Definitive), NKX2-2 (GenCC Strong)
• Cohort genes: 47
• ClinVar variants: 1,577
• Clinical trials: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	monogenic diabetes
Mondo ID	MONDO:0015967
EFO	EFO:1001511
Orphanet	183625
NCIT	C129739
UMLS	C3888631
MedGen	1392102
Is cancer (heuristic)	no

Also known as: monogenic diabetes · rare genetic diabetes mellitus

Data availability: 1,577 ClinVar variants · 1,103 ClinGen variant curations · 5 GenCC gene-disease records · 14 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 › pancreas disorder › endocrine pancreas disorder › diabetes mellitus › monogenic diabetes

Related subtypes (7): type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes, maternally-inherited diabetes and deafness, diabetic ketoacidosis, type 5 diabetes mellitus, cystic fibrosis-related diabetes

Subtypes (2): neonatal diabetes mellitus, maturity-onset diabetes of the young

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:

165 pathogenic, 156 uncertain significance, 153 likely pathogenic, 49 conflicting classifications of pathogenicity, 32 benign/likely benign, 31 benign, 8 likely benign, 5 pathogenic/likely pathogenic, 1 pathogenic/likely pathogenic/likely risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
1315998	NM_000545.8(HNF1A):c.1781G>T (p.Ser594Ile)	C12orf43	Pathogenic	reviewed by expert panel
1098819	NM_000162.5(GCK):c.1139A>C (p.His380Pro)	GCK	Pathogenic	reviewed by expert panel
1172896	NM_000162.5(GCK):c.660C>A (p.Cys220Ter)	GCK	Pathogenic	reviewed by expert panel
1191898	NM_000162.5(GCK):c.617C>T (p.Thr206Met)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1195505	NM_000162.5(GCK):c.564_567dup (p.Lys190fs)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
1200795	NM_000162.5(GCK):c.679+1G>A	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
1256304	NM_000162.5(GCK):c.1145G>A (p.Cys382Tyr)	GCK	Pathogenic	reviewed by expert panel
129140	NM_000162.5(GCK):c.1112G>T (p.Cys371Phe)	GCK	Pathogenic	reviewed by expert panel
129142	NM_000162.5(GCK):c.449T>A (p.Phe150Tyr)	GCK	Pathogenic	reviewed by expert panel
129143	NM_000162.5(GCK):c.523G>A (p.Gly175Arg)	GCK	Pathogenic	reviewed by expert panel
129144	NM_000162.5(GCK):c.544G>A (p.Val182Met)	GCK	Pathogenic	reviewed by expert panel
129145	NM_000162.5(GCK):c.616A>C (p.Thr206Pro)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320655	NM_000162.5(GCK):c.1322C>G (p.Ser441Trp)	GCK	Pathogenic	reviewed by expert panel
1343440	NM_000162.5(GCK):c.179C>T (p.Thr60Ile)	GCK	Pathogenic	reviewed by expert panel
1365679	NM_000162.5(GCK):c.1340_1368del (p.Arg447fs)	GCK	Pathogenic	reviewed by expert panel
1405403	NM_000162.5(GCK):c.1019G>A (p.Ser340Asn)	GCK	Pathogenic	reviewed by expert panel
1452320	NM_000162.5(GCK):c.140dup (p.Glu48fs)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
1464253	NM_000162.5(GCK):c.671T>C (p.Met224Thr)	GCK	Pathogenic	reviewed by expert panel
1472875	NM_000162.5(GCK):c.1228G>C (p.Gly410Arg)	GCK	Pathogenic	reviewed by expert panel
1490297	NM_000162.5(GCK):c.503C>T (p.Thr168Ile)	GCK	Pathogenic	reviewed by expert panel
16134	NM_000162.5(GCK):c.683C>T (p.Thr228Met)	GCK	Pathogenic	reviewed by expert panel
16135	NM_000162.5(GCK):c.781G>A (p.Gly261Arg)	GCK	Pathogenic	reviewed by expert panel
16141	NM_000162.5(GCK):c.629T>A (p.Met210Lys)	GCK	Pathogenic	reviewed by expert panel
16145	NM_000162.5(GCK):c.1132G>A (p.Ala378Thr)	GCK	Pathogenic	reviewed by expert panel
1679545	NM_000162.5(GCK):c.771G>A (p.Trp257Ter)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679547	NM_000162.5(GCK):c.1079C>A (p.Ser360Ter)	GCK	Pathogenic	reviewed by expert panel
1679549	NM_000162.5(GCK):c.475A>G (p.Ile159Val)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700674	NM_000162.5(GCK):c.1247A>G (p.His416Arg)	GCK	Pathogenic	reviewed by expert panel
1700683	NM_000162.5(GCK):c.864-1G>C	GCK	Pathogenic	reviewed by expert panel
1741488	NM_000162.5(GCK):c.455T>C (p.Phe152Ser)	GCK	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 27 · Orphanet: 118 · 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
HNF1A	Definitive	Autosomal dominant	monogenic diabetes	11
NEUROD1	Strong	Autosomal recessive	permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome	10
NKX2-2	Strong	Autosomal recessive	neonatal diabetes mellitus	2
PAX4	Supportive	Autosomal dominant	maturity-onset diabetes of the young	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HNF1A	Orphanet:319303	Chromophobe renal cell carcinoma
HNF1A	Orphanet:324575	Hyperinsulinism due to HNF1A deficiency
HNF1A	Orphanet:404511	Clear cell papillary renal cell carcinoma
HNF1A	Orphanet:552	MODY
NEUROD1	Orphanet:552	MODY
PAX4	Orphanet:552	MODY
BLK	Orphanet:536	Systemic lupus erythematosus
BLK	Orphanet:552	MODY
SIM1	Orphanet:171829	6q16 microdeletion syndrome
SIM1	Orphanet:369873	Obesity due to SIM1 deficiency
SIM1	Orphanet:398079	SIM1-related Prader-Willi-like syndrome
SLC19A2	Orphanet:49827	Thiamine-responsive megaloblastic anemia syndrome
SLC2A2	Orphanet:2088	Fanconi-Bickel syndrome
HNF1B	Orphanet:1309	Medullary sponge kidney
HNF1B	Orphanet:1331	Familial prostate cancer
HNF1B	Orphanet:2578	Mayer-Rokitansky-Küster-Hauser syndrome type 2
HNF1B	Orphanet:261265	17q12 microdeletion syndrome
HNF1B	Orphanet:93111	HNF1B-related autosomal dominant tubulointerstitial kidney disease
HNF1B	Orphanet:93172	Renal dysplasia, unilateral
HNF1B	Orphanet:93173	Renal dysplasia, bilateral
HNF1B	Orphanet:97363	Unilateral multicystic dysplastic kidney
HNF1B	Orphanet:97364	Bilateral multicystic dysplastic kidney
KLF11	Orphanet:552	MODY
WFS1	Orphanet:3463	Wolfram syndrome
WFS1	Orphanet:411590	Wolfram-like syndrome
WFS1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
WFS1	Orphanet:98991	Early-onset nuclear cataract
CAV1	Orphanet:220393	Diffuse cutaneous systemic sclerosis
CAV1	Orphanet:220402	Limited cutaneous systemic sclerosis
CAV1	Orphanet:275777	Heritable pulmonary arterial hypertension
CAV1	Orphanet:696206	Congenital generalized lipodystrophy type 3
BSCL2	Orphanet:100998	Autosomal dominant spastic paraplegia type 17
BSCL2	Orphanet:139536	Distal hereditary motor neuropathy type 5
BSCL2	Orphanet:363400	Progressive encephalopathy-severe neurodegeneration-lipodystrophy syndrome
BSCL2	Orphanet:696289	Congenital generalized lipodystrophy type 2
CEL	Orphanet:552	MODY
ZFP57	Orphanet:99886	Transient neonatal diabetes mellitus
PDHX	Orphanet:255182	Pyruvate dehydrogenase E3-binding protein deficiency
RFX6	Orphanet:293864	Hypoplastic pancreas-intestinal atresia-hypoplastic gallbladder syndrome
PTF1A	Orphanet:2805	Partial pancreatic agenesis
PTF1A	Orphanet:65288	Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome
APPL1	Orphanet:552	MODY
GLIS3	Orphanet:79118	Neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidneys syndrome
AGPAT2	Orphanet:696189	Congenital generalized lipodystrophy type 1
EIF2AK3	Orphanet:1667	Wolcott-Rallison syndrome
GATA6	Orphanet:2140	Congenital diaphragmatic hernia
GATA6	Orphanet:2255	Pancreatic hypoplasia-diabetes-congenital heart disease syndrome
GATA6	Orphanet:3303	Tetralogy of Fallot
GATA6	Orphanet:334	Hereditary atrial fibrillation
GATA6	Orphanet:665044	Common arterial trunk with aortic dominance

Cohort genes → proteins

47 cohort genes, 44 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	47

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HNF1A	HGNC:11621	ENSG00000135100	P20823	Hepatocyte nuclear factor 1-alpha	gencc,clinvar
NEUROD1	HGNC:7762	ENSG00000162992	Q13562	Neurogenic differentiation factor 1	gencc,clinvar
PAX4	HGNC:8618	ENSG00000106331	O43316	Paired box protein Pax-4	gencc,clinvar
NKX2-2	HGNC:7835	ENSG00000125820	O95096	Homeobox protein Nkx-2.2	gencc
BLK	HGNC:1057	ENSG00000136573	P51451	Tyrosine-protein kinase Blk	clinvar
SIM1	HGNC:10882	ENSG00000112246	P81133	Single-minded homolog 1	clinvar
SLC19A2	HGNC:10938	ENSG00000117479	O60779	Thiamine transporter 1	clinvar
SLC2A2	HGNC:11006	ENSG00000163581	P11168	Solute carrier family 2, facilitated glucose transporter member 2	clinvar
HNF1B	HGNC:11630	ENSG00000275410	P35680	Hepatocyte nuclear factor 1-beta	clinvar
KLF11	HGNC:11811	ENSG00000172059	O14901	Krueppel-like factor 11	clinvar
WFS1	HGNC:12762	ENSG00000109501	O76024	Wolframin	clinvar
CAV1	HGNC:1527	ENSG00000105974	Q03135	Caveolin-1	clinvar
BSCL2	HGNC:15832	ENSG00000168000	Q96G97	Seipin	clinvar
CEL	HGNC:1848	ENSG00000170835	P19835	Bile salt-activated lipase	clinvar
ZFP57	HGNC:18791	ENSG00000204644	Q9NU63	Zinc finger protein 57 homolog	clinvar
PDHX	HGNC:21350	ENSG00000110435	O00330	Pyruvate dehydrogenase protein X component, mitochondrial	clinvar
RFX6	HGNC:21478	ENSG00000185002	Q8HWS3	DNA-binding protein RFX6	clinvar
PTF1A	HGNC:23734	ENSG00000168267	Q7RTS3	Pancreas transcription factor 1 subunit alpha	clinvar
APPL1	HGNC:24035	ENSG00000157500	Q9UKG1	DCC-interacting protein 13-alpha	clinvar
C12orf43	HGNC:25719	ENSG00000157895	Q96C57	Protein CUSTOS	clinvar
GLIS3-AS1	HGNC:28260	ENSG00000237009		GLIS3 antisense RNA 1	clinvar
GLIS3	HGNC:28510	ENSG00000107249	Q8NEA6	Zinc finger protein GLIS3	clinvar
AGPAT2	HGNC:325	ENSG00000169692	O15120	1-acyl-sn-glycerol-3-phosphate acyltransferase beta	clinvar
EIF2AK3	HGNC:3255	ENSG00000172071	Q9NZJ5	Eukaryotic translation initiation factor 2-alpha kinase 3	clinvar
GATA6	HGNC:4174	ENSG00000141448	Q92908	Transcription factor GATA-6	clinvar
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	clinvar
ALMS1	HGNC:428	ENSG00000116127	Q8TCU4	Centrosome-associated protein ALMS1	clinvar
GLUD1	HGNC:4335	ENSG00000148672	P00367	Glutamate dehydrogenase 1, mitochondrial	clinvar
GNG3	HGNC:4405	ENSG00000162188	P63215	Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3	clinvar
HADH	HGNC:4799	ENSG00000138796	Q16836	Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial	clinvar
HNRNPUL2-BSCL2	HGNC:49189	ENSG00000234857		HNRNPUL2-BSCL2 readthrough (NMD candidate)	clinvar
HNF4A	HGNC:5024	ENSG00000101076	P41235	Hepatocyte nuclear factor 4-alpha	clinvar
BLK-AS1	HGNC:58190	ENSG00000269954		BLK antisense RNA 1	clinvar
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	clinvar
INS	HGNC:6081	ENSG00000254647	P01308	Insulin	clinvar
INSR	HGNC:6091	ENSG00000171105	P06213	Insulin receptor	clinvar
FOXP3	HGNC:6106	ENSG00000049768	Q9BZS1	Forkhead box protein P3	clinvar
PDX1	HGNC:6107	ENSG00000139515	P52945	Pancreas/duodenum homeobox protein 1	clinvar
KCNJ11	HGNC:6257	ENSG00000187486	Q14654	ATP-sensitive inward rectifier potassium channel 11	clinvar
LEP	HGNC:6553	ENSG00000174697	P41159	Leptin	clinvar
LEPR	HGNC:6554	ENSG00000116678	P48357	Leptin receptor	clinvar
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	clinvar
MC4R	HGNC:6932	ENSG00000166603	P32245	Melanocortin receptor 4	clinvar
PLIN1	HGNC:9076	ENSG00000166819	O60240	Perilipin-1	clinvar
PPARG	HGNC:9236	ENSG00000132170	P37231	Peroxisome proliferator-activated receptor gamma	clinvar
PPP1R3A	HGNC:9291	ENSG00000154415	Q16821	Protein phosphatase 1 regulatory subunit 3A	clinvar
CAVIN1	HGNC:9688	ENSG00000177469	Q6NZI2	Caveolae-associated protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HNF1A	Hepatocyte nuclear factor 1-alpha	Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver.
NEUROD1	Neurogenic differentiation factor 1	Acts as a transcriptional activator: mediates transcriptional activation by binding to E box-containing promoter consensus core sequences 5’-CANNTG-3'.
PAX4	Paired box protein Pax-4	Plays an important role in the differentiation and development of pancreatic islet beta cells.
NKX2-2	Homeobox protein Nkx-2.2	Transcriptional activator involved in the development of insulin-producting beta cells in the endocrine pancreas.
BLK	Tyrosine-protein kinase Blk	Non-receptor tyrosine kinase involved in B-lymphocyte development, differentiation and signaling.
SIM1	Single-minded homolog 1	Transcriptional factor that may have pleiotropic effects during embryogenesis and in the adult.
SLC19A2	Thiamine transporter 1	High-affinity transporter for the intake of thiamine.
SLC2A2	Solute carrier family 2, facilitated glucose transporter member 2	Facilitative hexose transporter that mediates the transport of glucose, fructose and galactose.
HNF1B	Hepatocyte nuclear factor 1-beta	Transcription factor that binds to the inverted palindrome 5’-GTTAATNATTAAC-3'.
KLF11	Krueppel-like factor 11	Transcription factor.
WFS1	Wolframin	Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store.
CAV1	Caveolin-1	May act as a scaffolding protein within caveolar membranes.
BSCL2	Seipin	Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis.
CEL	Bile salt-activated lipase	Catalyzes the hydrolysis of a wide range of substrates including cholesteryl esters, phospholipids, lysophospholipids, di- and tri-acylglycerols, and fatty acid esters of hydroxy fatty acids (FAHFAs).
ZFP57	Zinc finger protein 57 homolog	Transcription regulator required to maintain maternal and paternal gene imprinting, a process by which gene expression is restricted in a parent of origin-specific manner by epigenetic modification of genomic DNA and chromatin, including D…
PDHX	Pyruvate dehydrogenase protein X component, mitochondrial	Required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes.
RFX6	DNA-binding protein RFX6	Transcription factor required to direct islet cell differentiation during endocrine pancreas development.
PTF1A	Pancreas transcription factor 1 subunit alpha	Transcription factor implicated in the cell fate determination in various organs.
APPL1	DCC-interacting protein 13-alpha	Multifunctional adapter protein that binds to various membrane receptors, nuclear factors and signaling proteins to regulate many processes, such as cell proliferation, immune response, endosomal trafficking and cell metabolism.
C12orf43	Protein CUSTOS	Plays a role in the regulation of Wnt signaling pathway during early development.
GLIS3	Zinc finger protein GLIS3	Acts both as a repressor and an activator of transcription.
AGPAT2	1-acyl-sn-glycerol-3-phosphate acyltransferase beta	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.
EIF2AK3	Eukaryotic translation initiation factor 2-alpha kinase 3	Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress, such as unfolded protein response (UPR).
GATA6	Transcription factor GATA-6	Transcriptional activator.
GCK	Hexokinase-4	Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively).
ALMS1	Centrosome-associated protein ALMS1	Involved in PCM1-dependent intracellular transport.
GLUD1	Glutamate dehydrogenase 1, mitochondrial	Mitochondrial glutamate dehydrogenase that catalyzes the conversion of L-glutamate into alpha-ketoglutarate.
GNG3	Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3	Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems.
HADH	Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial	Mitochondrial fatty acid beta-oxidation enzyme that catalyzes the third step of the beta-oxidation cycle for medium and short-chain 3-hydroxy fatty acyl-CoAs (C4 to C10).
HNF4A	Hepatocyte nuclear factor 4-alpha	Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes.
ABCC8	ATP-binding cassette sub-family C member 8	Regulator subunit of pancreatic ATP-sensitive potassium channel (KATP), playing a major role in the regulation of insulin release.
INS	Insulin	Insulin decreases blood glucose concentration.
INSR	Insulin receptor	Receptor tyrosine kinase which mediates the pleiotropic actions of insulin.
FOXP3	Forkhead box protein P3	Transcriptional regulator which is crucial for the development and inhibitory function of regulatory T-cells (Treg).
PDX1	Pancreas/duodenum homeobox protein 1	Activates insulin, somatostatin, glucokinase, islet amyloid polypeptide and glucose transporter type 2 gene transcription.
KCNJ11	ATP-sensitive inward rectifier potassium channel 11	Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells.
LEP	Leptin	Key player in the regulation of energy balance and body weight control.
LEPR	Leptin receptor	Receptor for hormone LEP/leptin.
LMNA	Prelamin-A/C	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.
MC4R	Melanocortin receptor 4	G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha- and beta-MSH) and corticotropin/ACTH, which are peptide products of the POMC precursor.
PLIN1	Perilipin-1	Modulator of adipocyte lipid metabolism.
PPARG	Peroxisome proliferator-activated receptor gamma	Ligand-activated transcription factor that forms obligate heterodimers with the retinoic acid receptor and acts as a key regulator of biological processes, such as adipocyte differentiation, lipid metabolism, glucose homeostasis and beta-o…
PPP1R3A	Protein phosphatase 1 regulatory subunit 3A	Seems to act as a glycogen-targeting subunit for PP1.
CAVIN1	Caveolae-associated protein 1	Plays an important role in caveolae formation and organization.

Protein-family classification

Druggable: 17 · Difficult: 14 · Unknown: 16 · Druggable fraction: 0.36

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
Transcription factor	13	2.3×	0.031
Nuclear receptor	2	16.4×	0.033
Transporter	3	5.0×	0.075
Kinase	4	2.4×	0.222
Ion channel	1	2.4×	0.591
Enzyme (other)	5	1.3×	0.591
Antibody/Immunoglobulin	1	0.6×	0.999
Other/Unknown	16	0.6×	0.999
GPCR	1	0.5×	0.999
Scaffold/PPI	1	0.4×	0.999

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HNF1A	Transcription factor	no		HD, HNF1b_C, HNF1a_C
NEUROD1	Transcription factor	no		bHLH_dom, TF_bHLH_NeuroD, NeuroD_DUF
PAX4	Transcription factor	no		HD, Paired_dom, Homeodomain-like_sf
NKX2-2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
BLK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
SIM1	Transcription factor	no		PAS, PAC, SIM_C
SLC19A2	Transporter	yes		Folate_carrier, ThTr-1, MFS_trans_sf
SLC2A2	Transporter	yes		Glc_transpt_2, Sugar/inositol_transpt, MFS_sugar_transport-like
HNF1B	Transcription factor	no		HD, HNF1b_C, HNF-1_N
KLF11	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
WFS1	Other/Unknown	no		TPR-like_helical_dom_sf, Wolframin, Wolframin_fam
CAV1	Other/Unknown	no		Caveolin, Caveolin_CS
BSCL2	Other/Unknown	no		Seipin
CEL	Enzyme (other)	yes	3.1.1.13	CarbesteraseB, Carboxylesterase_B_CS, Carboxylesterase_B_AS
ZFP57	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
PDHX	Enzyme (other)	yes	1.2.1.104	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS
RFX6	Other/Unknown	no		DNA-bd_RFX, WH-like_DNA-bd_sf, WH_DNA-bd_sf
PTF1A	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, E-box_TF_Regulators
APPL1	Scaffold/PPI	no		PH_domain, BAR_dom, PTB/PI_dom
C12orf43	Other/Unknown	no		CUSTOS
GLIS3-AS1	Other/Unknown	no
GLIS3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
AGPAT2	Enzyme (other)	yes	2.3.1.51	Plipid/glycerol_acylTrfase, AGP_acyltrans
EIF2AK3	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
GATA6	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N
ALMS1	Other/Unknown	no		ALMS_motif, ALMS_repeat
GLUD1	Enzyme (other)	yes	1.4.1.3	Glu/Leu/Phe/Val/Trp_DH, Glu/Leu/Phe/Val/Trp_DH_C, Glu/Leu/Phe/Val/Trp_DH_dimer
GNG3	Other/Unknown	no		G-protein_gamma, G-protein_gamma-like_dom, GGL_sf
HADH	Enzyme (other)	yes	1.1.1.35	3HC_DH_C, 3-OHacyl-CoA_DH_NAD-bd, 3-OHacyl-CoA_DH_CS
HNRNPUL2-BSCL2	Other/Unknown	no
HNF4A	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
BLK-AS1	Other/Unknown	no
ABCC8	Transporter	yes		ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd
INS	Other/Unknown	no		Insulin, Insulin-like, Ins/IGF/rlx
INSR	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
FOXP3	Transcription factor	no		Fork_head_dom, Znf_C2H2_type, TF_fork_head_CS_2
PDX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
KCNJ11	Ion channel	yes		K_chnl_inward-rec_Kir6.2, K_chnl_inward-rec_Kir_cyto, Ig_E-set
LEP	Other/Unknown	no		Leptin, 4_helix_cytokine-like_core
LEPR	Antibody/Immunoglobulin	yes		Hematopoietin_rcpt_Gp130_CS, Hempt_rcpt_S_F1_CS, FN3_dom
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf
MC4R	GPCR	yes		Mcort_rcpt_4, GPCR_Rhodpsn, Melcrt_ACTH_rcpt
PLIN1	Other/Unknown	no		Perilipin, PLIN1
PPARG	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
PPP1R3A	Other/Unknown	no		CBM21_dom, CBM21_dom_sf, PP1_regulatory_subunit_3
CAVIN1	Other/Unknown	no		Cavin_fam

Expression context

Cohort genes with no expression data: 0.

37 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)	47
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	8
male germ line stem cell (sensu Vertebrata) in testis	6
right lobe of liver	5
body of pancreas	5
buccal mucosa cell	5
primordial germ cell in gonad	4
mucosa of transverse colon	3
biceps brachii	3
skeletal muscle tissue of biceps brachii	3
oocyte	3
secondary oocyte	3
pancreas	3
skeletal muscle tissue of rectus abdominis	3
liver	2
cerebellar vermis	2
lymph node	2
spleen	2
gastrocnemius	2
jejunal mucosa	2
parietal pleura	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HNF1A	81	tissue_specific	yes	right lobe of liver, mucosa of transverse colon, liver
NEUROD1	115	broad	marker	paraflocculus, cerebellar vermis, cerebellum
PAX4	32	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, cerebellar vermis, Brodmann (1909) area 10
NKX2-2	100	tissue_specific	marker	inferior vagus X ganglion, subthalamic nucleus, medulla oblongata
BLK	145	tissue_specific	marker	spleen, male germ line stem cell (sensu Vertebrata) in testis, lymph node
SIM1	76	broad	yes	renal medulla, skeletal muscle tissue of biceps brachii, biceps brachii
SLC19A2	282	ubiquitous	marker	secondary oocyte, oocyte, gastrocnemius
SLC2A2	80	tissue_specific	marker	right lobe of liver, liver, jejunal mucosa
HNF1B	74	broad	marker	metanephros cortex, adult mammalian kidney, kidney
KLF11	260	ubiquitous	marker	secondary oocyte, oocyte, primordial germ cell in gonad
WFS1	280	ubiquitous	marker	right ovary, left ovary, body of uterus
CAV1	287	ubiquitous	marker	parietal pleura, lower lobe of lung, pleura
BSCL2	149	ubiquitous	marker	superior frontal gyrus, primary visual cortex, pituitary gland
CEL	186	tissue_specific	marker	body of pancreas, type B pancreatic cell, pancreas
ZFP57	112	tissue_specific	yes	primordial germ cell in gonad, C1 segment of cervical spinal cord, male germ line stem cell (sensu Vertebrata) in testis
PDHX	296	ubiquitous	marker	biceps brachii, heart right ventricle, skeletal muscle tissue of biceps brachii
RFX6	55	tissue_specific	marker	islet of Langerhans, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
PTF1A	96	tissue_specific	marker	body of pancreas, pancreas, islet of Langerhans
APPL1	284	ubiquitous	marker	calcaneal tendon, biceps brachii, germinal epithelium of ovary
C12orf43	266	ubiquitous	marker	secondary oocyte, oocyte, prefrontal cortex
GLIS3-AS1	127	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium
GLIS3	213	ubiquitous	marker	buccal mucosa cell, epithelial cell of pancreas, pancreatic ductal cell
AGPAT2	257	ubiquitous	marker	mucosa of transverse colon, ileal mucosa, right lobe of liver
EIF2AK3	286	ubiquitous	marker	body of pancreas, mucosa of paranasal sinus, calcaneal tendon
GATA6	204	ubiquitous	marker	germinal epithelium of ovary, parietal pleura, jejunal mucosa
GCK	155	tissue_specific	marker	pituitary gland, adenohypophysis, islet of Langerhans
ALMS1	275	ubiquitous	marker	buccal mucosa cell, periodontal ligament, cardia of stomach
GLUD1	291	ubiquitous	marker	right lobe of liver, nucleus accumbens, superior vestibular nucleus
GNG3	193	broad	marker	right frontal lobe, right hemisphere of cerebellum, cerebellar hemisphere
HADH	296	ubiquitous	marker	islet of Langerhans, heart right ventricle, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 101.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
INS	11,670
PPARG	7,747
LMNA	7,173
CAV1	6,673
HNF4A	4,731
LEP	4,556
INSR	4,446
FOXP3	4,306
EIF2AK3	4,018
PDHX	3,542

Intra-cohort edges

A	B	Sources
ABCC8	GCK	string_interaction
ABCC8	GLIS3	string_interaction
ABCC8	HNF1A	string_interaction
ABCC8	INS	string_interaction
ABCC8	KCNJ11	biogrid_interaction, intact, string_interaction
ABCC8	KLF11	string_interaction
ABCC8	PAX4	string_interaction
ABCC8	PDX1	string_interaction
ABCC8	SLC19A2	string_interaction
ABCC8	SLC2A2	string_interaction
ABCC8	WFS1	string_interaction
ABCC8	ZFP57	string_interaction
AGPAT2	BSCL2	string_interaction
AGPAT2	CAV1	string_interaction
AGPAT2	CAVIN1	string_interaction
AGPAT2	LMNA	string_interaction
ALMS1	INS	string_interaction
APPL1	KLF11	string_interaction
BLK	HNF1A	string_interaction
BLK	KLF11	string_interaction
BLK	NEUROD1	string_interaction
BLK	PAX4	string_interaction
BSCL2	CAV1	string_interaction
BSCL2	CAVIN1	string_interaction
BSCL2	LMNA	string_interaction
BSCL2	PLIN1	biogrid_interaction
CAV1	CAVIN1	intact, string_interaction
CAV1	PPARG	biogrid_interaction
GCK	HNF1A	string_interaction
GCK	HNF1B	string_interaction
GCK	INS	string_interaction
GCK	KCNJ11	string_interaction
GCK	KLF11	string_interaction
GCK	PDX1	string_interaction
GCK	RFX6	string_interaction
GCK	SLC2A2	string_interaction
GLIS3	KCNJ11	string_interaction
GLIS3	NEUROD1	string_interaction
GLIS3	PTF1A	string_interaction
GLIS3	RFX6	string_interaction
GLIS3	SLC19A2	string_interaction
HNF1A	HNF1B	biogrid_interaction, intact, string_interaction
HNF1A	HNF4A	string_interaction
HNF1A	INS	string_interaction
HNF1A	KCNJ11	string_interaction
HNF1A	KLF11	string_interaction
HNF1A	NEUROD1	string_interaction
HNF1A	PAX4	string_interaction
HNF1A	PDX1	string_interaction
HNF1A	PTF1A	string_interaction

Structural data

PDB: 26 · AlphaFold-only: 18 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INS	P01308	382
PPARG	P37231	380
INSR	P06213	88
GCK	P35557	35
LMNA	P02545	28
EIF2AK3	Q9NZJ5	15
HADH	Q16836	12
MC4R	P32245	12
LEP	P41159	10
KCNJ11	Q14654	9
LEPR	P48357	9
APPL1	Q9UKG1	8
HNF4A	P41235	8
ABCC8	Q09428	8
CEL	P19835	7
GLUD1	P00367	7
HNF1A	P20823	6
PDHX	O00330	5
HNF1B	P35680	3
CAVIN1	Q6NZI2	3
SLC19A2	O60779	2
FOXP3	Q9BZS1	2
PDX1	P52945	2
CAV1	Q03135	1
BSCL2	Q96G97	1
PPP1R3A	Q16821	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AGPAT2	O15120	91.66
SLC2A2	P11168	86.56
GNG3	P63215	85.44
BLK	P51451	81.89
WFS1	O76024	73.85
PAX4	O43316	70.35
NKX2-2	O95096	64.62
C12orf43	Q96C57	64.08
NEUROD1	Q13562	62.39
PTF1A	Q7RTS3	61.81
SIM1	P81133	60.70
RFX6	Q8HWS3	59.23
ZFP57	Q9NU63	56.76
PLIN1	O60240	54.52
GATA6	Q92908	53.48
GLIS3	Q8NEA6	49.95
KLF11	O14901	49.73
ALMS1	Q8TCU4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 233. Enrichment computed across 47 evidence-associated genes (37 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 37 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of gene expression in beta cells	9	126.3×	2e-15	HNF1A, NEUROD1, SLC2A2, RFX6, GCK, HNF4A, INS, PDX1 (+1 more)
Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells	3	185.2×	4e-05	NEUROD1, PAX4, NKX2-2
Regulation of gene expression in early pancreatic precursor cells	3	115.7×	1e-04	HNF1B, PTF1A, PDX1
Developmental Lineage of Pancreatic Acinar Cells	4	32.5×	4e-04	HNF1B, CEL, PTF1A, PDX1
Defective ABCC8 can cause hypo- and hyper-glycemias	2	308.6×	5e-04	ABCC8, KCNJ11
Regulation of insulin secretion	4	23.7×	9e-04	SLC2A2, ABCC8, INS, KCNJ11
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	3	48.7×	1e-03	HNF1B, GATA6, PDX1
ATP sensitive Potassium channels	2	154.3×	0.002	ABCC8, KCNJ11
IRS activation	2	123.5×	0.003	INS, INSR
Signaling by Leptin	2	56.1×	0.012	LEP, LEPR
Signal attenuation	2	56.1×	0.012	INS, INSR
Signaling by Insulin receptor	2	47.5×	0.014	INS, INSR
Nephron development	2	47.5×	0.014	HNF1B, HNF4A
Inwardly rectifying K+ channels	2	38.6×	0.017	ABCC8, KCNJ11
Regulation of beta-cell development	2	38.6×	0.017	NEUROD1, INS
Integration of energy metabolism	3	14.2×	0.017	ABCC8, INS, KCNJ11
Insulin receptor signalling cascade	2	36.3×	0.018	INS, INSR
Synthesis, secretion, and deacylation of Ghrelin	2	32.5×	0.022	INS, LEP
Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)	1	308.6×	0.033	GCK
Defective SLC2A2 causes Fanconi-Bickel syndrome (FBS)	1	308.6×	0.033	SLC2A2
Triglyceride catabolism	2	25.7×	0.033	CAV1, PLIN1
ABC transporter disorders	2	23.7×	0.033	ABCC8, KCNJ11
Transcriptional regulation of white adipocyte differentiation	3	10.5×	0.033	LEP, PLIN1, PPARG
Insulin receptor recycling	2	20.6×	0.039	INS, INSR
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	2	20.6×	0.039	GCK, INS
FOXO-mediated transcription	2	18.2×	0.048	CAV1, INS
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	154.3×	0.056	KCNJ11
Negative regulation of the PI3K/AKT network	2	15.1×	0.064	INS, INSR
Peptide hormone metabolism	2	14.7×	0.065	INS, LEP
Breakdown of the nuclear lamina	1	102.9×	0.072	LMNA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 44 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glucose homeostasis	11	32.7×	1e-11	HNF1A, NEUROD1, WFS1, RFX6, GCK, HNF4A, INS, INSR (+3 more)
regulation of insulin secretion	8	71.3×	5e-11	NEUROD1, RFX6, GCK, HADH, HNF4A, ABCC8, KCNJ11, LEP
insulin secretion	6	58.9×	2e-07	HNF1A, NEUROD1, HNF1B, PDX1, LEP, MC4R
type B pancreatic cell differentiation	4	191.5×	5e-07	PAX4, RFX6, GATA6, PDX1
endocrine pancreas development	4	85.1×	2e-05	NEUROD1, HNF1B, RFX6, EIF2AK3
positive regulation of cold-induced thermogenesis	6	22.3×	3e-05	CAV1, BSCL2, ALMS1, HADH, LEP, LEPR
pancreas development	4	61.3×	5e-05	HNF1A, HNF1B, WFS1, PTF1A
glucose metabolic process	5	29.0×	5e-05	GCK, INS, PDX1, KCNJ11, LEP
response to glucose	5	29.0×	5e-05	NEUROD1, HNF1B, GCK, HNF4A, NKX2-2
positive regulation of insulin secretion	5	29.0×	5e-05	NEUROD1, BLK, GCK, GLUD1, PDX1
negative regulation of type B pancreatic cell apoptotic process	3	143.6×	6e-05	NEUROD1, WFS1, PDX1
exocrine pancreas development	3	114.9×	1e-04	PTF1A, INSR, PDX1
positive regulation of insulin secretion involved in cellular response to glucose stimulus	4	34.0×	3e-04	SLC2A2, RFX6, ABCC8, PDX1
pancreatic A cell fate commitment	2	383.0×	3e-04	NEUROD1, NKX2-2
pancreatic PP cell fate commitment	2	383.0×	3e-04	NEUROD1, NKX2-2
positive regulation of glycogen biosynthetic process	3	67.6×	4e-04	GCK, INS, INSR
regulation of transcription by RNA polymerase II	14	3.7×	4e-04	HNF1A, PAX4, SIM1, HNF1B, KLF11, ZFP57, RFX6, PTF1A (+6 more)
sexual reproduction	2	255.3×	7e-04	LEP, LEPR
negative regulation of gluconeogenesis	3	54.7×	7e-04	GCK, INS, LEPR
positive regulation of DNA-templated transcription	9	5.7×	7e-04	HNF1A, NEUROD1, HNF1B, RFX6, GATA6, HNF4A, INSR, FOXP3 (+1 more)
transcription by RNA polymerase II	6	9.6×	0.001	NEUROD1, PTF1A, GLIS3, HNF4A, FOXP3, PDX1
positive regulation of developmental growth	2	191.5×	0.001	INSR, LEP
response to insulin	4	21.0×	0.001	HADH, ABCC8, LEP, MC4R
response to xenobiotic stimulus	6	9.4×	0.001	AGPAT2, GATA6, HADH, ABCC8, PDX1, KCNJ11
positive regulation of respiratory burst	2	153.2×	0.002	INS, INSR
negative regulation of insulin secretion	3	33.8×	0.002	HADH, ABCC8, KCNJ11
regulation of bone remodeling	2	127.7×	0.003	LEP, LEPR
pancreatic A cell differentiation	2	109.4×	0.003	RFX6, GATA6
leptin-mediated signaling pathway	2	109.4×	0.003	LEP, LEPR
bone growth	2	109.4×	0.003	LEP, LEPR

Therapeutics

Drug target analysis

Approved (phase 4): 8 · Phase ≥3: 9 · Phased (≥1): 12 · Undrugged: 35

Druggability breadth: 23 of 47 evidence-associated genes (49%) 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
BLK	AFATINIB
ABCC8	REPAGLINIDE
INSR	FEDRATINIB
KCNJ11	PINACIDIL ANHYDROUS
LMNA	BEPRIDIL
MC4R	BEPRIDIL
PLIN1	NIFEDIPINE
PPARG	METHYLENE BLUE ANHYDROUS

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
PPARG	83	4
BLK	62	4
MC4R	57	4
INSR	36	4
KCNJ11	7	4
PLIN1	7	4
ABCC8	6	4
GCK	5	2
SLC19A2	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AFATINIB	4	BLK
FEDRATINIB	4	BLK, INSR
AXITINIB	4	BLK
SORAFENIB	4	BLK, INSR
NERATINIB	4	BLK, INSR
IBRUTINIB	4	BLK
ENTRECTINIB	4	BLK, INSR
BELUMOSUDIL	4	BLK
AFATINIB DIMALEATE	4	BLK
VANDETANIB	4	BLK
NILOTINIB	4	BLK
BOSUTINIB	4	BLK, MC4R
BRIGATINIB	4	BLK, INSR
ACALABRUTINIB	4	BLK
ZANUBRUTINIB	4	BLK
TIRABRUTINIB	4	BLK
RITLECITINIB	4	BLK
PAZOPANIB	4	BLK
NINTEDANIB	4	BLK, INSR, PPARG
SUNITINIB	4	BLK, INSR, LMNA
DASATINIB	4	BLK
ERLOTINIB	4	BLK, LMNA
QUIZARTINIB	4	BLK
CRIZOTINIB	4	BLK, INSR, MC4R
MIDOSTAURIN	4	BLK
GEFITINIB	4	BLK
IMATINIB	4	BLK, LMNA
REPAGLINIDE	4	ABCC8, LMNA
DIAZOXIDE	4	ABCC8, KCNJ11, LMNA
GLYBURIDE	4	ABCC8, KCNJ11, LMNA, PPARG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 9.

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

Symbol	Assays	Type breakdown
PPARG	2,033	Binding:1593, Functional:380, ADMET:56, Toxicity:3, Unclassified:1
INSR	954	Binding:900, Functional:49, ADMET:4, Toxicity:1
MC4R	663	Binding:364, Functional:293, ADMET:6
BLK	483	Binding:477, ADMET:4, Functional:2
GCK	228	Binding:226, ADMET:1, Functional:1
EIF2AK3	153	Binding:151, Functional:2
HNF4A	106	Binding:97, Functional:9
KCNJ11	102	Functional:59, Binding:43
ABCC8	84	Functional:52, Binding:32
SLC2A2	12	Binding:11, Functional:1
LMNA	12	Binding:9, Functional:3
INS	8	Binding:7, ADMET:1
CEL	7	Binding:7
AGPAT2	6	Binding:6
CAV1	5	Binding:5
FOXP3	4	Binding:4
LEPR	3	Binding:3
SLC19A2	2	Functional:1, Binding:1
PLIN1	2	Functional:1, Binding:1
HNF1A	1	Binding:1
WFS1	1	Binding:1
PDHX	1	Binding:1
HADH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BLK	2.7.10.2	non-specific protein-tyrosine kinase
CEL	3.1.1.13	sterol esterase
PDHX	1.2.1.104	pyruvate dehydrogenase system
AGPAT2	2.3.1.51	1-acylglycerol-3-phosphate O-acyltransferase
EIF2AK3	2.7.11.1	non-specific serine/threonine protein kinase
GCK	2.7.1.1	hexokinase
GLUD1	1.4.1.3	glutamate dehydrogenase [NAD(P)+]
HADH	1.1.1.35	3-hydroxyacyl-CoA dehydrogenase
INSR	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BLK	483
EIF2AK3	153
GCK	228
HNF4A	106
INSR	954
KCNJ11	102
MC4R	663
PPARG	2,033

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

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)
AFATINIB	4	BLK
FEDRATINIB	4	BLK, INSR
AXITINIB	4	BLK
SORAFENIB	4	BLK, INSR
NERATINIB	4	BLK, INSR
IBRUTINIB	4	BLK
ENTRECTINIB	4	BLK, INSR
BELUMOSUDIL	4	BLK
AFATINIB DIMALEATE	4	BLK
VANDETANIB	4	BLK
NILOTINIB	4	BLK
BOSUTINIB	4	BLK, MC4R
BRIGATINIB	4	BLK, INSR
ACALABRUTINIB	4	BLK
ZANUBRUTINIB	4	BLK
TIRABRUTINIB	4	BLK
RITLECITINIB	4	BLK
PAZOPANIB	4	BLK
NINTEDANIB	4	BLK, INSR, PPARG
SUNITINIB	4	BLK, INSR, LMNA
DASATINIB	4	BLK
ERLOTINIB	4	BLK, LMNA
QUIZARTINIB	4	BLK
CRIZOTINIB	4	BLK, INSR, MC4R
MIDOSTAURIN	4	BLK
GEFITINIB	4	BLK
IMATINIB	4	BLK, LMNA
REPAGLINIDE	4	ABCC8, LMNA
DIAZOXIDE	4	ABCC8, KCNJ11, LMNA
GLYBURIDE	4	ABCC8, KCNJ11, LMNA, PPARG

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	8	BLK, ABCC8, INSR, KCNJ11, LMNA, MC4R, PLIN1, PPARG
B	Phased (≥1) drug, not yet approved	4	SLC19A2, SLC2A2, EIF2AK3, GCK
C	Druggable family + PDB, no drug	6	CEL, PDHX, GLUD1, HADH, HNF4A, LEPR
D	Druggable family + AlphaFold only, no drug	1	AGPAT2
E	Difficult family or no structure, no drug	28	HNF1A, NEUROD1, PAX4, NKX2-2, SIM1, HNF1B, KLF11, WFS1, CAV1, BSCL2 (+18 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HNF1A	1	GCK
NEUROD1	0	SLC2A2
SIM1	0	MC4R
KLF11	0	BLK
WFS1	1	ABCC8
BSCL2	0	LMNA
INS	8	INSR
PDX1	0	GCK
HNF4A	106	—
PAX4	0	—
NKX2-2	0	—
HNF1B	0	—
CAV1	5	—
CEL	7	—
ZFP57	0	—
PDHX	1	—
RFX6	0	—
PTF1A	0	—
APPL1	0	—
C12orf43	0	—
GLIS3-AS1	0	—
GLIS3	0	—
AGPAT2	6	—
GATA6	0	—
ALMS1	0	—
GLUD1	0	—
GNG3	0	—
HADH	1	—
HNRNPUL2-BSCL2	0	—
BLK-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE2/PHASE3	1
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04409795	PHASE2/PHASE3	COMPLETED	Oral Hypoglycemic Therapy for Monogenic Variant Carriers of the Joslin Medalist Study
NCT06976658	PHASE2	RECRUITING	Glucokinase Activator in Monogenic Diabetes
NCT01795144	PHASE1	COMPLETED	Incretin Regulation of Insulin Secretion in Monogenic Diabetes
NCT03988764	Not specified	RECRUITING	Monogenic Diabetes Misdiagnosed as Type 1
NCT05586594	Not specified	NOT_YET_RECRUITING	Identifying Maturity-onset Diabetes of the Young in Emirati Patients
NCT06478121	Not specified	RECRUITING	Understanding Beta Cell Disorders Through the Study of Rare Genotypes (ENDURE)
NCT06746610	Not specified	RECRUITING	Screening and Molecular Diagnosis-based Individualized Precision Management of Monogenic Diabetes
NCT07492004	Not specified	RECRUITING	China Monogenic Diabetes Registry
NCT07564518	Not specified	NOT_YET_RECRUITING	Application of FreeStyle Libre 2 for Evaluating Glycemic Variability Characteristics in Patients With Extreme Glucose Metabolism Phenotypes

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SITAGLIPTIN	4	1
AVEXITIDE	3	1
DORZAGLIATIN	3	1
GLP-1	2	1
GLUCAGON-LIKE PEPTIDE 1	1	1