Permanent neonatal diabetes mellitus 1

Summary

Permanent neonatal diabetes mellitus 1 (MONDO:0100165) is a disease caused by GCK (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: GCK (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 119

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	permanent neonatal diabetes mellitus 1
Mondo ID	MONDO:0100165
OMIM	606176
UMLS	C5393570
MedGen	1717586
GARD	0026070
Is cancer (heuristic)	no

Also known as: diabetes mellitus, permanent neonatal 1 · PDMI · PNDM1

Data availability: 119 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › permanent neonatal diabetes mellitus 1

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

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

119 retrieved; paginated sample, class counts are floors:

51 uncertain significance, 19 pathogenic, 14 conflicting classifications of pathogenicity, 11 benign/likely benign, 8 likely pathogenic, 7 pathogenic/likely pathogenic, 3 likely benign, 2 uncertain significance/uncertain risk allele, 2 likely risk allele, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1074406	NM_000162.5(GCK):c.359dup (p.Met121fs)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172896	NM_000162.5(GCK):c.660C>A (p.Cys220Ter)	GCK	Pathogenic	reviewed by expert panel
16134	NM_000162.5(GCK):c.683C>T (p.Thr228Met)	GCK	Pathogenic	reviewed by expert panel
16141	NM_000162.5(GCK):c.629T>A (p.Met210Lys)	GCK	Pathogenic	reviewed by expert panel
21078	NM_000162.5(GCK):c.790G>A (p.Gly264Ser)	GCK	Pathogenic	reviewed by expert panel
236014	NM_000162.5(GCK):c.1148C>T (p.Ser383Leu)	GCK	Pathogenic	reviewed by expert panel
2500039	NM_000162.5(GCK):c.232G>T (p.Asp78Tyr)	GCK	Pathogenic	reviewed by expert panel
3233994	NM_000162.5(GCK):c.1234G>A (p.Val412Met)	GCK	Pathogenic	reviewed by expert panel
3382762	NM_000162.5(GCK):c.800dup (p.Asp267fs)	GCK	Pathogenic	criteria provided, single submitter
36243	NM_000162.5(GCK):c.676G>A (p.Val226Met)	GCK	Pathogenic	reviewed by expert panel
36263	NM_000162.5(GCK):c.871A>T (p.Lys291Ter)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
393451	NM_000162.5(GCK):c.748C>T (p.Arg250Cys)	GCK	Pathogenic	reviewed by expert panel
419624	NM_000162.5(GCK):c.184G>A (p.Val62Met)	GCK	Pathogenic	reviewed by expert panel
426122	NM_000162.5(GCK):c.571C>T (p.Arg191Trp)	GCK	Pathogenic	reviewed by expert panel
429500	NM_000162.5(GCK):c.1340G>A (p.Arg447Gln)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447402	NM_000162.5(GCK):c.469G>A (p.Glu157Lys)	GCK	Pathogenic	reviewed by expert panel
447419	NM_000162.5(GCK):c.793G>A (p.Glu265Lys)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
503699	NM_000162.5(GCK):c.1155del (p.Leu386fs)	GCK	Pathogenic	reviewed by expert panel
585911	NM_000162.5(GCK):c.127C>T (p.Arg43Cys)	GCK	Pathogenic	reviewed by expert panel
585923	NM_000162.5(GCK):c.608T>C (p.Val203Ala)	GCK	Pathogenic	reviewed by expert panel
585928	NM_000162.5(GCK):c.863+1G>A	GCK	Pathogenic	reviewed by expert panel
76898	NM_000162.5(GCK):c.130G>A (p.Gly44Ser)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
804852	NM_000162.5(GCK):c.629T>C (p.Met210Thr)	GCK	Pathogenic	reviewed by expert panel
551187	NM_000525.4(KCNJ11):c.560C>T (p.Ala187Val)	KCNJ11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
557416	NM_000525.4(KCNJ11):c.100C>T (p.Arg34Cys)	KCNJ11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8683	NM_000525.4(KCNJ11):c.902G>A (p.Arg301His)	KCNJ11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16138	NM_000162.5(GCK):c.391T>C (p.Ser131Pro)	GCK	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500233	NM_000162.5(GCK):c.122_123insAGGAGATG (p.Met41fs)	GCK	Likely pathogenic	criteria provided, single submitter
2571663	NM_000162.5(GCK):c.1368del (p.Cys457fs)	GCK	Likely pathogenic	reviewed by expert panel
3594705	NM_000162.5(GCK):c.1241A>T (p.Lys414Met)	GCK	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GCK	Definitive	Autosomal dominant	maturity-onset diabetes of the young type 2	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GCK	Orphanet:552	MODY
GCK	Orphanet:79299	Congenital glucokinase-related hyperinsulinism
GCK	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
KCNJ11	Orphanet:276580	Autosomal dominant hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:276603	Diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:552	MODY
KCNJ11	Orphanet:79134	DEND syndrome
KCNJ11	Orphanet:79644	Autosomal recessive hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
KCNJ11	Orphanet:99886	Transient neonatal diabetes mellitus
KCNJ11	Orphanet:99989	Intermediate DEND syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	gencc,clinvar
KCNJ11	HGNC:6257	ENSG00000187486	Q14654	ATP-sensitive inward rectifier potassium channel 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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).
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.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Ion channel	1	55.8×	0.036
Kinase	1	13.9×	0.071

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N
KCNJ11	Ion channel	yes		K_chnl_inward-rec_Kir6.2, K_chnl_inward-rec_Kir_cyto, Ig_E-set

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
islet of Langerhans	1
pituitary gland	1
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GCK	155	tissue_specific	marker	pituitary gland, adenohypophysis, islet of Langerhans
KCNJ11	161	broad	yes	gastrocnemius, hindlimb stylopod muscle, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GCK	2,245
KCNJ11	1,715

Intra-cohort edges

A	B	Sources
GCK	KCNJ11	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCK	P35557	35
KCNJ11	Q14654	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)	1	5710.0×	0.003	GCK
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	2855.0×	0.003	KCNJ11
Defective ABCC8 can cause hypo- and hyper-glycemias	1	2855.0×	0.003	KCNJ11
ATP sensitive Potassium channels	1	1427.5×	0.004	KCNJ11
Inwardly rectifying K+ channels	1	356.9×	0.013	KCNJ11
Regulation of gene expression in beta cells	1	259.6×	0.013	GCK
ABC transporter disorders	1	219.6×	0.013	KCNJ11
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	190.3×	0.013	GCK
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	178.4×	0.013	GCK
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	178.4×	0.013	GCK
Glycolysis	1	142.8×	0.015	GCK
Regulation of insulin secretion	1	109.8×	0.017	KCNJ11
Ion homeostasis	1	102.0×	0.017	KCNJ11
Integration of energy metabolism	1	87.8×	0.019	KCNJ11
Disorders of transmembrane transporters	1	69.6×	0.021	KCNJ11
Potassium Channels	1	67.2×	0.021	KCNJ11
ABC-family protein mediated transport	1	60.7×	0.022	KCNJ11
Cardiac conduction	1	54.4×	0.023	KCNJ11
Muscle contraction	1	38.6×	0.031	KCNJ11
Neuronal System	1	22.1×	0.051	KCNJ11
Transport of small molecules	1	12.6×	0.085	KCNJ11
Disease	1	6.5×	0.154	KCNJ11
Metabolism	1	5.8×	0.165	KCNJ11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of insulin secretion	2	391.9×	2e-04	GCK, KCNJ11
glucose metabolic process	2	255.3×	3e-04	GCK, KCNJ11
response to resveratrol	1	1685.2×	0.005	KCNJ11
CAMKK-AMPK signaling cascade	1	1404.3×	0.005	KCNJ11
glucose catabolic process	1	1203.7×	0.005	GCK
ventricular cardiac muscle tissue development	1	1053.2×	0.005	KCNJ11
regulation of potassium ion transport	1	936.2×	0.005	GCK
NADP+ metabolic process	1	766.0×	0.005	GCK
cellular response to leptin stimulus	1	766.0×	0.005	GCK
glucose 6-phosphate metabolic process	1	648.1×	0.005	GCK
regulation of glycolytic process	1	601.9×	0.005	GCK
nervous system process	1	601.9×	0.005	KCNJ11
response to ATP	1	495.6×	0.005	KCNJ11
positive regulation of glycogen biosynthetic process	1	495.6×	0.005	GCK
obsolete inorganic cation transmembrane transport	1	468.1×	0.005	KCNJ11
negative regulation of gluconeogenesis	1	401.2×	0.005	GCK
calcium ion import	1	401.2×	0.005	GCK
regulation of monoatomic ion transmembrane transport	1	366.4×	0.005	KCNJ11
canonical glycolysis	1	351.1×	0.005	GCK
intracellular glucose homeostasis	1	290.6×	0.006	GCK
negative regulation of insulin secretion	1	247.8×	0.007	KCNJ11
cellular response to nutrient levels	1	234.1×	0.007	KCNJ11
determination of adult lifespan	1	216.1×	0.007	KCNJ11
glycolytic process	1	191.5×	0.008	GCK
potassium ion import across plasma membrane	1	183.2×	0.008	KCNJ11
action potential	1	179.3×	0.008	KCNJ11
response to glucose	1	127.7×	0.010	GCK
positive regulation of insulin secretion	1	127.7×	0.010	GCK
response to ischemia	1	125.8×	0.010	KCNJ11
regulation of membrane potential	1	115.4×	0.010	KCNJ11

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
KCNJ11	PINACIDIL ANHYDROUS

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNJ11	7	4
GCK	5	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PINACIDIL ANHYDROUS	4	KCNJ11
GLYBURIDE	4	KCNJ11
PROPAFENONE	4	KCNJ11
DIAZOXIDE	4	KCNJ11
PIRAGLIATIN	2	GCK
NERIGLIATIN	2	GCK
PF-04991532	2	GCK
AZD-1656	2	GCK
MK-0941 FREE BASE	2	GCK
CROMAKALIM	2	KCNJ11
CLAMIKALANT	2	KCNJ11
TIFENAZOXIDE	2	KCNJ11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GCK	228	Binding:226, ADMET:1, Functional:1
KCNJ11	102	Functional:59, Binding:43

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCK	2.7.1.1	hexokinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GCK	228
KCNJ11	102

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

12 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)
PINACIDIL ANHYDROUS	4	KCNJ11
GLYBURIDE	4	KCNJ11
PROPAFENONE	4	KCNJ11
DIAZOXIDE	4	KCNJ11
PIRAGLIATIN	2	GCK
NERIGLIATIN	2	GCK
PF-04991532	2	GCK
AZD-1656	2	GCK
MK-0941 FREE BASE	2	GCK
CROMAKALIM	2	KCNJ11
CLAMIKALANT	2	KCNJ11
TIFENAZOXIDE	2	KCNJ11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNJ11
B	Phased (≥1) drug, not yet approved	1	GCK
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.