Maturity-onset diabetes of the young type 2

Summary

Maturity-onset diabetes of the young type 2 (MONDO:0007453) is a disease caused by GCK (GenCC Definitive), with 4 cohort genes and 1 clinical trial.

At a glance

• Causal gene: GCK (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 420
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	maturity-onset diabetes of the young type 2
Mondo ID	MONDO:0007453
OMIM	125851
DOID	DOID:0111100
NCIT	C129741
SNOMED CT	237604008
UMLS	C0342277
MedGen	87434
GARD	0010657
Is cancer (heuristic)	no

Also known as: diabetes mellitus MODY type 2 · GCK maturity-onset diabetes of the young (disease) · GCK-associated diabetes mellitus · glucokinase-associated diabetes mellitus · maturity onset diabetes of the Young, type 2 · maturity-onset diabetes of the young (disease) caused by mutation in GCK · maturity-onset diabetes of the young, type 2 · MODY 2 monogenic diabetes type 2 · MODY, type II · MODY2 · type 2 maturity-onset diabetes of the young

Data availability: 420 ClinVar variants · 12 ClinGen variant curations · 4 GenCC gene-disease records · 5 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › pancreas disorder › endocrine pancreas disorder › diabetes mellitus › monogenic diabetes › maturity-onset diabetes of the young › maturity-onset diabetes of the young type 2

Related subtypes (14): maturity-onset diabetes of the young type 1, renal cysts and diabetes syndrome, maturity-onset diabetes of the young type 3, maturity-onset diabetes of the young type 4, maturity-onset diabetes of the young type 6, maturity-onset diabetes of the young type 8, maturity-onset diabetes of the young type 7, maturity-onset diabetes of the young type 9, maturity-onset diabetes of the young type 10, maturity-onset diabetes of the young type 11, Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young, maturity-onset diabetes of the young type 13, maturity-onset diabetes of the young type 14, maturity-onset diabetes of the young, type 12

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

420 retrieved; paginated sample, class counts are floors:

102 pathogenic, 92 likely pathogenic, 74 conflicting classifications of pathogenicity, 68 uncertain significance, 30 pathogenic/likely pathogenic, 24 benign/likely benign, 9 likely benign, 8 benign, 7 uncertain significance/uncertain risk allele, 4 likely pathogenic/likely risk allele, 1 uncertain risk allele, 1 pathogenic/likely pathogenic/likely risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
129144	NM_000162.5(GCK):c.544G>A (p.Val182Met)	GCK	Pathogenic	reviewed by expert panel
1365679	NM_000162.5(GCK):c.1340_1368del (p.Arg447fs)	GCK	Pathogenic	reviewed by expert panel
1464253	NM_000162.5(GCK):c.671T>C (p.Met224Thr)	GCK	Pathogenic	reviewed by expert panel
16132	NM_000162.5(GCK):c.835G>T (p.Glu279Ter)	GCK	Pathogenic	no assertion criteria provided
16133	NM_000162.5(GCK):c.556C>T (p.Arg186Ter)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
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
16136	NM_000162.5(GCK):c.895G>C (p.Gly299Arg)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16139	NM_000162.5(GCK):c.793G>T (p.Glu265Ter)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
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
1678597	NM_000162.5(GCK):c.751A>G (p.Met251Val)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
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
1679552	NM_000162.5(GCK):c.208G>A (p.Glu70Lys)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679553	NM_000162.5(GCK):c.208+2T>C	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685845	NM_000162.5(GCK):c.501G>C (p.Trp167Cys)	GCK	Pathogenic	criteria provided, single submitter
1698944	NM_000162.5(GCK):c.641dup (p.Tyr214Ter)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700672	NM_000162.5(GCK):c.1019+2T>C	GCK	Pathogenic	criteria provided, single submitter
1700674	NM_000162.5(GCK):c.1247A>G (p.His416Arg)	GCK	Pathogenic	reviewed by expert panel
1700676	NM_000162.5(GCK):c.209-1G>A	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700677	NM_000162.5(GCK):c.296G>A (p.Trp99Ter)	GCK	Pathogenic	criteria provided, single submitter
1700678	NM_000162.5(GCK):c.351_358del (p.Thr118fs)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700680	NM_000162.5(GCK):c.484-2A>G	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
1700681	NM_000162.5(GCK):c.580-13_580-1del	GCK	Pathogenic	criteria provided, single submitter
1700683	NM_000162.5(GCK):c.864-1G>C	GCK	Pathogenic	reviewed by expert panel
1700684	NM_000162.5(GCK):c.878T>G (p.Ile293Arg)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 8 · 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
UCP2	Orphanet:276556	Hyperinsulinism due to UCP2 deficiency
CARS2	Orphanet:477774	Combined oxidative phosphorylation defect type 27
HNF4A	Orphanet:263455	Congenital hyperinsulinism due to HNF4A deficiency
HNF4A	Orphanet:544628	Atypical Fanconi syndrome-neonatal hyperinsulinism syndrome
HNF4A	Orphanet:552	MODY

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	gencc,clinvar
UCP2	HGNC:12518	ENSG00000175567	P55851	Dicarboxylate carrier SLC25A8	clinvar
CARS2	HGNC:25695	ENSG00000134905	Q9HA77	Probable cysteine–tRNA ligase, mitochondrial	clinvar
HNF4A	HGNC:5024	ENSG00000101076	P41235	Hepatocyte nuclear factor 4-alpha	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).
UCP2	Dicarboxylate carrier SLC25A8	Antiporter that exports dicarboxylate intermediates of the Krebs cycle in exchange for phosphate plus a proton across the inner membrane of mitochondria, a process driven by mitochondrial motive force with an overall impact on glycolysis,…
CARS2	Probable cysteine–tRNA ligase, mitochondrial	Mitochondrial cysteine-specific aminoacyl-tRNA synthetase that catalyzes the ATP-dependent ligation of cysteine to tRNA(Cys).
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.

Protein-family classification

Druggable: 4 · 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
Nuclear receptor	1	96.5×	0.041
Transporter	1	19.4×	0.101
Kinase	1	6.9×	0.182
Enzyme (other)	1	3.0×	0.294

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N
UCP2	Transporter	yes		MCP, MCP_transmembrane, MCP_dom_sf
CARS2	Enzyme (other)	yes	6.1.1.16	tRNAsynth_Ia_anticodon-bd, Rossmann-like_a/b/a_fold, Cys-tRNA-ligase
HNF4A	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
adenohypophysis	1
islet of Langerhans	1
pituitary gland	1
bronchial epithelial cell	1
epithelium of bronchus	1
monocyte	1
mononuclear cell	1
duodenum	1
mucosa of transverse colon	1
right lobe of liver	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
UCP2	291	ubiquitous	marker	granulocyte, bronchial epithelial cell, epithelium of bronchus
CARS2	273	ubiquitous	marker	monocyte, mononuclear cell, granulocyte
HNF4A	110	tissue_specific	marker	right lobe of liver, mucosa of transverse colon, duodenum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNF4A	4,731
CARS2	2,256
GCK	2,245
UCP2	2,154

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCK	P35557	35
HNF4A	P41235	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CARS2	Q9HA77	86.68
UCP2	P55851	62.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 4 evidence-associated genes (4 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 4 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	2	259.6×	3e-04	GCK, HNF4A
Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)	1	2855.0×	0.002	GCK
The fatty acid cycling model	1	571.0×	0.008	UCP2
Nephron development	1	219.6×	0.015	HNF4A
Mitochondrial tRNA aminoacylation	1	129.8×	0.018	CARS2
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	95.2×	0.018	GCK
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	89.2×	0.018	GCK
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	89.2×	0.018	GCK
tRNA Aminoacylation	1	71.4×	0.018	CARS2
Glycolysis	1	71.4×	0.018	GCK
Nuclear Receptor transcription pathway	1	50.1×	0.023	HNF4A
Translation	1	15.5×	0.068	CARS2
Metabolism of proteins	1	3.1×	0.286	CARS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 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	195.9×	0.001	GCK, HNF4A
glycolytic process	2	191.5×	0.001	GCK, UCP2
response to glucose	2	127.7×	0.002	GCK, HNF4A
C4-dicarboxylate transport	1	4213.0×	0.002	UCP2
regulation of growth hormone receptor signaling pathway	1	4213.0×	0.002	HNF4A
obsolete regulation of ornithine metabolic process	1	4213.0×	0.002	HNF4A
cellular response to insulin stimulus	2	85.1×	0.002	GCK, UCP2
glucose homeostasis	2	65.3×	0.003	GCK, HNF4A
cysteinyl-tRNA aminoacylation	1	2106.5×	0.003	CARS2
cellular response to lead ion	1	1404.3×	0.004	UCP2
negative regulation of calcium import into the mitochondrion	1	1404.3×	0.004	UCP2
response to superoxide	1	842.6×	0.006	UCP2
regulation of gastrulation	1	702.2×	0.007	HNF4A
glucose catabolic process	1	601.9×	0.008	GCK
regulation of potassium ion transport	1	468.1×	0.009	GCK
negative regulation of insulin secretion involved in cellular response to glucose stimulus	1	421.3×	0.009	UCP2
mitochondrial transmembrane transport	1	421.3×	0.009	UCP2
NADP+ metabolic process	1	383.0×	0.009	GCK
cellular response to leptin stimulus	1	383.0×	0.009	GCK
L-glutamine metabolic process	1	324.1×	0.009	UCP2
glucose 6-phosphate metabolic process	1	324.1×	0.009	GCK
regulation of glycolytic process	1	300.9×	0.009	GCK
response to dexamethasone	1	300.9×	0.009	UCP2
long-chain fatty acid transport	1	280.9×	0.009	UCP2
mitochondrial fission	1	263.3×	0.009	UCP2
response to fatty acid	1	263.3×	0.009	UCP2
adaptive thermogenesis	1	263.3×	0.009	UCP2
positive regulation of glycogen biosynthetic process	1	247.8×	0.009	GCK
phospholipid homeostasis	1	247.8×	0.009	HNF4A
sex differentiation	1	210.7×	0.010	HNF4A

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GCK	5	2
UCP2	0	0
CARS2	0	0
HNF4A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PIRAGLIATIN	2	GCK
NERIGLIATIN	2	GCK
PF-04991532	2	GCK
AZD-1656	2	GCK
MK-0941 FREE BASE	2	GCK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
GCK	228	Binding:226, ADMET:1, Functional:1
HNF4A	106	Binding:97, Functional:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCK	2.7.1.1	hexokinase
CARS2	6.1.1.16	cysteine-tRNA ligase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GCK	228
HNF4A	106

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

5 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)
PIRAGLIATIN	2	GCK
NERIGLIATIN	2	GCK
PF-04991532	2	GCK
AZD-1656	2	GCK
MK-0941 FREE BASE	2	GCK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	GCK
C	Druggable family + PDB, no drug	1	HNF4A
D	Druggable family + AlphaFold only, no drug	2	UCP2, CARS2
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HNF4A	106	—
UCP2	0	—
CARS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02971202	PHASE1	COMPLETED	Contribution of Hyperinsulinemia vs. Hyperglycemia to Insulin Resistance in Type 1 Diabetes and Maturity Onset Diabetes of the Young, Type 2 (MODY2)