Maturity-onset diabetes of the young type 1

Summary

Maturity-onset diabetes of the young type 1 (MONDO:0007452) is a disease caused by HNF4A (GenCC Definitive), with 3 cohort genes and 2 clinical trials. The dominant Reactome pathway is Regulation of gene expression in beta cells (3 cohort genes).

At a glance

• Causal gene: HNF4A (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 278
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	maturity-onset diabetes of the young type 1
Mondo ID	MONDO:0007452
MeSH	C565101
OMIM	125850
DOID	DOID:0111099
NCIT	C129744
SNOMED CT	609562003
UMLS	C1852093
MedGen	377589
GARD	0003418
Is cancer (heuristic)	no

Also known as: diabetes mellitus MODY type 1 · hepatocyte nuclear Factor 4-Alpha associated monogenic diabetes · HNF4A-associated monogenic diabetes · maturity onset diabetes of the Young, type 1 · maturity-onset diabetes of the young, type 1 · mild juvenile diabetes mellitus · MODY HNF4A related · MODY, type I · MODY1 · type 1 maturity-onset diabetes of the young

Data availability: 278 ClinVar variants · 5 GenCC gene-disease records · 68 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 1

Related subtypes (14): maturity-onset diabetes of the young type 2, 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

278 retrieved; paginated sample, class counts are floors:

83 conflicting classifications of pathogenicity, 76 uncertain significance, 34 likely pathogenic, 31 benign/likely benign, 26 pathogenic, 14 benign, 9 likely benign, 4 uncertain significance/uncertain risk allele, 1 likely pathogenic/likely risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
1299750	NM_175914.5(HNF4A):c.-181G>A	HNF4A	Pathogenic	reviewed by expert panel
1299753	NM_175914.5(HNF4A):c.48C>A (p.Tyr16Ter)	HNF4A	Pathogenic	criteria provided, single submitter
1299754	NM_175914.5(HNF4A):c.48C>G (p.Tyr16Ter)	HNF4A	Pathogenic	reviewed by expert panel
1457657	NM_175914.5(HNF4A):c.352C>T (p.Arg118Ter)	HNF4A	Pathogenic	reviewed by expert panel
156152	NM_175914.5(HNF4A):c.187C>T (p.Arg63Trp)	HNF4A	Pathogenic	reviewed by expert panel
1700659	NM_175914.5(HNF4A):c.537G>A (p.Trp179Ter)	HNF4A	Pathogenic	criteria provided, multiple submitters, no conflicts
1700662	NM_175914.5(HNF4A):c.1064-1G>T	HNF4A	Pathogenic	criteria provided, single submitter
1700669	NM_175914.5(HNF4A):c.1086dup (p.Ala363fs)	HNF4A	Pathogenic	criteria provided, single submitter
3238969	NM_175914.5(HNF4A):c.583-1G>A	HNF4A	Pathogenic	reviewed by expert panel
36364	NM_175914.5(HNF4A):c.925C>T (p.Arg309Cys)	HNF4A	Pathogenic	reviewed by expert panel
36365	NM_175914.5(HNF4A):c.931C>T (p.Arg311Cys)	HNF4A	Pathogenic	reviewed by expert panel
393110	NM_175914.5(HNF4A):c.224+2T>C	HNF4A	Pathogenic	reviewed by expert panel
427034	NM_175914.5(HNF4A):c.335G>A (p.Arg112Gln)	HNF4A	Pathogenic	reviewed by expert panel
435436	NM_175914.5(HNF4A):c.200G>A (p.Arg67Gln)	HNF4A	Pathogenic	reviewed by expert panel
435438	NM_175914.5(HNF4A):c.740T>C (p.Leu247Pro)	HNF4A	Pathogenic	reviewed by expert panel
435439	NM_175914.5(HNF4A):c.944TGC[6] (p.Leu319dup)	HNF4A	Pathogenic	reviewed by expert panel
4531754	NM_175914.5(HNF4A):c.745del (p.Glu249fs)	HNF4A	Pathogenic	criteria provided, single submitter
4818860	NM_175914.5(HNF4A):c.792T>A (p.Tyr264Ter)	HNF4A	Pathogenic	criteria provided, single submitter
586023	NM_175914.5(HNF4A):c.932G>A (p.Arg311His)	HNF4A	Pathogenic	reviewed by expert panel
617653	NM_175914.5(HNF4A):c.265C>T (p.Gln89Ter)	HNF4A	Pathogenic	criteria provided, multiple submitters, no conflicts
804918	NM_175914.5(HNF4A):c.869G>A (p.Arg290His)	HNF4A	Pathogenic	reviewed by expert panel
9210	NM_175914.5(HNF4A):c.763C>T (p.Gln255Ter)	HNF4A	Pathogenic	reviewed by expert panel
9211	NM_175914.5(HNF4A):c.421C>T (p.Arg141Ter)	HNF4A	Pathogenic	reviewed by expert panel
9214	HNF4A, 1-BP DEL, PHE75T	HNF4A	Pathogenic	no assertion criteria provided
9215	NM_175914.5(HNF4A):c.583-2del	HNF4A	Pathogenic	reviewed by expert panel
994902	NM_175914.5(HNF4A):c.322G>A (p.Val108Ile)	HNF4A	Pathogenic	reviewed by expert panel
585916	NM_000162.5(GCK):c.1364T>A (p.Val455Glu)	GCK	Likely pathogenic	reviewed by expert panel
1186689	NM_175914.5(HNF4A):c.691C>T (p.Arg231Trp)	HNF4A	Likely pathogenic	reviewed by expert panel
1299751	NM_175914.5(HNF4A):c.3G>A (p.Met1Ile)	HNF4A	Likely pathogenic	reviewed by expert panel
1299752	NM_175914.5(HNF4A):c.1del (p.Met1fs)	HNF4A	Likely pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 10 · 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
HNF4A	Definitive	Autosomal dominant	maturity-onset diabetes of the young type 1	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HNF4A	Orphanet:263455	Congenital hyperinsulinism due to HNF4A deficiency
HNF4A	Orphanet:544628	Atypical Fanconi syndrome-neonatal hyperinsulinism syndrome
HNF4A	Orphanet:552	MODY
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
GCK	Orphanet:552	MODY
GCK	Orphanet:79299	Congenital glucokinase-related hyperinsulinism
GCK	Orphanet:99885	Isolated permanent neonatal diabetes mellitus

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HNF4A	HGNC:5024	ENSG00000101076	P41235	Hepatocyte nuclear factor 4-alpha	gencc,clinvar
HNF1A	HGNC:11621	ENSG00000135100	P20823	Hepatocyte nuclear factor 1-alpha	clinvar
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.
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).

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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	128.6×	0.023
Kinase	1	9.2×	0.157
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HNF4A	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
HNF1A	Transcription factor	no		HD, HNF1b_C, HNF1a_C
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	2
right lobe of liver	2
duodenum	1
liver	1
adenohypophysis	1
islet of Langerhans	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HNF4A	110	tissue_specific	marker	right lobe of liver, mucosa of transverse colon, duodenum
HNF1A	81	tissue_specific	yes	right lobe of liver, mucosa of transverse colon, liver
GCK	155	tissue_specific	marker	pituitary gland, adenohypophysis, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNF4A	4,731
HNF1A	2,491
GCK	2,245

Intra-cohort edges

A	B	Sources
GCK	HNF1A	string_interaction
HNF1A	HNF4A	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCK	P35557	35
HNF4A	P41235	8
HNF1A	P20823	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (3 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 3 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	3	519.1×	5e-08	HNF4A, HNF1A, GCK
Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)	1	3806.7×	0.001	GCK
Nephron development	1	292.8×	0.009	HNF4A
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	126.9×	0.011	GCK
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	119.0×	0.011	GCK
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	119.0×	0.011	GCK
Glycolysis	1	95.2×	0.012	GCK
Nuclear Receptor transcription pathway	1	66.8×	0.015	HNF4A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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	3	130.6×	2e-05	HNF4A, HNF1A, GCK
regulation of insulin secretion	2	261.3×	4e-04	HNF4A, GCK
response to glucose	2	170.2×	7e-04	HNF4A, GCK
regulation of growth hormone receptor signaling pathway	1	5617.3×	0.002	HNF4A
obsolete regulation of ornithine metabolic process	1	5617.3×	0.002	HNF4A
renal D-glucose absorption	1	1872.4×	0.004	HNF1A
regulation of gastrulation	1	936.2×	0.007	HNF4A
glucose catabolic process	1	802.5×	0.007	GCK
regulation of potassium ion transport	1	624.1×	0.008	GCK
NADP+ metabolic process	1	510.7×	0.008	GCK
cellular response to leptin stimulus	1	510.7×	0.008	GCK
glucose 6-phosphate metabolic process	1	432.1×	0.009	GCK
regulation of glycolytic process	1	401.2×	0.009	GCK
positive regulation of glycogen biosynthetic process	1	330.4×	0.009	GCK
phospholipid homeostasis	1	330.4×	0.009	HNF4A
sex differentiation	1	280.9×	0.009	HNF4A
obsolete D-glucose import	1	280.9×	0.009	HNF1A
negative regulation of gluconeogenesis	1	267.5×	0.009	GCK
calcium ion import	1	267.5×	0.009	GCK
positive regulation of DNA-templated transcription	2	18.6×	0.009	HNF4A, HNF1A
signal transduction involved in regulation of gene expression	1	234.1×	0.009	HNF4A
canonical glycolysis	1	234.1×	0.009	GCK
pancreas development	1	224.7×	0.009	HNF1A
intracellular glucose homeostasis	1	193.7×	0.010	GCK
triglyceride homeostasis	1	160.5×	0.012	HNF4A
regulation of lipid metabolic process	1	144.0×	0.012	HNF4A
insulin secretion	1	144.0×	0.012	HNF1A
glycolytic process	1	127.7×	0.013	GCK
lipid homeostasis	1	112.3×	0.014	HNF4A
positive regulation of transcription initiation by RNA polymerase II	1	90.6×	0.016	HNF1A

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
HNF4A	0	0
HNF1A	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): 1.

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
HNF1A	1	Binding:1

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
HNF4A	106
GCK	228

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	0
E	Difficult family or no structure, no drug	1	HNF1A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HNF1A	1	GCK
HNF4A	106	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04239586	PHASE4	UNKNOWN	Switching From Insulin to Sulfonylurea in Diabetes Associated With Variants in MODY Genes
NCT03246828	Not specified	COMPLETED	Glucagon in MODY (Maturity Onset Diabetes of the Young)