Maturity-onset diabetes of the young type 3

Summary

Maturity-onset diabetes of the young type 3 (MONDO:0010894) is a disease caused by HNF1A (GenCC Strong), with 5 cohort genes and 4 clinical trials. The dominant Reactome pathway is Regulation of gene expression in beta cells (3 cohort genes). Top therapeutic interventions include empagliflozin.

At a glance

• Causal gene: HNF1A (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 348
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	maturity-onset diabetes of the young type 3
Mondo ID	MONDO:0010894
MeSH	C563933
OMIM	600496
DOID	DOID:0111102
NCIT	C129742
SNOMED CT	609570008
UMLS	C1838100
MedGen	324942
GARD	0010658
Is cancer (heuristic)	no

Also known as: diabetes mellitus MODY type 3 · hepatocyte nuclear Factor 1-Alpha-associated monogenic diabetes · HNF1A maturity-onset diabetes of the young (disease) · HNF1A-associated monogenic diabetes · maturity-onset diabetes of the young (disease) caused by mutation in HNF1A · maturity-onset diabetes of the young type 3 · maturity-onset diabetes of the young, type 3 · MODY hepatocyte nuclear factor-1-alpha related · MODY type 3 · MODY, type III · MODY3 · type 3 maturity-onset diabetes of the young

Data availability: 348 ClinVar variants · 3 GenCC gene-disease records · 3 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 3

Related subtypes (14): maturity-onset diabetes of the young type 1, maturity-onset diabetes of the young type 2, renal cysts and diabetes syndrome, 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

348 retrieved; paginated sample, class counts are floors:

119 uncertain significance, 53 conflicting classifications of pathogenicity, 49 pathogenic, 44 likely pathogenic, 25 benign, 23 benign/likely benign, 13 likely benign, 12 pathogenic/likely pathogenic, 9 uncertain significance/uncertain risk allele, 1 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
16135	NM_000162.5(GCK):c.781G>A (p.Gly261Arg)	GCK	Pathogenic	reviewed by expert panel
1683779	NM_000162.5(GCK):c.579G>T (p.Gly193=)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1033090	NM_000545.8(HNF1A):c.58G>A (p.Gly20Arg)	HNF1A	Pathogenic	reviewed by expert panel
129235	NM_000545.8(HNF1A):c.608G>A (p.Arg203His)	HNF1A	Pathogenic	reviewed by expert panel
1328238	NM_000545.8(HNF1A):c.863_864insC (p.Pro289fs)	HNF1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1451668	NM_000545.8(HNF1A):c.661C>T (p.Gln221Ter)	HNF1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14927	NM_000545.8(HNF1A):c.872dup (p.Gly292fs)	HNF1A	Pathogenic	reviewed by expert panel
14928	NM_000545.8(HNF1A):c.1340C>T (p.Pro447Leu)	HNF1A	Pathogenic	reviewed by expert panel
14929	NM_000545.8(HNF1A):c.876del (p.Pro293fs)	HNF1A	Pathogenic	no assertion criteria provided
14931	NM_000545.8(HNF1A):c.815G>A (p.Arg272His)	HNF1A	Pathogenic	reviewed by expert panel
14933	NG_011731.2:g.4741A>C	HNF1A	Pathogenic	reviewed by expert panel
14942	NM_000545.8(HNF1A):c.335C>T (p.Pro112Leu)	HNF1A	Pathogenic	reviewed by expert panel
14943	NM_000545.8(HNF1A):c.391C>T (p.Arg131Trp)	HNF1A	Pathogenic	reviewed by expert panel
14945	NM_000545.8(HNF1A):c.827C>A (p.Ala276Asp)	HNF1A	Pathogenic	reviewed by expert panel
14946	NM_000545.8(HNF1A):c.1333_1334del (p.Ser445fs)	HNF1A	Pathogenic	no assertion criteria provided
1693221	NM_000545.8(HNF1A):c.1556C>T (p.Pro519Leu)	HNF1A	Pathogenic	reviewed by expert panel
1700001	NM_000545.8(HNF1A):c.404del (p.Asp135fs)	HNF1A	Pathogenic	reviewed by expert panel
1700665	NM_000545.8(HNF1A):c.1456del (p.Gln486fs)	HNF1A	Pathogenic	criteria provided, single submitter
1700667	NM_000545.8(HNF1A):c.1487_1494del (p.Leu496fs)	HNF1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700668	NM_000545.8(HNF1A):c.1623+1G>T	HNF1A	Pathogenic	criteria provided, single submitter
1700670	NM_000545.8(HNF1A):c.1726C>T (p.Gln576Ter)	HNF1A	Pathogenic	criteria provided, single submitter
1700671	NM_000545.8(HNF1A):c.347C>T (p.Ala116Val)	HNF1A	Pathogenic	reviewed by expert panel
2502593	NM_000545.8(HNF1A):c.998_1013del (p.Val333fs)	HNF1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2575051	NM_000545.8(HNF1A):c.523C>T (p.Gln175Ter)	HNF1A	Pathogenic	reviewed by expert panel
3237529	NM_000545.8(HNF1A):c.1324C>T (p.Gln442Ter)	HNF1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3338324	NM_000545.8(HNF1A):c.671C>A (p.Pro224His)	HNF1A	Pathogenic	no assertion criteria provided
3574303	NM_000545.8(HNF1A):c.1456C>T (p.Gln486Ter)	HNF1A	Pathogenic	criteria provided, single submitter
36798	NM_000545.8(HNF1A):c.130del (p.Leu44fs)	HNF1A	Pathogenic	reviewed by expert panel
36814	NM_000545.8(HNF1A):c.1A>G (p.Met1Val)	HNF1A	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 18 · 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

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

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HNF1A	HGNC:11621	ENSG00000135100	P20823	Hepatocyte nuclear factor 1-alpha	gencc,clinvar
C12orf43	HGNC:25719	ENSG00000157895	Q96C57	Protein CUSTOS	clinvar
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	clinvar
HNF4A	HGNC:5024	ENSG00000101076	P41235	Hepatocyte nuclear factor 4-alpha	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)
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.
C12orf43	Protein CUSTOS	Plays a role in the regulation of Wnt signaling pathway during early development.
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).
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.
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: 3 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.6

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	77.2×	0.064
Ion channel	1	22.3×	0.110
Kinase	1	5.5×	0.280
Transcription factor	1	1.6×	0.595
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HNF1A	Transcription factor	no		HD, HNF1b_C, HNF1a_C
C12orf43	Other/Unknown	no		CUSTOS
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N
HNF4A	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
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.

3 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	2
right lobe of liver	2
liver	1
oocyte	1
prefrontal cortex	1
secondary oocyte	1
adenohypophysis	1
islet of Langerhans	1
pituitary gland	1
duodenum	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
HNF1A	81	tissue_specific	yes	right lobe of liver, mucosa of transverse colon, liver
C12orf43	266	ubiquitous	marker	secondary oocyte, oocyte, prefrontal cortex
GCK	155	tissue_specific	marker	pituitary gland, adenohypophysis, islet of Langerhans
HNF4A	110	tissue_specific	marker	right lobe of liver, mucosa of transverse colon, duodenum
KCNJ11	161	broad	yes	gastrocnemius, hindlimb stylopod muscle, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNF4A	4,731
HNF1A	2,491
GCK	2,245
KCNJ11	1,715
C12orf43	621

Intra-cohort edges

A	B	Sources
GCK	HNF1A	string_interaction
GCK	KCNJ11	string_interaction
HNF1A	HNF4A	string_interaction
HNF1A	KCNJ11	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCK	P35557	35
KCNJ11	Q14654	9
HNF4A	P41235	8
HNF1A	P20823	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C12orf43	Q96C57	64.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 5 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	3	389.3×	6e-07	HNF1A, GCK, HNF4A
Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)	1	2855.0×	0.004	GCK
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	1427.5×	0.004	KCNJ11
Defective ABCC8 can cause hypo- and hyper-glycemias	1	1427.5×	0.004	KCNJ11
ATP sensitive Potassium channels	1	713.8×	0.007	KCNJ11
Nephron development	1	219.6×	0.019	HNF4A
Inwardly rectifying K+ channels	1	178.4×	0.020	KCNJ11
ABC transporter disorders	1	109.8×	0.025	KCNJ11
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	95.2×	0.025	GCK
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	89.2×	0.025	GCK
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	89.2×	0.025	GCK
Glycolysis	1	71.4×	0.029	GCK
Regulation of insulin secretion	1	54.9×	0.033	KCNJ11
Ion homeostasis	1	51.0×	0.033	KCNJ11
Nuclear Receptor transcription pathway	1	50.1×	0.033	HNF4A
Integration of energy metabolism	1	43.9×	0.035	KCNJ11
Disorders of transmembrane transporters	1	34.8×	0.041	KCNJ11
Potassium Channels	1	33.6×	0.041	KCNJ11
ABC-family protein mediated transport	1	30.4×	0.043	KCNJ11
Cardiac conduction	1	27.2×	0.045	KCNJ11
Muscle contraction	1	19.3×	0.061	KCNJ11
Neuronal System	1	11.1×	0.099	KCNJ11
Transport of small molecules	1	6.3×	0.163	KCNJ11
Disease	1	3.3×	0.284	KCNJ11
Metabolism	1	2.9×	0.302	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 5 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	3	235.1×	1e-05	GCK, HNF4A, KCNJ11
glucose homeostasis	3	78.4×	1e-04	HNF1A, GCK, HNF4A
glucose metabolic process	2	102.1×	0.003	GCK, KCNJ11
response to glucose	2	102.1×	0.003	GCK, HNF4A
regulation of growth hormone receptor signaling pathway	1	3370.4×	0.003	HNF4A
obsolete regulation of ornithine metabolic process	1	3370.4×	0.003	HNF4A
renal D-glucose absorption	1	1123.5×	0.008	HNF1A
Spemann organizer formation	1	1123.5×	0.008	C12orf43
response to resveratrol	1	674.1×	0.011	KCNJ11
regulation of gastrulation	1	561.7×	0.011	HNF4A
CAMKK-AMPK signaling cascade	1	561.7×	0.011	KCNJ11
glucose catabolic process	1	481.5×	0.012	GCK
ventricular cardiac muscle tissue development	1	421.3×	0.012	KCNJ11
regulation of potassium ion transport	1	374.5×	0.013	GCK
NADP+ metabolic process	1	306.4×	0.014	GCK
cellular response to leptin stimulus	1	306.4×	0.014	GCK
glucose 6-phosphate metabolic process	1	259.3×	0.015	GCK
regulation of glycolytic process	1	240.7×	0.015	GCK
nervous system process	1	240.7×	0.015	KCNJ11
response to ATP	1	198.3×	0.016	KCNJ11
positive regulation of glycogen biosynthetic process	1	198.3×	0.016	GCK
phospholipid homeostasis	1	198.3×	0.016	HNF4A
obsolete inorganic cation transmembrane transport	1	187.2×	0.016	KCNJ11
sex differentiation	1	168.5×	0.016	HNF4A
obsolete D-glucose import	1	168.5×	0.016	HNF1A
negative regulation of gluconeogenesis	1	160.5×	0.016	GCK
calcium ion import	1	160.5×	0.016	GCK
regulation of monoatomic ion transmembrane transport	1	146.5×	0.016	KCNJ11
signal transduction involved in regulation of gene expression	1	140.4×	0.016	HNF4A
canonical glycolysis	1	140.4×	0.016	GCK

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 5 evidence-associated genes (80%) 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
HNF1A	0	0
C12orf43	0	0
HNF4A	0	0

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
HNF4A	106	Binding:97, Functional:9
KCNJ11	102	Functional:59, Binding:43
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
GCK	228
HNF4A	106
KCNJ11	102

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	1	HNF4A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	HNF1A, C12orf43

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)
HNF1A	1	GCK
HNF4A	106	—
C12orf43	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE4	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
NCT03081676	Not specified	COMPLETED	The Effect of GIP and GLP-1 on Insulin and Glucagon Secretion in Patients With HNF1A-diabetes Treated With or Without Sulphonylurea
NCT03246828	Not specified	COMPLETED	Glucagon in MODY (Maturity Onset Diabetes of the Young)
NCT05417646	Not specified	COMPLETED	Impact of SGLT2 on Glucosuria in HNF1A-MODY

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EMPAGLIFLOZIN	4	1