Monogenic diabetes: genes and variants

Genes linked to Monogenic diabetes

• GCK: Hexokinase-4

  It sets the glucose threshold for insulin secretion in pancreatic beta cells and controls hepatic glucose phosphorylation after meals. Heterozygous loss-of-function variants cause GCK-MODY, stronger loss can cause neonatal diabetes, and activating variants can cause hyperinsulinemic hypoglycemia.

  235 disease-causing and 67 uncertain variants in GCK are linked to Monogenic diabetes.

• HNF4A: Hepatocyte nuclear factor 4-alpha

  It coordinates transcription of genes involved in hepatic metabolism and pancreatic beta-cell function. Heterozygous pathogenic variants can cause maturity-onset diabetes of the young, often with fetal overgrowth and transient neonatal hyperinsulinemic hypoglycemia in affected families.

  50 disease-causing and 70 uncertain variants in HNF4A are linked to Monogenic diabetes.

• ABCC8: ATP-binding cassette sub-family C member 8

  It senses cellular nucleotide levels as the regulatory component of pancreatic beta-cell ATP-sensitive potassium channels and thereby couples glucose metabolism to insulin secretion. Loss-of-function variants cause congenital hyperinsulinism, whereas activating variants can cause neonatal diabetes.

  2 disease-causing and 12 uncertain variants in ABCC8 are linked to Monogenic diabetes.

• KCNJ11: ATP-sensitive inward rectifier potassium channel 11

  Together with SUR1, its ATP-sensitive potassium conductance couples pancreatic beta-cell metabolism to membrane depolarization and insulin secretion. Activating variants cause neonatal diabetes, whereas loss-of-function variants can cause congenital hyperinsulinism.

  1 disease-causing and 4 uncertain variants in KCNJ11 are linked to Monogenic diabetes.

• INS: Insulin

  After processing to insulin, it lowers blood glucose by promoting cellular glucose uptake, glycogen and lipid synthesis, and suppression of hepatic glucose production. Pathogenic variants can cause neonatal diabetes, maturity-onset diabetes of the young, or hyperproinsulinemia depending on their effect on folding and secretion.

  1 disease-causing and 1 uncertain variants in INS are linked to Monogenic diabetes.

• LEPR: Leptin receptor

  It transmits leptin signals to hypothalamic circuits that regulate appetite, body weight, endocrine axes, and energy expenditure. Biallelic loss-of-function variants cause severe early-onset obesity with intense hyperphagia and frequently hypogonadotropic hypogonadism.

  0 disease-causing and 11 uncertain variants in LEPR are linked to Monogenic diabetes.

• INSR: Insulin receptor

  Its activation by insulin coordinates glucose uptake, metabolism, growth, and gene expression through PI3K-AKT and MAPK pathways. Biallelic severe loss-of-function variants cause Donohue or Rabson-Mendenhall syndromes, while heterozygous variants can cause severe insulin resistance.

  0 disease-causing and 8 uncertain variants in INSR are linked to Monogenic diabetes.

• PDX1: Pancreas/duodenum homeobox protein 1

  It directs pancreatic development and later maintains beta-cell identity and insulin transcription. Biallelic severe loss can cause pancreatic agenesis and neonatal diabetes, while heterozygous variants can cause maturity-onset diabetes of the young.

  0 disease-causing and 9 uncertain variants in PDX1 are linked to Monogenic diabetes.

• ALMS1: Centrosome-associated protein ALMS1

  It contributes to primary-cilium function, intracellular trafficking, and metabolic homeostasis in multiple tissues. Biallelic pathogenic variants cause Alstrom syndrome, which typically combines retinal degeneration, hearing loss, obesity, insulin resistance, and cardiomyopathy.

  0 disease-causing and 7 uncertain variants in ALMS1 are linked to Monogenic diabetes.

• GATA6: Transcription factor GATA-6

  It regulates developmental programs in the pancreas, heart, gut, and other endoderm-derived tissues. Haploinsufficiency is a major cause of pancreatic agenesis and neonatal diabetes and can also produce congenital heart disease and other developmental abnormalities.

  0 disease-causing and 5 uncertain variants in GATA6 are linked to Monogenic diabetes.

• HNF1B: Hepatocyte nuclear factor 1-beta

  It controls developmental and metabolic gene programs in kidney, pancreas, liver, and genital tract. Haploinsufficiency or intragenic pathogenic variants cause a multisystem disorder often featuring renal cysts or malformations, maturity-onset diabetes of the young, hypomagnesemia, and genital abnormalities.

  0 disease-causing and 7 uncertain variants in HNF1B are linked to Monogenic diabetes.

• SLC2A2: Solute carrier family 2, facilitated glucose transporter member 2

  It enables high-capacity bidirectional glucose transport in liver, intestine, kidney, and pancreatic cells, matching transport to changing glucose concentrations. Biallelic loss-of-function variants cause Fanconi-Bickel syndrome with hepatomegaly, abnormal glucose homeostasis, and renal tubular dysfunction.

  0 disease-causing and 3 uncertain variants in SLC2A2 are linked to Monogenic diabetes.

Weakly linked (only a few uncertain records): MC4R, LMNA, FOXP3, LEP and PPARG.

Where Monogenic diabetes variants cluster

• HNF4A Nuclear receptor (positions 57–132): 14 of 50 disease-causing changes, 1.8× more than its size predicts.

Known disease-causing variants in Monogenic diabetes

Showing 60 of 289.

Uncertain variants in Monogenic diabetes that look disease-causing

Which prediction tools work for Monogenic diabetes

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• MetaLR: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 94 out of 100
• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 86 out of 100
• SIFT: 83 out of 100
• MutPred2: 82 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 79 out of 100

Same protein, different disease

• Maturity-onset diabetes of the young is also caused by GCK variants; they fall in the same places as the Monogenic diabetes variants (68 disease-causing).
• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by GCK variants; they fall in the same places as the Monogenic diabetes variants (7 disease-causing).
• Permanent neonatal diabetes mellitus is also caused by GCK variants; they fall in the same places as the Monogenic diabetes variants (4 disease-causing).
• Maturity-onset diabetes of the young is also caused by HNF4A variants; they fall partly in the same places as the Monogenic diabetes variants (9 disease-causing).
• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by ABCC8 variants; they fall mostly in different places as the Monogenic diabetes variants (31 disease-causing).
• Type 2 diabetes mellitus is also caused by ABCC8 variants; they fall mostly in different places as the Monogenic diabetes variants (27 disease-causing).
• Hereditary hyperinsulinism is also caused by ABCC8 variants; they fall mostly in different places as the Monogenic diabetes variants (22 disease-causing).
• Familial hyperinsulinism is also caused by ABCC8 variants; they fall mostly in different places as the Monogenic diabetes variants (20 disease-causing).
• Diabetes mellitus, transient neonatal, 2 is also caused by ABCC8 variants; they fall mostly in different places as the Monogenic diabetes variants (19 disease-causing).
• Neonatal diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Monogenic diabetes variants (8 disease-causing).
• Diabetes mellitus, permanent neonatal 3 is also caused by KCNJ11 variants; they fall mostly in different places as the Monogenic diabetes variants (7 disease-causing).
• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by KCNJ11 variants; they fall mostly in different places as the Monogenic diabetes variants (7 disease-causing).
• Diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Monogenic diabetes variants (6 disease-causing).
• Familial hyperinsulinism is also caused by KCNJ11 variants; they fall mostly in different places as the Monogenic diabetes variants (6 disease-causing).
• Diabetes mellitus, permanent neonatal 3 is also caused by INS variants; they fall mostly in different places as the Monogenic diabetes variants (11 disease-causing).
• Neonatal diabetes mellitus is also caused by INS variants; they fall mostly in different places as the Monogenic diabetes variants (11 disease-causing).
• Type 1 diabetes mellitus is also caused by INS variants; they fall mostly in different places as the Monogenic diabetes variants (8 disease-causing).
• Hyperproinsulinemia is also caused by INS variants; they fall mostly in different places as the Monogenic diabetes variants (6 disease-causing).
• Maturity-onset diabetes of the young is also caused by INS variants; they fall mostly in different places as the Monogenic diabetes variants (3 disease-causing).

Diseases related to Monogenic diabetes

• Type 2 diabetes mellitus, also linked to ABCC8, GCK, HNF1B, HNF4A and 6 more
• Maturity-onset diabetes of the young, also linked to ABCC8, GCK, HNF1B, HNF4A and 3 more
• Diabetes mellitus, also linked to ABCC8, HNF1B, HNF4A, INS and 3 more
• Permanent neonatal diabetes mellitus, also linked to ABCC8, GCK, INS and KCNJ11
• Hyperinsulinemic hypoglycemia, familial, 1, also linked to ABCC8, GCK and KCNJ11
• Diabetes mellitus, permanent neonatal 3, also linked to ABCC8, INS and KCNJ11
• Neonatal diabetes mellitus, also linked to ABCC8, INS and KCNJ11
• Familial hyperinsulinism, also linked to ABCC8, GCK and KCNJ11
• Renal cysts and diabetes syndrome, also linked to HNF1B and HNF4A
• Atrial septal defect, also linked to ABCC8 and GATA6
• Diabetes mellitus, transient neonatal, 2, also linked to ABCC8 and KCNJ11
• Type 1 diabetes mellitus, also linked to INS and INSR

Frequently asked questions

Which genes are linked to Monogenic diabetes?

In CATVariant, Monogenic diabetes is linked to 12 analyzed proteins: GCK (Hexokinase-4), HNF4A (Hepatocyte nuclear factor 4-alpha), ABCC8 (ATP-binding cassette sub-family C member 8), KCNJ11 (ATP-sensitive inward rectifier potassium channel 11), INS (Insulin), LEPR (Leptin receptor) and 6 more.

How many genetic variants are linked to Monogenic diabetes?

547 variants: 289 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 210 are of uncertain significance or have conflicting reports.

Which uncertain variants in Monogenic diabetes look disease-causing?

25 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example HNF4A G124D, ABCC8 R1379S, GCK S441L, GCK G318W and HNF4A D282N. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Monogenic diabetes?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 135 disease-causing and 179 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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