Type 2 diabetes mellitus: genes and variants

Genes linked to Type 2 diabetes mellitus

• 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.

  27 disease-causing and 70 uncertain variants in ABCC8 are linked to Type 2 diabetes mellitus.

• 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.

  6 disease-causing and 39 uncertain variants in KCNJ11 are linked to Type 2 diabetes mellitus.

• 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.

  4 disease-causing and 49 uncertain variants in HNF1B are linked to Type 2 diabetes mellitus.

• 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.

  2 disease-causing and 17 uncertain variants in GCK are linked to Type 2 diabetes mellitus.

• AKT2: RAC-beta serine/threonine-protein kinase

  Downstream of insulin and PI3K signaling, it promotes glucose uptake, glycogen synthesis, and metabolic homeostasis in insulin-responsive tissues. Loss-of-function variants can cause severe insulin resistance, whereas activating variants can produce hypoglycemia and asymmetric overgrowth.

  1 disease-causing and 41 uncertain variants in AKT2 are linked to Type 2 diabetes mellitus.

• 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.

  1 disease-causing and 36 uncertain variants in SLC2A2 are linked to Type 2 diabetes mellitus.

• IRS1: Insulin receptor substrate 1

  It acts as a major intracellular docking protein for insulin and IGF-1 receptors, transmitting signals to PI3K-AKT and other metabolic pathways. Common and rare variation can influence insulin sensitivity and type 2 diabetes risk, although effects are often context dependent.

  1 disease-causing and 1 uncertain variants in IRS1 are linked to Type 2 diabetes mellitus.

• 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 Type 2 diabetes mellitus.

• PPARG: Peroxisome proliferator-activated receptor gamma

  It drives adipocyte differentiation, lipid storage, and insulin-sensitive metabolic programs in response to endogenous lipids and thiazolidinedione drugs. Dominant-negative variants cause familial partial lipodystrophy type 3 with severe insulin resistance and dyslipidemia.

  1 disease-causing and 1 uncertain variants in PPARG are linked to Type 2 diabetes mellitus.

• 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.

  1 disease-causing and 0 uncertain variants in INSR are linked to Type 2 diabetes mellitus.

• 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.

  0 disease-causing and 30 uncertain variants in HNF4A are linked to Type 2 diabetes mellitus.

• LIPC: Hepatic triacylglycerol lipase

  It hydrolyzes triglycerides and phospholipids in HDL and remnant particles at the liver surface, helping remodel circulating lipoproteins. Loss-of-function variants can raise HDL cholesterol and alter remnant metabolism, with variable effects on atherosclerotic risk.

  0 disease-causing and 7 uncertain variants in LIPC are linked to Type 2 diabetes mellitus.

• IRS2: Insulin receptor substrate 2

  It relays insulin and growth-factor signals in liver, pancreatic beta cells, brain, and other tissues, supporting metabolic control and cell survival. Altered signaling can contribute to insulin resistance and diabetes, but strong monogenic human disease associations are limited.

  0 disease-causing and 3 uncertain variants in IRS2 are linked to Type 2 diabetes mellitus.

• SLC30A8: Proton-coupled zinc antiporter SLC30A8

  It transports zinc into insulin secretory granules, supporting insulin crystallization, storage, and beta-cell function. Common variants influence type 2 diabetes risk, while rare loss-of-function variants are associated with reduced disease risk in population studies.

  0 disease-causing and 1 uncertain variants in SLC30A8 are linked to Type 2 diabetes mellitus.

• TCF7L2: Transcription factor 7-like 2

  It mediates Wnt-dependent transcription and also influences pancreatic, hepatic, and intestinal programs involved in glucose metabolism. Common intronic variants at this locus are among the strongest and most reproducible genetic risk factors for type 2 diabetes.

  0 disease-causing and 4 uncertain variants in TCF7L2 are linked to Type 2 diabetes mellitus.

• ACE: Angiotensin-converting enzyme

  A membrane-associated enzyme that removes terminal dipeptides from hormones and signaling peptides, including angiotensin I and bradykinin. By generating angiotensin II and inactivating vasodilators, it helps regulate blood pressure, fluid balance, and aspects of nervous-system signaling.

  0 disease-causing and 0 uncertain variants in ACE are linked to Type 2 diabetes mellitus.

• ADCY5: Adenylate cyclase type 5

  It generates cyclic AMP downstream of G-protein-coupled receptors and is particularly important in striatal and cardiac signaling. Gain-of-function and loss-of-function variants can both cause movement disorders, with ADCY5-related dyskinesia often featuring episodic chorea, dystonia, and nocturnal exacerbations.

  0 disease-causing and 0 uncertain variants in ADCY5 are linked to Type 2 diabetes mellitus.

• AGTR1: Type-1 angiotensin II receptor

  Its activation by angiotensin II promotes vasoconstriction, aldosterone release, sodium retention, and vascular remodeling. Excessive signaling contributes to hypertension and cardiovascular disease, and the pathway is therapeutically blocked by angiotensin-receptor blockers.

  0 disease-causing and 0 uncertain variants in AGTR1 are linked to Type 2 diabetes mellitus.

• ANGPTL4: Angiopoietin-related protein 4

  It regulates lipid partitioning by inhibiting lipoprotein lipase in a tissue- and nutritional-state-dependent manner. Loss-of-function variants can lower triglyceride levels and have been associated with reduced coronary-disease risk, although the protein also has broader roles in metabolism and tissue responses.

  0 disease-causing and 0 uncertain variants in ANGPTL4 are linked to Type 2 diabetes mellitus.

• APOE: Apolipoprotein E

  It redistributes cholesterol and other lipids between tissues by directing remnant lipoproteins to LDL-receptor-family members. The common epsilon4 isoform strongly increases late-onset Alzheimer disease risk and also influences plasma lipids and cardiovascular risk.

  0 disease-causing and 0 uncertain variants in APOE are linked to Type 2 diabetes mellitus.

• FGFR4: Fibroblast growth factor receptor 4

  It transmits fibroblast-growth-factor signals involved in metabolism, tissue repair, development, and cell proliferation, with FGF19 as an important metabolic ligand. Aberrant signaling can support tumor growth, and activating alterations are therapeutic targets in selected cancers.

  0 disease-causing and 0 uncertain variants in FGFR4 are linked to Type 2 diabetes mellitus.

• FTO: Alpha-ketoglutarate-dependent dioxygenase FTO

  It removes selected methyl modifications from RNA and participates in regulation of energy balance and cellular metabolism. Common intronic variation at the FTO locus has one of the strongest replicated genetic associations with body-mass index and obesity risk.

  0 disease-causing and 0 uncertain variants in FTO are linked to Type 2 diabetes mellitus.

• GAA: Lysosomal alpha-glucosidase

  It degrades lysosomal glycogen to free glucose. Biallelic loss-of-function variants cause Pompe disease, ranging from severe infantile cardiomyopathy to later-onset progressive skeletal and respiratory muscle weakness.

  0 disease-causing and 0 uncertain variants in GAA are linked to Type 2 diabetes mellitus.

• HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase

  It controls the rate-limiting step of the mevalonate pathway and therefore strongly regulates endogenous cholesterol production. Statins lower LDL cholesterol by inhibiting this activity, causing the liver to increase LDL-receptor-mediated clearance from blood.

  0 disease-causing and 0 uncertain variants in HMGCR are linked to Type 2 diabetes mellitus.

• KCNQ1: Potassium voltage-gated channel subfamily KQT member 1

  The protein forms the pore of a voltage-gated potassium channel that helps set electrical activity in heart muscle. Its partnerships with KCNE subunits also support normal function in the inner ear and other tissues, while KCNQ1 variants are linked to long-QT and short-QT syndromes.

  0 disease-causing and 0 uncertain variants in KCNQ1 are linked to Type 2 diabetes mellitus.

• 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 0 uncertain variants in LEPR are linked to Type 2 diabetes mellitus.

• LPL: Lipoprotein lipase

  It hydrolyzes triglycerides in circulating chylomicrons and very-low-density lipoproteins so tissues can take up released fatty acids. Severe biallelic loss causes familial chylomicronemia, while common variation strongly influences triglyceride levels and cardiovascular risk.

  0 disease-causing and 0 uncertain variants in LPL are linked to Type 2 diabetes mellitus.

• MC4R: Melanocortin receptor 4

  Its melanocortin signaling in hypothalamic circuits suppresses appetite and helps regulate energy expenditure and body weight. Loss-of-function variants are the most common known cause of monogenic obesity and typically produce early hyperphagia.

  0 disease-causing and 0 uncertain variants in MC4R are linked to Type 2 diabetes mellitus.

• SLC5A2: Sodium/glucose cotransporter 2

  It reabsorbs most filtered glucose from the renal proximal tubule together with sodium. Loss-of-function variants cause familial renal glucosuria, while pharmacologic inhibition lowers blood glucose and provides major cardiovascular and kidney benefits.

  0 disease-causing and 0 uncertain variants in SLC5A2 are linked to Type 2 diabetes mellitus.

• TFRC: Transferrin receptor protein 1

  0 disease-causing and 0 uncertain variants in TFRC are linked to Type 2 diabetes mellitus.

• ZFHX3: Zinc finger homeobox protein 3

  0 disease-causing and 0 uncertain variants in ZFHX3 are linked to Type 2 diabetes mellitus.

• 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 35 uncertain variants in PDX1 are linked to Type 2 diabetes mellitus.

Weakly linked (only a few uncertain records): SLC2A4.

Where Type 2 diabetes mellitus variants cluster

• ABCC8 ABC transporter 2 (positions 1344–1578): 15 of 27 disease-causing changes, 3.7× more than its size predicts.

Known disease-causing variants in Type 2 diabetes mellitus

Uncertain variants in Type 2 diabetes mellitus that look disease-causing

Which prediction tools work for Type 2 diabetes mellitus

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

• REVEL: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 93 out of 100
• CADD: 93 out of 100
• MetaLR: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 88 out of 100
• MutPred2: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 82 out of 100

Same protein, different disease

• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by ABCC8 variants; they fall mostly in different places as the Type 2 diabetes mellitus variants (31 disease-causing).
• Hereditary hyperinsulinism is also caused by ABCC8 variants; they fall partly in the same places as the Type 2 diabetes mellitus variants (22 disease-causing).
• Familial hyperinsulinism is also caused by ABCC8 variants; they fall partly in the same places as the Type 2 diabetes mellitus variants (20 disease-causing).
• Diabetes mellitus, permanent neonatal 3 is also caused by ABCC8 variants; they fall mostly in different places as the Type 2 diabetes mellitus variants (17 disease-causing).
• Neonatal diabetes mellitus is also caused by ABCC8 variants; they fall mostly in different places as the Type 2 diabetes mellitus variants (10 disease-causing).
• Neonatal diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Type 2 diabetes mellitus variants (8 disease-causing).
• Diabetes mellitus, permanent neonatal 3 is also caused by KCNJ11 variants; they fall mostly in different places as the Type 2 diabetes mellitus variants (7 disease-causing).
• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by KCNJ11 variants; they fall mostly in different places as the Type 2 diabetes mellitus variants (7 disease-causing).
• Diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Type 2 diabetes mellitus variants (6 disease-causing).
• Familial hyperinsulinism is also caused by KCNJ11 variants; they fall partly in the same places as the Type 2 diabetes mellitus variants (6 disease-causing).
• Renal cysts and diabetes syndrome is also caused by HNF1B variants; they fall mostly in different places as the Type 2 diabetes mellitus variants (71 disease-causing).
• Maturity-onset diabetes of the young is also caused by HNF1B variants; they fall mostly in different places as the Type 2 diabetes mellitus variants (4 disease-causing).
• Monogenic diabetes is also caused by GCK variants; they fall mostly in different places as the Type 2 diabetes mellitus variants (235 disease-causing).
• Maturity-onset diabetes of the young is also caused by GCK variants; they fall mostly in different places as the Type 2 diabetes mellitus variants (68 disease-causing).
• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by GCK variants; they fall mostly in different places as the Type 2 diabetes mellitus variants (7 disease-causing).
• Permanent neonatal diabetes mellitus is also caused by GCK variants; they fall mostly in different places as the Type 2 diabetes mellitus variants (4 disease-causing).
• Fanconi-Bickel syndrome is also caused by SLC2A2 variants; they fall mostly in different places as the Type 2 diabetes mellitus variants (10 disease-causing).

Diseases related to Type 2 diabetes mellitus

• Diabetes mellitus, also linked to ABCC8, ACE, AGTR1, AKT2 and 14 more
• Monogenic diabetes, 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
• Myocardial infarction, also linked to ACE, AGTR1, APOE, HMGCR and 1 more
• Permanent neonatal diabetes mellitus, also linked to ABCC8, GCK, INS and KCNJ11
• Type 1 diabetes mellitus, also linked to INS, INSR, SLC5A2 and TCF7L2
• Alzheimer disease, also linked to ACE, APOE and HMGCR
• Hyperinsulinemic hypoglycemia, familial, 1, also linked to ABCC8, GCK and KCNJ11
• Hyperlipoproteinemia, also linked to APOE, HMGCR and LPL
• 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

Frequently asked questions

Which genes are linked to Type 2 diabetes mellitus?

In CATVariant, Type 2 diabetes mellitus is linked to 32 analyzed proteins: ABCC8 (ATP-binding cassette sub-family C member 8), KCNJ11 (ATP-sensitive inward rectifier potassium channel 11), HNF1B (Hepatocyte nuclear factor 1-beta), GCK (Hexokinase-4), AKT2 (RAC-beta serine/threonine-protein kinase), SLC2A2 (Solute carrier family 2, facilitated glucose transporter member 2) and 26 more.

How many genetic variants are linked to Type 2 diabetes mellitus?

432 variants: 45 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 335 are of uncertain significance or have conflicting reports.

Which uncertain variants in Type 2 diabetes mellitus look disease-causing?

3 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example KCNJ11 R136H, ABCC8 R1352H and ABCC8 R1420H. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Type 2 diabetes mellitus?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.93, based on 14 disease-causing and 71 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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