Diabetes mellitus: genes and variants

Genes linked to 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 2 uncertain variants in KCNJ11 are linked to 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 0 uncertain variants in INS are linked to 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.

  0 disease-causing and 1 uncertain variants in ABCC8 are linked to 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.

  0 disease-causing and 1 uncertain variants in HNF1B are linked to 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 0 uncertain variants in SLC30A8 are linked to 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 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 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.

  0 disease-causing and 0 uncertain variants in AKT2 are linked to 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 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 Diabetes mellitus.

• CACNA1C: Voltage-dependent L-type calcium channel subunit alpha-1C

  Its opening provides a major source of depolarization-triggered calcium entry in cardiomyocytes, smooth muscle, and neurons, coupling electrical activity to contraction and signaling. Pathogenic variants can cause Timothy syndrome, Brugada or long-QT phenotypes, and several neurodevelopmental disorders.

  0 disease-causing and 0 uncertain variants in CACNA1C are linked to Diabetes mellitus.

• CACNA1D: Voltage-dependent L-type calcium channel subunit alpha-1D

  It supports calcium entry in endocrine cells, neurons, and cardiac pacemaker tissue, influencing hormone secretion, neuronal excitability, and sinoatrial activity. Activating variants can cause primary aldosteronism with seizures and neurologic abnormalities, while other variants cause neurodevelopmental or hearing phenotypes.

  0 disease-causing and 0 uncertain variants in CACNA1D are linked to Diabetes mellitus.

• CACNA1S: Voltage-dependent L-type calcium channel subunit alpha-1S

  Its voltage sensing in skeletal-muscle transverse tubules mechanically activates RYR1 and couples membrane depolarization to sarcoplasmic-reticulum calcium release. Pathogenic variants can cause hypokalemic periodic paralysis, malignant-hyperthermia susceptibility, and congenital myopathy.

  0 disease-causing and 0 uncertain variants in CACNA1S are linked to Diabetes mellitus.

• CCND2: G1/S-specific cyclin-D2

  It promotes G1-to-S cell-cycle progression through activation of CDK4 and CDK6 and is important in proliferating neural and endocrine tissues. Activating germline variants can cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, while overexpression occurs in several cancers.

  0 disease-causing and 0 uncertain variants in CCND2 are linked to 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 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 0 uncertain variants in HNF4A are linked to 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.

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

  0 disease-causing and 0 uncertain variants in PPARG are linked to Diabetes mellitus.

• PTPN22: Tyrosine-protein phosphatase non-receptor type 22

  It tunes antigen-receptor signaling thresholds in T and B cells and helps maintain immune tolerance. The common R620W variant is a major non-HLA genetic risk factor for several autoimmune diseases, including type 1 diabetes and rheumatoid arthritis.

  0 disease-causing and 0 uncertain variants in PTPN22 are linked to 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 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 0 uncertain variants in TCF7L2 are linked to 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.

  1 disease-causing and 0 uncertain variants in PDX1 are linked to Diabetes mellitus.

Weakly linked (only a few uncertain records): FOXP3.

Known disease-causing variants in Diabetes mellitus

Which prediction tools work for Diabetes mellitus

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

• SIFT: 88 out of 100

Same protein, different disease

• Neonatal diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the 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 Diabetes mellitus variants (7 disease-causing).
• Hyperinsulinemic hypoglycemia, familial, 1 is also caused by KCNJ11 variants; they fall mostly in different places as the Diabetes mellitus variants (7 disease-causing).
• Familial hyperinsulinism is also caused by KCNJ11 variants; they fall mostly in different places as the Diabetes mellitus variants (6 disease-causing).
• Permanent neonatal diabetes mellitus is also caused by KCNJ11 variants; they fall mostly in different places as the Diabetes mellitus variants (6 disease-causing).
• Diabetes mellitus, permanent neonatal 3 is also caused by INS variants; they fall mostly in different places as the Diabetes mellitus variants (11 disease-causing).
• Neonatal diabetes mellitus is also caused by INS variants; they fall mostly in different places as the Diabetes mellitus variants (11 disease-causing).
• Type 1 diabetes mellitus is also caused by INS variants; they fall mostly in different places as the Diabetes mellitus variants (8 disease-causing).
• Hyperproinsulinemia is also caused by INS variants; they fall mostly in different places as the Diabetes mellitus variants (6 disease-causing).
• Maturity-onset diabetes of the young is also caused by INS variants; they fall mostly in different places as the Diabetes mellitus variants (3 disease-causing).
• Maturity-onset diabetes of the young is also caused by PDX1 variants; they fall mostly in different places as the Diabetes mellitus variants (4 disease-causing).

Diseases related to Diabetes mellitus

• Type 2 diabetes mellitus, also linked to ABCC8, ACE, AGTR1, AKT2 and 14 more
• Monogenic diabetes, also linked to ABCC8, HNF1B, HNF4A, INS and 3 more
• Maturity-onset diabetes of the young, also linked to ABCC8, HNF1B, HNF4A, INS and 2 more
• Myocardial infarction, also linked to ACE, AGTR1, APOE, CACNA1C and 2 more
• Type 1 diabetes mellitus, also linked to INS, INSR, PTPN22, SLC5A2 and 1 more
• Epilepsy, also linked to CACNA1C, CACNA1D, CACNA1S and KCNQ1
• Diabetes mellitus, permanent neonatal 3, also linked to ABCC8, INS and KCNJ11
• Neonatal diabetes mellitus, also linked to ABCC8, INS and KCNJ11
• Permanent neonatal diabetes mellitus, also linked to ABCC8, INS and KCNJ11
• Chronic kidney disease, also linked to AGTR1, FTO and SLC5A2
• Long QT syndrome, also linked to CACNA1C and KCNQ1
• Alzheimer disease, also linked to ACE and APOE

Frequently asked questions

Which genes are linked to Diabetes mellitus?

In CATVariant, Diabetes mellitus is linked to 23 analyzed proteins: KCNJ11 (ATP-sensitive inward rectifier potassium channel 11), INS (Insulin), ABCC8 (ATP-binding cassette sub-family C member 8), HNF1B (Hepatocyte nuclear factor 1-beta), SLC30A8 (Proton-coupled zinc antiporter SLC30A8), ACE (Angiotensin-converting enzyme) and 17 more.

How many genetic variants are linked to Diabetes mellitus?

15 variants: 8 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 5 are of uncertain significance or have conflicting reports.

Which uncertain variants in Diabetes mellitus look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Diabetes mellitus?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.88, based on 8 disease-causing and 264 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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