Diabetes: genes and variants

Genes linked to 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.

  12 ClinVar pathogenic / likely pathogenic and 5 uncertain variants in KCNJ11 have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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.

  12 ClinVar pathogenic / likely pathogenic and 1 uncertain variants in INS have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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.

  10 ClinVar pathogenic / likely pathogenic and 9 uncertain variants in ABCC8 have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 1 uncertain variants in HNF1B have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in SLC30A8 have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in ACE have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in AGTR1 have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in AKT2 have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in ANGPTL4 have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in APOE have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in CACNA1C have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in CACNA1D have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in CACNA1S have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in CCND2 have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in FTO have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in HNF4A have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in INSR have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in KCNQ1 have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in PPARG have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in PTPN22 have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in SLC5A2 have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in TCF7L2 have source records linked to Diabetes. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in PDX1 have source records linked to Diabetes. Association strength is not clinical gene validity.

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

Where Diabetes variants cluster

• ABCC8 Cytoplasmic (positions 187–303): 3 of 10 ClinVar pathogenic / likely pathogenic variants, 4.0× more than its size predicts.
• ABCC8 ABC transporter 2 (positions 1344–1578): 3 of 10 ClinVar pathogenic / likely pathogenic variants, 2.0× more than its size predicts.
• KCNJ11 Cytoplasmic (positions 1–65): 3 of 12 ClinVar pathogenic / likely pathogenic variants, 1.5× more than its size predicts.

ClinVar pathogenic and likely pathogenic variants linked to Diabetes

Which prediction tools work for Diabetes

Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.

• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 93 out of 100
• AlphaMissense: 90 out of 100
• phyloP: 88 out of 100
• CADD: 87 out of 100
• PolyPhen-2: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 82 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 77 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 75 out of 100

Same protein, different disease

• Diabetes mellitus, permanent neonatal 3 also has ClinVar records linked to INS variants; they fall partly in the same places as the Diabetes variants (11 pathogenic / likely pathogenic).
• Type 1 diabetes mellitus also has ClinVar records linked to INS variants; they fall partly in the same places as the Diabetes variants (8 pathogenic / likely pathogenic).
• Hyperproinsulinemia also has ClinVar records linked to INS variants; they fall in the same places as the Diabetes variants (6 pathogenic / likely pathogenic).
• MODY also has ClinVar records linked to INS variants; they fall mostly in different places as the Diabetes variants (3 pathogenic / likely pathogenic).
• Diabetes mellitus, permanent neonatal 3 also has ClinVar records linked to KCNJ11 variants; they fall mostly in different places as the Diabetes variants (7 pathogenic / likely pathogenic).
• Hyperinsulinemic hypoglycemia, familial, 1 also has ClinVar records linked to KCNJ11 variants; they fall mostly in different places as the Diabetes variants (7 pathogenic / likely pathogenic).
• Familial hyperinsulinism also has ClinVar records linked to KCNJ11 variants; they fall mostly in different places as the Diabetes variants (6 pathogenic / likely pathogenic).
• Permanent neonatal diabetes mellitus also has ClinVar records linked to KCNJ11 variants; they fall mostly in different places as the Diabetes variants (6 pathogenic / likely pathogenic).
• Type 2 diabetes mellitus also has ClinVar records linked to KCNJ11 variants; they fall mostly in different places as the Diabetes variants (6 pathogenic / likely pathogenic).
• Hyperinsulinemic hypoglycemia, familial, 1 also has ClinVar records linked to ABCC8 variants; they fall mostly in different places as the Diabetes variants (31 pathogenic / likely pathogenic).
• Type 2 diabetes mellitus also has ClinVar records linked to ABCC8 variants; they fall mostly in different places as the Diabetes variants (27 pathogenic / likely pathogenic).
• Hereditary hyperinsulinism also has ClinVar records linked to ABCC8 variants; they fall mostly in different places as the Diabetes variants (22 pathogenic / likely pathogenic).
• Familial hyperinsulinism also has ClinVar records linked to ABCC8 variants; they fall mostly in different places as the Diabetes variants (20 pathogenic / likely pathogenic).
• Diabetes mellitus, transient neonatal, 2 also has ClinVar records linked to ABCC8 variants; they fall mostly in different places as the Diabetes variants (19 pathogenic / likely pathogenic).
• MODY also has ClinVar records linked to PDX1 variants; they fall mostly in different places as the Diabetes variants (4 pathogenic / likely pathogenic).

Diseases related to Diabetes

• 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
• MODY, 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
• Permanent neonatal diabetes mellitus, also linked to ABCC8, INS and KCNJ11
• Long QT syndrome, also linked to CACNA1C and KCNQ1
• Alzheimer disease, also linked to ACE and APOE
• Cardiac arrhythmia, also linked to CACNA1C and KCNQ1
• Renal cysts and diabetes syndrome, also linked to HNF1B and HNF4A

Frequently asked questions

Which genes have records linked to Diabetes?

This view contains 23 analyzed proteins: KCNJ11, INS, ABCC8, HNF1B, SLC30A8 and 18 more. Links come from clinical records and association databases. They do not imply that every listed gene is a validated cause, and missing genes may not yet be analyzed.

What do the clinical classifications mean?

Linked records include 35 pathogenic or likely pathogenic variants, 5 variants of uncertain significance and 12 with conflicting classifications. Labels summarize source records; multi-condition records may not make a separate assertion for this disease. Check the original record and review status.

Does the evidence score change a VUS classification?

No. 0 VUS or conflicting variants reach the likely-pathogenic points range on the computable criteria available here. This is a research prioritization signal, not a clinical classification. Patient, family and other required evidence may be missing.

Can I download the variant evidence?

Download the CSV for all 55 variants in the selected disease scope, including clinical labels, review status, evidence criteria, predictor scores, functional measurements and population frequency where available.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from eligible public CATVariant analyses 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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