Type 1 diabetes mellitus: genes and variants

Genes linked to Type 1 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.

  8 disease-causing and 7 uncertain variants in INS are linked to Type 1 diabetes mellitus.

• IL2RA: Interleukin-2 receptor subunit alpha

  It contributes to the high-affinity IL-2 receptor on activated T cells and regulatory T cells, supporting lymphocyte proliferation and immune tolerance. Loss-of-function variants can cause immunodeficiency with autoimmunity, while abnormal expression is therapeutically targeted in selected immune disorders.

  0 disease-causing and 2 uncertain variants in IL2RA are linked to Type 1 diabetes mellitus.

• BACH2: Transcription regulator protein BACH2

  It controls transcriptional programs that balance lymphocyte differentiation, immune tolerance, and effector-cell development. Haploinsufficiency can cause immunodeficiency with autoimmunity, and common variation influences susceptibility to several autoimmune diseases.

  0 disease-causing and 0 uncertain variants in BACH2 are linked to Type 1 diabetes mellitus.

• CD3E: T-cell surface glycoprotein CD3 epsilon chain

  It helps assemble the T-cell receptor complex and transduces antigen-recognition signals through its cytoplasmic signaling motifs. Biallelic pathogenic variants can impair T-cell development and cause severe combined immunodeficiency.

  0 disease-causing and 0 uncertain variants in CD3E are linked to Type 1 diabetes mellitus.

• CTLA4: Cytotoxic T-lymphocyte protein 4

  It restrains T-cell activation by competing with CD28 for CD80 and CD86 and by delivering inhibitory signals after immune activation. Haploinsufficiency causes immune dysregulation with autoimmunity and lymphoproliferation, while therapeutic blockade enhances antitumor immunity.

  0 disease-causing and 0 uncertain variants in CTLA4 are linked to Type 1 diabetes mellitus.

• FOXP3: Forkhead box protein P3

  It establishes the transcriptional program of regulatory T cells and is essential for maintaining peripheral immune tolerance. Loss-of-function variants cause IPEX syndrome with severe early-onset autoimmunity, enteropathy, eczema, and endocrine disease.

  0 disease-causing and 0 uncertain variants in FOXP3 are linked to Type 1 diabetes mellitus.

• IL10: Interleukin-10

  It suppresses excessive inflammatory cytokine production and restrains antigen-presenting cells and effector lymphocytes, protecting tissues from immune-mediated damage. Loss of IL-10 signaling causes severe early-onset intestinal inflammation and inflammatory bowel disease.

  0 disease-causing and 0 uncertain variants in IL10 are linked to Type 1 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 Type 1 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 Type 1 diabetes mellitus.

• SH2B3: SH2B adapter protein 3

  It restrains cytokine and growth-factor signaling in hematopoietic cells, including JAK-STAT pathways controlling blood-cell production. Loss-of-function variants can increase blood-cell proliferation and predispose to myeloproliferative neoplasms, while common variants influence autoimmune and hematologic traits.

  0 disease-causing and 0 uncertain variants in SH2B3 are linked to Type 1 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 1 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 Type 1 diabetes mellitus.

• TYK2: Non-receptor tyrosine-protein kinase TYK2

  It transmits signals from type I interferon, IL-12, IL-23, and related cytokine receptors. Severe loss-of-function can cause immunodeficiency, common variants influence autoimmune susceptibility, and partial pharmacologic inhibition is effective in inflammatory disease.

  0 disease-causing and 0 uncertain variants in TYK2 are linked to Type 1 diabetes mellitus.

Weakly linked (only a few uncertain records): CCR5, KCNJ11 and LIPC.

Known disease-causing variants in Type 1 diabetes mellitus

Same protein, different disease

• Diabetes mellitus, permanent neonatal 3 is also caused by INS variants; they fall mostly in different places as the Type 1 diabetes mellitus variants (11 disease-causing).
• Neonatal diabetes mellitus is also caused by INS variants; they fall mostly in different places as the Type 1 diabetes mellitus variants (11 disease-causing).
• Maturity-onset diabetes of the young is also caused by INS variants; they fall mostly in different places as the Type 1 diabetes mellitus variants (3 disease-causing).

Diseases related to Type 1 diabetes mellitus

• Diabetes mellitus, also linked to INS, INSR, PTPN22, SLC5A2 and 1 more
• Hypothyroidism, also linked to BACH2, CTLA4, PTPN22, SH2B3 and 1 more
• Type 2 diabetes mellitus, also linked to INS, INSR, SLC5A2 and TCF7L2
• Systemic lupus erythematosus, also linked to CTLA4, IL10, PTPN22 and TYK2
• Monogenic diabetes, also linked to INS and INSR
• Inflammatory bowel disease, also linked to BACH2 and IL10
• Renal cell carcinoma, also linked to CTLA4 and IL2RA
• Basal cell carcinoma, also linked to BACH2 and CTLA4
• Maturity-onset diabetes of the young, also linked to INS
• Diabetes mellitus, permanent neonatal 3, also linked to INS
• Neonatal diabetes mellitus, also linked to INS
• Colorectal cancer, also linked to TCF7L2

Frequently asked questions

Which genes are linked to Type 1 diabetes mellitus?

In CATVariant, Type 1 diabetes mellitus is linked to 13 analyzed proteins: INS (Insulin), IL2RA (Interleukin-2 receptor subunit alpha), BACH2 (Transcription regulator protein BACH2), CD3E (T-cell surface glycoprotein CD3 epsilon chain), CTLA4 (Cytotoxic T-lymphocyte protein 4), FOXP3 (Forkhead box protein P3) and 7 more.

How many genetic variants are linked to Type 1 diabetes mellitus?

20 variants: 8 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 12 are of uncertain significance or have conflicting reports.

Which uncertain variants in Type 1 diabetes mellitus look disease-causing?

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

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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