Crohn disease: genes and variants

Genes linked to Crohn disease

• NOD2: Nucleotide-binding oligomerization domain-containing protein 2

  It detects bacterial muramyl dipeptide in the cytosol and activates antimicrobial and inflammatory responses. Common loss-of-function variants strongly increase Crohn-disease susceptibility, whereas distinct gain-of-function variants cause Blau syndrome.

  9 ClinVar pathogenic / likely pathogenic and 131 uncertain variants in NOD2 have source records linked to Crohn disease. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in IL10 have source records linked to Crohn disease. Association strength is not clinical gene validity.

• IL12B: Interleukin-12 subunit beta

  It provides the p40 subunit shared by IL-12 and IL-23, linking innate immune activation to Th1 and Th17 responses. Biallelic loss-of-function variants impair IFN-gamma-mediated defense against mycobacteria and Salmonella, while therapeutic blockade is effective in several inflammatory diseases.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in IL12B have source records linked to Crohn disease. Association strength is not clinical gene validity.

• IL23A: Interleukin-23 subunit alpha

  It combines with p40 to form IL-23, which sustains pathogenic and protective Th17-cell responses at barrier tissues. Excess IL-23 signaling is central to psoriasis and inflammatory bowel disease, making the pathway a major therapeutic target.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in IL23A have source records linked to Crohn disease. Association strength is not clinical gene validity.

• IL23R: Interleukin-23 receptor

  It enables lymphocytes to respond to IL-23 and maintain Th17-type inflammatory programs. Common variants can strongly modify inflammatory bowel disease risk, and therapeutic interruption of IL-23 signaling is effective in several immune-mediated disorders.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in IL23R have source records linked to Crohn disease. Association strength is not clinical gene validity.

• JAK1: Tyrosine-protein kinase JAK1

  It couples many cytokine receptors to STAT transcription factors and is essential for interferon, interleukin, and growth-factor signaling. Loss-of-function can cause immunodeficiency, whereas activating alterations contribute to inflammatory disease and some malignancies.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in JAK1 have source records linked to Crohn disease. Association strength is not clinical gene validity.

• JAK2: Tyrosine-protein kinase JAK2

  It transmits signals from erythropoietin, thrombopoietin, growth hormone, and other cytokine receptors into STAT-dependent transcription. The V617F gain-of-function variant is a major driver of polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in JAK2 have source records linked to Crohn disease. Association strength is not clinical gene validity.

• JAK3: Tyrosine-protein kinase JAK3

  It carries signals from cytokine receptors using the common gamma chain and is essential for T-cell and NK-cell development. Biallelic loss-of-function variants cause severe combined immunodeficiency, while activating somatic variants occur in selected leukemias and lymphomas.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in JAK3 have source records linked to Crohn disease. Association strength is not clinical gene validity.

• NR3C1: Glucocorticoid receptor

  It converts glucocorticoid binding into transcriptional programs that regulate metabolism, stress responses, inflammation, and immune activity. Loss-of-function variants can cause glucocorticoid resistance, while excessive or prolonged signaling underlies many adverse effects of corticosteroid therapy.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in NR3C1 have source records linked to Crohn disease. 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 Crohn disease. Association strength is not clinical gene validity.

• STAT3: Signal transducer and activator of transcription 3

  It translates cytokine and growth-factor signals into transcriptional programs governing immune regulation, survival, proliferation, and tissue repair. Dominant-negative variants cause hyper-IgE syndrome, while activating germline variants cause early autoimmunity and lymphoproliferation and somatic activation contributes to cancer.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in STAT3 have source records linked to Crohn disease. Association strength is not clinical gene validity.

• TNF: Tumor necrosis factor

  It coordinates inflammation, fever, immune-cell activation, and cell survival or death through TNF receptors. Excessive TNF signaling is central to diseases such as rheumatoid arthritis and inflammatory bowel disease, making TNF blockade one of the most successful anti-inflammatory treatment strategies.

  0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in TNF have source records linked to Crohn disease. Association strength is not clinical gene validity.

• 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 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in TYK2 have source records linked to Crohn disease. Association strength is not clinical gene validity.

Where Crohn disease variants cluster

• NOD2 NACHT (positions 293–618): 8 of 9 ClinVar pathogenic / likely pathogenic variants, 2.8× more than its size predicts.

ClinVar pathogenic and likely pathogenic variants linked to Crohn disease

Which prediction tools work for Crohn disease

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

• MutPred2: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 91 out of 100
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 88 out of 100
• SIFT: 85 out of 100

Same protein, different disease

• Blau syndrome also has ClinVar records linked to NOD2 variants; they fall mostly in different places as the Crohn disease variants (12 pathogenic / likely pathogenic).

Diseases related to Crohn disease

• Inflammatory bowel disease, also linked to IL10, IL12B, IL23R, JAK2 and 1 more
• Type 1 diabetes mellitus, also linked to IL10, PTPN22 and TYK2
• Hypothyroidism, also linked to JAK1, PTPN22 and TYK2
• Systemic lupus erythematosus, also linked to IL10, PTPN22 and TYK2
• Essential thrombocythemia, also linked to JAK2 and JAK3
• Primary myelofibrosis, also linked to JAK1 and JAK2
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, also linked to JAK3
• Autosomal dominant hyper-IgE syndrome, also linked to STAT3
• STAT3 gain of function, also linked to STAT3
• Nephrotic syndrome, also linked to NR3C1
• Diabetes, also linked to PTPN22
• Severe combined immunodeficiency, also linked to JAK3

Frequently asked questions

Which genes have records linked to Crohn disease?

This view contains 13 analyzed proteins: NOD2, IL10, IL12B, IL23A, IL23R and 8 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 9 pathogenic or likely pathogenic variants, 98 variants of uncertain significance and 33 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 158 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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