Inherited Immunodeficiency Diseases: genes and variants

Genes linked to Inherited Immunodeficiency Diseases

• STAT1: Signal transducer and activator of transcription 1-alpha/beta

  It executes interferon-driven transcriptional programs required for antiviral and antimycobacterial immunity. Loss-of-function variants can cause severe infectious susceptibility, whereas gain-of-function variants classically cause chronic mucocutaneous candidiasis and autoimmunity.

  6 disease-causing and 1 uncertain variants in STAT1 are linked to Inherited Immunodeficiency Diseases.

• 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.

  1 disease-causing and 4 uncertain variants in STAT3 are linked to Inherited Immunodeficiency Diseases.

• 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.

  1 disease-causing and 1 uncertain variants in CTLA4 are linked to Inherited Immunodeficiency Diseases.

• RAG1: V(D)J recombination-activating protein 1

  It initiates V(D)J recombination by cutting antigen-receptor gene segments, creating the enormous receptor diversity required for adaptive immunity. Biallelic severe loss-of-function variants cause severe combined immunodeficiency, while hypomorphic alleles can cause Omenn syndrome or combined immunodeficiency with autoimmunity.

  1 disease-causing and 1 uncertain variants in RAG1 are linked to Inherited Immunodeficiency Diseases.

• AIRE: Autoimmune regulator

  It promotes immune tolerance by driving expression of tissue-restricted antigens in thymic medullary epithelial cells, helping eliminate self-reactive T cells. Biallelic loss-of-function variants cause autoimmune polyendocrine syndrome type 1.

  1 disease-causing and 0 uncertain variants in AIRE are linked to Inherited Immunodeficiency Diseases.

• CD19: B-lymphocyte antigen CD19

  It amplifies B-cell receptor signaling and helps set the threshold for B-cell activation throughout much of B-cell development. Loss-of-function variants can cause antibody deficiency, while its lineage-restricted surface expression makes it a major target for monoclonal antibodies and CAR-T therapy.

  1 disease-causing and 0 uncertain variants in CD19 are linked to Inherited Immunodeficiency Diseases.

• CD79A: B-cell antigen receptor complex-associated protein alpha chain

  Together with CD79B, it carries the intracellular signaling motifs that allow the B-cell receptor to transmit antigen-binding signals. Biallelic loss-of-function variants can block B-cell development and cause agammaglobulinemia.

  1 disease-causing and 0 uncertain variants in CD79A are linked to Inherited Immunodeficiency Diseases.

• DOCK8: Dedicator of cytokinesis protein 8

  It coordinates actin remodeling and signaling required for migration, survival, and immune synapse formation in lymphocytes. Biallelic loss-of-function variants cause DOCK8 deficiency, a combined immunodeficiency characterized by severe viral infections, allergy, eczema, and malignancy risk.

  1 disease-causing and 0 uncertain variants in DOCK8 are linked to Inherited Immunodeficiency Diseases.

Weakly linked (only a few uncertain records): ICOS, IL12RB1 and TERT.

Where Inherited Immunodeficiency Diseases variants cluster

• STAT1 Coiled coil (positions 136–317): 3 of 6 disease-causing changes, 2.1× more than its size predicts.

Known disease-causing variants in Inherited Immunodeficiency Diseases

Which prediction tools work for Inherited Immunodeficiency Diseases

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

• AlphaMissense: 90 out of 100
• CATVariant: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 82 out of 100
• EVE: 79 out of 100
• PolyPhen-2: 75 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 75 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 74 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome is also caused by STAT1 variants; they fall mostly in different places as the Inherited Immunodeficiency Diseases variants (47 disease-causing).
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency is also caused by STAT1 variants; they fall mostly in different places as the Inherited Immunodeficiency Diseases variants (38 disease-causing).
• Hyper-IgE recurrent infection syndrome 1, autosomal dominant is also caused by STAT3 variants; they fall mostly in different places as the Inherited Immunodeficiency Diseases variants (65 disease-causing).
• STAT3 gain of function is also caused by STAT3 variants; they fall mostly in different places as the Inherited Immunodeficiency Diseases variants (49 disease-causing).
• STAT3-related early-onset multisystem autoimmune disease is also caused by STAT3 variants; they fall mostly in different places as the Inherited Immunodeficiency Diseases variants (21 disease-causing).
• Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency is also caused by CTLA4 variants; they fall mostly in different places as the Inherited Immunodeficiency Diseases variants (13 disease-causing).
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive is also caused by RAG1 variants; they fall mostly in different places as the Inherited Immunodeficiency Diseases variants (52 disease-causing).
• Combined immunodeficiency with skin granulomas is also caused by RAG1 variants; they fall mostly in different places as the Inherited Immunodeficiency Diseases variants (49 disease-causing).
• Combined immunodeficiency due to partial RAG1 deficiency is also caused by RAG1 variants; they fall mostly in different places as the Inherited Immunodeficiency Diseases variants (13 disease-causing).
• Histiocytic medullary reticulosis is also caused by RAG1 variants; they fall mostly in different places as the Inherited Immunodeficiency Diseases variants (11 disease-causing).
• Severe combined immunodeficiency disease is also caused by RAG1 variants; they fall mostly in different places as the Inherited Immunodeficiency Diseases variants (8 disease-causing).
• Polyglandular autoimmune syndrome, type 1 is also caused by AIRE variants; they fall mostly in different places as the Inherited Immunodeficiency Diseases variants (37 disease-causing).

Diseases related to Inherited Immunodeficiency Diseases

• Hyper-IgE recurrent infection syndrome 1, autosomal dominant, also linked to DOCK8 and STAT3
• Severe combined immunodeficiency disease, also linked to DOCK8 and RAG1
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, also linked to RAG1
• Combined immunodeficiency with skin granulomas, also linked to RAG1
• STAT3 gain of function, also linked to STAT3
• Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, also linked to STAT1
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, also linked to STAT1
• Polyglandular autoimmune syndrome, type 1, also linked to AIRE
• Histiocytic medullary reticulosis, also linked to RAG1
• STAT3-related early-onset multisystem autoimmune disease, also linked to STAT3
• Non-small cell lung carcinoma, also linked to CTLA4
• Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency, also linked to CTLA4

Frequently asked questions

Which genes are linked to Inherited Immunodeficiency Diseases?

In CATVariant, Inherited Immunodeficiency Diseases is linked to 8 analyzed proteins: STAT1 (Signal transducer and activator of transcription 1-alpha/beta), STAT3 (Signal transducer and activator of transcription 3), CTLA4 (Cytotoxic T-lymphocyte protein 4), RAG1 (V(D)J recombination-activating protein 1), AIRE (Autoimmune regulator), CD19 (B-lymphocyte antigen CD19) and 2 more.

How many genetic variants are linked to Inherited Immunodeficiency Diseases?

23 variants: 13 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 10 are of uncertain significance or have conflicting reports.

Which uncertain variants in Inherited Immunodeficiency Diseases 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 Inherited Immunodeficiency Diseases?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.90, based on 9 disease-causing and 39 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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