Common variable immunodeficiency: genes and variants

Genes linked to Common variable immunodeficiency

• TNFRSF13B: Tumor necrosis factor receptor superfamily member 13B

  It responds to BAFF and APRIL and regulates B-cell survival, antibody production, and immunoglobulin class switching. Pathogenic variants are enriched in common variable immunodeficiency and can contribute to antibody deficiency, although penetrance is incomplete for many heterozygous alleles.

  1 disease-causing and 2 uncertain variants in TNFRSF13B are linked to Common variable immunodeficiency.

• RAG2: V(D)J recombination-activating protein 2

  Together with RAG1, it restricts and activates V(D)J recombination during lymphocyte development so immunoglobulin and T-cell receptor genes can be assembled. Biallelic loss-of-function variants cause severe combined immunodeficiency or hypomorphic immune-dysregulation syndromes.

  1 disease-causing and 0 uncertain variants in RAG2 are linked to Common variable immunodeficiency.

• NFKB1: Nuclear factor NF-kappa-B p105 subunit

  It produces p105 and the p50 NF-kappaB subunit, which regulate transcriptional responses to immune receptors, cytokines, and cellular stress. Haploinsufficiency can cause common-variable-immunodeficiency-like disease with recurrent infection, autoimmunity, and variable lymphoproliferation.

  0 disease-causing and 0 uncertain variants in NFKB1 are linked to Common variable immunodeficiency.

• NFKB2: Nuclear factor NF-kappa-B p100 subunit

  Processing of its p100 precursor generates p52 for the noncanonical NF-kappaB pathway, which is important for lymphoid-organ development and B-cell biology. Pathogenic variants can cause common variable immunodeficiency with endocrine and autoimmune abnormalities.

  0 disease-causing and 0 uncertain variants in NFKB2 are linked to Common variable immunodeficiency.

• BTK: Tyrosine-protein kinase BTK

  It relays B-cell-receptor signals needed for B-cell maturation, survival, and activation. Loss-of-function variants cause X-linked agammaglobulinemia, while pharmacologic inhibition is highly effective in several B-cell malignancies.

  0 disease-causing and 0 uncertain variants in BTK are linked to Common variable immunodeficiency.

• 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.

  0 disease-causing and 0 uncertain variants in CD19 are linked to Common variable immunodeficiency.

• ICOS: Inducible T-cell costimulator

  It provides costimulatory signals to activated T cells, particularly supporting T-follicular-helper cells, germinal-center responses, and cytokine production. Biallelic loss-of-function variants can cause common-variable-immunodeficiency-like disease with defective antibody responses.

  0 disease-causing and 0 uncertain variants in ICOS are linked to Common variable immunodeficiency.

Weakly linked (only a few uncertain records): CD40LG.

Known disease-causing variants in Common variable immunodeficiency

Same protein, different disease

• Combined immunodeficiency with skin granulomas is also caused by RAG2 variants; they fall mostly in different places as the Common variable immunodeficiency variants (33 disease-causing).
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive is also caused by RAG2 variants; they fall mostly in different places as the Common variable immunodeficiency variants (32 disease-causing).
• Recombinase activating gene 2 deficiency is also caused by RAG2 variants; they fall mostly in different places as the Common variable immunodeficiency variants (25 disease-causing).
• Histiocytic medullary reticulosis is also caused by RAG2 variants; they fall mostly in different places as the Common variable immunodeficiency variants (14 disease-causing).
• Inborn error of immunity is also caused by RAG2 variants; they fall mostly in different places as the Common variable immunodeficiency variants (10 disease-causing).

Diseases related to Common variable immunodeficiency

• Immunodeficiency, common variable, 10, also linked to CD19, ICOS, NFKB1, NFKB2 and 1 more
• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, also linked to RAG2
• Combined immunodeficiency with skin granulomas, also linked to RAG2
• Severe combined immunodeficiency disease, also linked to RAG2
• Histiocytic medullary reticulosis, also linked to RAG2
• Recombinase activating gene 2 deficiency, also linked to RAG2
• Primary ciliary dyskinesia, also linked to NFKB1
• Inherited Immunodeficiency Diseases, also linked to CD19
• Inborn error of immunity, also linked to RAG2
• Immunoglobulin A deficiency 2, also linked to TNFRSF13B

Frequently asked questions

Which genes are linked to Common variable immunodeficiency?

In CATVariant, Common variable immunodeficiency is linked to 7 analyzed proteins: TNFRSF13B (Tumor necrosis factor receptor superfamily member 13B), RAG2 (V(D)J recombination-activating protein 2), NFKB1 (Nuclear factor NF-kappa-B p105 subunit), NFKB2 (Nuclear factor NF-kappa-B p100 subunit), BTK (Tyrosine-protein kinase BTK), CD19 (B-lymphocyte antigen CD19) and 1 more.

How many genetic variants are linked to Common variable immunodeficiency?

25 variants: 2 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 3 are of uncertain significance or have conflicting reports.

Which uncertain variants in Common variable immunodeficiency 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.

Download every variant as CSV · Browse all diseases · Methods · About the Center