Inborn error of immunity: genes and variants

Genes linked to Inborn error of immunity

• 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.

  10 disease-causing and 5 uncertain variants in RAG2 are linked to Inborn error of immunity.

• MYD88: Myeloid differentiation primary response protein MyD88

  It relays signals from most Toll-like receptors and IL-1-family receptors to NF-kappaB and other inflammatory pathways. Loss-of-function variants impair innate immune defense, while the recurrent L265P gain-of-function variant drives several B-cell malignancies.

  0 disease-causing and 0 uncertain variants in MYD88 are linked to Inborn error of immunity.

• PGR: Progesterone receptor

  It converts progesterone binding into transcriptional programs governing reproductive-tract function, implantation, pregnancy, and mammary development. Altered signaling is important in hormone-responsive cancers and is targeted clinically by progesterone agonists and antagonists.

  0 disease-causing and 0 uncertain variants in PGR are linked to Inborn error of immunity.

Where Inborn error of immunity variants cluster

• RAG2 PHD-type (positions 416–484): 3 of 10 disease-causing changes, 2.3× more than its size predicts.

Known disease-causing variants in Inborn error of immunity

Which prediction tools work for Inborn error of immunity

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

• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 90 out of 100

Same protein, different disease

• Combined immunodeficiency with skin granulomas is also caused by RAG2 variants; they fall mostly in different places as the Inborn error of immunity 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 Inborn error of immunity variants (32 disease-causing).
• Recombinase activating gene 2 deficiency is also caused by RAG2 variants; they fall partly in the same places as the Inborn error of immunity variants (25 disease-causing).
• Histiocytic medullary reticulosis is also caused by RAG2 variants; they fall mostly in different places as the Inborn error of immunity variants (14 disease-causing).
• Severe combined immunodeficiency disease is also caused by RAG2 variants; they fall partly in the same places as the Inborn error of immunity variants (7 disease-causing).

Diseases related to Inborn error of immunity

• 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
• Common variable immunodeficiency, also linked to RAG2

Frequently asked questions

Which genes are linked to Inborn error of immunity?

In CATVariant, Inborn error of immunity is linked to 3 analyzed proteins: RAG2 (V(D)J recombination-activating protein 2), MYD88 (Myeloid differentiation primary response protein MyD88) and PGR (Progesterone receptor).

How many genetic variants are linked to Inborn error of immunity?

20 variants: 10 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 5 are of uncertain significance or have conflicting reports.

Which uncertain variants in Inborn error of immunity 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 Inborn error of immunity?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.91, based on 10 disease-causing and 19 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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