Severe combined immunodeficiency: genes and variants
Explore variant evidence for Severe combined immunodeficiency across 9 analyzed proteins (ADA, RAG1, RAG2, JAK3, IL7R and 4 more). Linked ClinVar records include 35 pathogenic or likely pathogenic variants, 1 variants of uncertain significance and 2 with conflicting classifications.
Coverage includes proteins already analyzed in CATVariant, not every gene involved in this condition. Database links are associations, not an assessment of clinical gene–disease validity. Computable evidence prioritizes variants for expert review and does not reclassify them. Source labels are pooled across this disease family.
Data updated 2026-10-10. Automated aggregation, not a clinical review date.
Download variant evidence (CSV)
Genes linked to Severe combined immunodeficiency
ADA: Adenosine deaminase
It degrades adenosine and deoxyadenosine, preventing accumulation of metabolites that are particularly toxic to developing lymphocytes. Biallelic deficiency causes severe combined immunodeficiency, while partial deficiency can present later with immune dysfunction.
12 ClinVar pathogenic / likely pathogenic and 2 uncertain variants in ADA have source records linked to Severe combined immunodeficiency. Association strength is not clinical gene validity.
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.
8 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in RAG1 have source records linked to Severe combined immunodeficiency. Association strength is not clinical gene validity.
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.
7 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in RAG2 have source records linked to Severe combined immunodeficiency. 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.
5 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in JAK3 have source records linked to Severe combined immunodeficiency. Association strength is not clinical gene validity.
IL7R: Interleukin-7 receptor subunit alpha
It transmits survival and developmental signals required for T-cell and lymphoid homeostasis. Biallelic loss-of-function variants cause T-cell-negative, B-cell-positive severe combined immunodeficiency, while somatic activating alterations occur in acute lymphoblastic leukemia.
2 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in IL7R have source records linked to Severe combined immunodeficiency. Association strength is not clinical gene validity.
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 ClinVar pathogenic / likely pathogenic and 1 uncertain variants in DOCK8 have source records linked to Severe combined immunodeficiency. Association strength is not clinical gene validity.
LCK: Tyrosine-protein kinase Lck
It phosphorylates the earliest signaling components downstream of the T-cell receptor and CD4 or CD8 coreceptors, making it essential for T-cell development and activation. Severe loss-of-function can cause combined immunodeficiency, while aberrant activity contributes to lymphoid malignancy.
0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in LCK have source records linked to Severe combined immunodeficiency. Association strength is not clinical gene validity.
IKBKB: Inhibitor of nuclear factor kappa-B kinase subunit beta
It phosphorylates inhibitory I-kappaB proteins after immune-receptor activation, allowing NF-kappaB transcription factors to enter the nucleus and drive inflammatory and survival genes. Biallelic loss-of-function variants can cause severe combined immunodeficiency.
0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in IKBKB have source records linked to Severe combined immunodeficiency. Association strength is not clinical gene validity.
MALT1: Mucosa-associated lymphoid tissue lymphoma translocation protein 1
It provides both scaffold and protease functions in antigen-receptor signaling, enabling NF-kappaB activation downstream of the CARD11-BCL10 complex. Biallelic loss-of-function variants cause combined immunodeficiency, while constitutive MALT1 signaling contributes to selected lymphomas.
0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in MALT1 have source records linked to Severe combined immunodeficiency. Association strength is not clinical gene validity.
Weakly linked (only a few uncertain records): CD3E.
Where Severe combined immunodeficiency variants cluster
- RAG1 NBD (positions 392–459): 3 of 8 ClinVar pathogenic / likely pathogenic variants, 5.8× more than its size predicts.
ClinVar pathogenic and likely pathogenic variants linked to Severe combined immunodeficiency
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| ADA R101L | 101 | Pathogenic / likely pathogenic (★★) | |
| ADA R156L | 156 | Pathogenic / likely pathogenic (★★) | |
| ADA R156S | 156 | Pathogenic / likely pathogenic (★★) | |
| ADA R101Q | 101 | Pathogenic / likely pathogenic (★★) | |
| ADA R156P | 156 | Pathogenic / likely pathogenic (★★) | |
| ADA R156H | 156 | Pathogenic / likely pathogenic (★★) | |
| ADA R156C | 156 | Pathogenic / likely pathogenic (★★) | |
| ADA V177M | 177 | Pathogenic / likely pathogenic (★★) | |
| RAG2 H140R | 140 | Pathogenic / likely pathogenic (★★) | |
| JAK3 R103C | 103 | FERM | Pathogenic / likely pathogenic (★★) |
| JAK3 R103H | 103 | FERM | Pathogenic / likely pathogenic (★★) |
| ADA P126Q | 126 | Required for binding to DDP4 | Pathogenic / likely pathogenic (★★) |
| JAK3 G589S | 589 | Protein kinase 1 | Pathogenic / likely pathogenic (★★) |
| RAG1 R404W | 404 | NBD | Pathogenic / likely pathogenic (★★) |
| RAG1 R559S | 559 | Pathogenic / likely pathogenic (★★) | |
| RAG1 V782D | 782 | Pathogenic / likely pathogenic (★★) | |
| RAG1 R841Q | 841 | Pathogenic / likely pathogenic (★★) | |
| RAG2 G32E | 32 | Pathogenic / likely pathogenic (★★) | |
| RAG2 G35V | 35 | Pathogenic / likely pathogenic (★★) | |
| RAG2 N101K | 101 | Pathogenic / likely pathogenic (★★) | |
| ADA G74V | 74 | Pathogenic / likely pathogenic (★★) | |
| ADA L107P | 107 | Pathogenic / likely pathogenic (★★) | |
| ADA R282L | 282 | Pathogenic / likely pathogenic (★★) | |
| IL7R G215V | 215 | Fibronectin type-III | Pathogenic / likely pathogenic (★★) |
| JAK3 T714M | 714 | Protein kinase 1 | Pathogenic / likely pathogenic (★★) |
| RAG1 R410W | 410 | NBD | Pathogenic / likely pathogenic (★★) |
| RAG1 V433M | 433 | NBD | Pathogenic / likely pathogenic (★★) |
| RAG1 R973H | 973 | Pathogenic / likely pathogenic (★★) | |
| RAG1 R975W | 975 | Pathogenic / likely pathogenic (★★) | |
| RAG2 L155P | 155 | Pathogenic / likely pathogenic (★★) | |
| RAG2 R159C | 159 | Pathogenic / likely pathogenic (★★) | |
| IL7R M1R | 1 | Pathogenic / likely pathogenic (★★) | |
| JAK3 R402H | 402 | SH2 | Pathogenic / likely pathogenic (★★) |
| DOCK8 K473R | 473 | Pathogenic / likely pathogenic (★★) | |
| RAG2 W453R | 453 | PHD-type | Pathogenic / likely pathogenic (★) |
Which prediction tools work for Severe combined immunodeficiency
Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.
- REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 95 out of 100
- SIFT: 93 out of 100
- PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MetaLR: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- phyloP: 82 out of 100
Same protein, different disease
- Severe combined immunodeficiency due to adenosine deaminase deficiency also has ClinVar records linked to ADA variants; they fall mostly in different places as the Severe combined immunodeficiency variants (44 pathogenic / likely pathogenic).
- Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive also has ClinVar records linked to RAG1 variants; they fall mostly in different places as the Severe combined immunodeficiency variants (52 pathogenic / likely pathogenic).
- Combined immunodeficiency with skin granulomas also has ClinVar records linked to RAG1 variants; they fall mostly in different places as the Severe combined immunodeficiency variants (49 pathogenic / likely pathogenic).
- Combined immunodeficiency due to partial RAG1 deficiency also has ClinVar records linked to RAG1 variants; they fall mostly in different places as the Severe combined immunodeficiency variants (13 pathogenic / likely pathogenic).
- Histiocytic medullary reticulosis also has ClinVar records linked to RAG1 variants; they fall mostly in different places as the Severe combined immunodeficiency variants (11 pathogenic / likely pathogenic).
- Recombinase activating gene 1 deficiency also has ClinVar records linked to RAG1 variants; they fall mostly in different places as the Severe combined immunodeficiency variants (8 pathogenic / likely pathogenic).
- Combined immunodeficiency with skin granulomas also has ClinVar records linked to RAG2 variants; they fall mostly in different places as the Severe combined immunodeficiency variants (33 pathogenic / likely pathogenic).
- Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive also has ClinVar records linked to RAG2 variants; they fall mostly in different places as the Severe combined immunodeficiency variants (32 pathogenic / likely pathogenic).
- Recombinase activating gene 2 deficiency also has ClinVar records linked to RAG2 variants; they fall mostly in different places as the Severe combined immunodeficiency variants (25 pathogenic / likely pathogenic).
- Histiocytic medullary reticulosis also has ClinVar records linked to RAG2 variants; they fall mostly in different places as the Severe combined immunodeficiency variants (14 pathogenic / likely pathogenic).
- Inborn error of immunity also has ClinVar records linked to RAG2 variants; they fall mostly in different places as the Severe combined immunodeficiency variants (10 pathogenic / likely pathogenic).
- T-B+ severe combined immunodeficiency due to JAK3 deficiency also has ClinVar records linked to JAK3 variants; they fall mostly in different places as the Severe combined immunodeficiency variants (22 pathogenic / likely pathogenic).
Diseases related to Severe combined immunodeficiency
- Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, also linked to JAK3, RAG1 and RAG2
- Combined immunodeficiency with skin granulomas, also linked to RAG1 and RAG2
- Histiocytic medullary reticulosis, also linked to RAG1 and RAG2
- T-B+ severe combined immunodeficiency due to JAK3 deficiency, also linked to IL7R and JAK3
- Inherited Immunodeficiency Diseases, also linked to DOCK8 and RAG1
- Autosomal dominant hyper-IgE syndrome, also linked to DOCK8
- Severe combined immunodeficiency due to adenosine deaminase deficiency, also linked to ADA
- Recombinase activating gene 2 deficiency, also linked to RAG2
- Combined immunodeficiency due to partial RAG1 deficiency, also linked to RAG1
- Inborn error of immunity, also linked to RAG2
- Crohn disease, also linked to JAK3
- Essential thrombocythemia, also linked to JAK3
Frequently asked questions
Which genes have records linked to Severe combined immunodeficiency?
This view contains 9 analyzed proteins: ADA, RAG1, RAG2, JAK3, IL7R and 4 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 35 pathogenic or likely pathogenic variants, 1 variants of uncertain significance and 2 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 84 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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