X-linked severe combined immunodeficiency: genes and variants
X-linked severe combined immunodeficiency is linked to 1 analyzed protein (IL2RG). 30 DNA variants are known to cause it; 88 more are uncertain, and 1 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to X-linked severe combined immunodeficiency
IL2RG: Cytokine receptor common subunit gamma
It is the shared signaling chain used by receptors for several interleukins required for lymphocyte development and survival. Loss-of-function variants cause X-linked severe combined immunodeficiency with profound T-cell and natural-killer-cell deficiency.
30 disease-causing and 88 uncertain variants in IL2RG are linked to X-linked severe combined immunodeficiency.
Where X-linked severe combined immunodeficiency variants cluster
- IL2RG Fibronectin type-III (positions 156–253): 17 of 30 disease-causing changes, 2.1× more than its size predicts.
Known disease-causing variants in X-linked severe combined immunodeficiency
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| IL2RG R222C | 222 | Fibronectin type-III | Disease-causing (★★★) |
| IL2RG R226C | 226 | Fibronectin type-III | Disease-causing (★★★) |
| IL2RG R224W | 224 | Fibronectin type-III | Disease-causing (★★★) |
| IL2RG C62R | 62 | Extracellular | Disease-causing (★★★) |
| IL2RG C62S | 62 | Extracellular | Disease-causing (★★★) |
| IL2RG C182Y | 182 | Fibronectin type-III | Disease-causing (★★★) |
| IL2RG R224P | 224 | Fibronectin type-III | Disease-causing (★★★) |
| IL2RG R226H | 226 | Fibronectin type-III | Disease-causing (★★★) |
| IL2RG V152G | 152 | Extracellular | Disease-causing (★★★) |
| IL2RG E68K | 68 | Extracellular | Disease-causing (★★★) |
| IL2RG R285Q | 285 | Cytoplasmic | Disease-causing (★★) |
| IL2RG M1T | 1 | Disease-causing (★★) | |
| IL2RG A156V | 156 | Fibronectin type-III | Disease-causing (★★) |
| IL2RG W240R | 240 | Fibronectin type-III | Disease-causing (★★) |
| IL2RG G114C | 114 | Extracellular | Disease-causing (★) |
| IL2RG G114S | 114 | Extracellular | Disease-causing (★) |
| IL2RG C115F | 115 | Extracellular | Disease-causing (★) |
| IL2RG C115Y | 115 | Extracellular | Disease-causing (★) |
| IL2RG R222G | 222 | Fibronectin type-III | Disease-causing (★) |
| IL2RG C182S | 182 | Fibronectin type-III | Disease-causing (★) |
| IL2RG S225R | 225 | Fibronectin type-III | Disease-causing (★) |
| IL2RG L172M | 172 | Fibronectin type-III | Disease-causing (★) |
| IL2RG L172Q | 172 | Fibronectin type-III | Disease-causing (★) |
| IL2RG Y125C | 125 | Extracellular | Disease-causing (★) |
| IL2RG L162R | 162 | Fibronectin type-III | Disease-causing (★) |
| IL2RG G232V | 232 | Fibronectin type-III | Disease-causing (★) |
| IL2RG S238N | 238 | Fibronectin type-III | Disease-causing (★) |
| IL2RG L146P | 146 | Extracellular | Disease-causing (★) |
| IL2RG C231Y | 231 | Fibronectin type-III | Disease-causing (★) |
| IL2RG L14P | 14 | Disease-causing |
Uncertain variants in X-linked severe combined immunodeficiency that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| IL2RG G232R | 232 | Fibronectin type-III | Uncertain (★★★) | +6: 2 other pathogenic changes within 3 positions; G232V at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.91 |
Which prediction tools work for X-linked severe combined immunodeficiency
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- SIFT: 92 out of 100
Diseases related to X-linked severe combined immunodeficiency
- Renal cell carcinoma, also linked to IL2RG
- Combined immunodeficiency, also linked to IL2RG
Frequently asked questions
Which genes are linked to X-linked severe combined immunodeficiency?
In CATVariant, X-linked severe combined immunodeficiency is linked to 1 analyzed protein: IL2RG (Cytokine receptor common subunit gamma).
How many genetic variants are linked to X-linked severe combined immunodeficiency?
140 variants: 30 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 88 are of uncertain significance or have conflicting reports.
Which uncertain variants in X-linked severe combined immunodeficiency look disease-causing?
1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example IL2RG G232R. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for X-linked severe combined immunodeficiency?
Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.92, based on 29 disease-causing and 23 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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