Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency: genes and variants
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency is linked to 2 analyzed proteins (CTLA4 and KCNH2). 14 DNA variants are known to cause it; 100 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 Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
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.
13 disease-causing and 100 uncertain variants in CTLA4 are linked to Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency.
KCNH2: Voltage-gated inwardly rectifying potassium channel KCNH2
Its unusually rapid inactivation and slow deactivation shape the rapid delayed-rectifier current IKr, a major determinant of ventricular repolarization. Loss-of-function variants can prolong repolarization and cause long-QT syndrome, whereas gain-of-function variants can cause short-QT syndrome.
1 disease-causing and 0 uncertain variants in KCNH2 are linked to Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency.
Where Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency variants cluster
- CTLA4 Important for interaction with CD80 and CD86 (positions 134–139): 7 of 13 disease-causing changes, 20.0× more than its size predicts.
Known disease-causing variants in Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| CTLA4 P137L | 137 | Ig-like V-type | Disease-causing (★★★) |
| CTLA4 P137R | 137 | Ig-like V-type | Disease-causing (★★★) |
| CTLA4 Y139C | 139 | Ig-like V-type | Disease-causing (★★★) |
| CTLA4 P136L | 136 | Ig-like V-type | Disease-causing (★★★) |
| CTLA4 R75W | 75 | Ig-like V-type | Disease-causing (★★★) |
| CTLA4 D153N | 153 | Homodimerization | Disease-causing (★★★) |
| KCNH2 G572S | 572 | Extracellular | Disease-causing (★★) |
| CTLA4 R70Q | 70 | Ig-like V-type | Disease-causing (★★) |
| CTLA4 R70W | 70 | Ig-like V-type | Disease-causing (★★) |
| CTLA4 G146R | 146 | Extracellular | Disease-causing (★★) |
| CTLA4 Y139S | 139 | Ig-like V-type | Disease-causing (★) |
| CTLA4 Y139H | 139 | Ig-like V-type | Disease-causing (★) |
| CTLA4 P138T | 138 | Ig-like V-type | Disease-causing (★) |
| CTLA4 A54P | 54 | Ig-like V-type | Disease-causing (★) |
Uncertain variants in Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| CTLA4 P137Q | 137 | Ig-like V-type | Conflicting reports (★) | +6: 7 other pathogenic changes within 3 positions; P137L at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.61 |
Which prediction tools work for Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- PolyPhen-2: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- SIFT: 90 out of 100
- CATVariant: 67 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MetaLR: 66 out of 100 (learned from overlapping clinical labels, so this is optimistic)
Same protein, different disease
- Long QT syndrome is also caused by KCNH2 variants; they fall mostly in different places as the Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency variants (114 disease-causing).
- Cardiac arrhythmia is also caused by KCNH2 variants; they fall mostly in different places as the Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency variants (15 disease-causing).
- Short QT syndrome type 3 is also caused by KCNH2 variants; they fall mostly in different places as the Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency variants (4 disease-causing).
Diseases related to Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
- Long QT syndrome, also linked to KCNH2
- Cardiac arrhythmia, also linked to KCNH2
- Short QT syndrome type 3, also linked to KCNH2
- Non-small cell lung carcinoma, also linked to CTLA4
- Primary familial hypertrophic cardiomyopathy, also linked to KCNH2
- Inherited Immunodeficiency Diseases, also linked to CTLA4
- Hyperthyroidism, also linked to CTLA4
- Type 1 diabetes mellitus, also linked to CTLA4
- Hypothyroidism, also linked to CTLA4
- Hepatocellular carcinoma, also linked to CTLA4
- Renal cell carcinoma, also linked to CTLA4
- Melanoma, also linked to CTLA4
Frequently asked questions
Which genes are linked to Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency?
In CATVariant, Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency is linked to 2 analyzed proteins: CTLA4 (Cytotoxic T-lymphocyte protein 4) and KCNH2 (Voltage-gated inwardly rectifying potassium channel KCNH2).
How many genetic variants are linked to Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency?
135 variants: 14 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 100 are of uncertain significance or have conflicting reports.
Which uncertain variants in Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency look disease-causing?
1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example CTLA4 P137Q. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency?
Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.90, based on 14 disease-causing and 27 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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