CTLA4
Chr 2ADcytotoxic T-lymphocyte associated protein 4
Also known as: ALPS5, CD, CD152, CELIAC3, CTLA-4, GRD4, GSE, IDDM12
The CTLA4 protein is an inhibitory receptor that acts as a major negative regulator of T-cell immune responses by outcompeting the stimulatory CD28 receptor for binding to CD80 and CD86 ligands. Mutations cause CTLA4 haploinsufficiency, which presents with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)-like syndrome featuring recurrent infections, autoimmune manifestations, and lymphoproliferation, typically with onset in infancy or early childhood. The gene is highly constrained against loss-of-function variants (pLI=0.94, LOEUF=0.33) and follows autosomal dominant inheritance with variable expressivity.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
CTLA4 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
RC48 in Combination With AK104 and Bevacizumab in OCCC
RECRUITINGExploring the Efficacy, Safety and Cost-effectiveness Analysis of Cadonilimab in the Treatment of Cervical Cancer
RECRUITINGNeoadjuvant and Adjuvant Anti-PD1 or Combinations for Locoregionally Advanced Melanoma
RECRUITINGAtezolizumab With Stereotactic Ablative Radiotherapy in Patients With Metastatic Tumours
ACTIVE NOT RECRUITINGImmun Checkpoint Washout in Patients With Invasive Ductal Breast Cancer
RECRUITINGRecombinant Human IL-21-expressing Oncolytic Vaccinia Virus Injection (hV01) in Advanced Pancreatic Cancer
RECRUITINGA Clinical Study of TQB2029 for Injection in Subjects With Multiple Myeloma
RECRUITINGFeasibility Study of MET-4: Evaluating Fecal Microbiome Effects in Immunotherapy Patients
ACTIVE NOT RECRUITINGAn Open-Label Phase II Study of Nivolumab or Nivolumab/Ipilimumab in Adult Participants With Progessive/ Recurrent Meningioma
ACTIVE NOT RECRUITINGIpilimumab and Nivolumab in Combination With Radiation Therapy in Treating Patients With Stage 2-3 Non-small Lung Cancer
ACTIVE NOT RECRUITINGMonitoring of Immunological Mechanisms and Biomarkers Underlying Efficacy and Toxicity of Cancer Immunotherapy
RECRUITINGDabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAFV600 Melanoma
ACTIVE NOT RECRUITINGExternal Resources
Links to major genomics databases and tools