CTLA4 Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human CTLA4 — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene CTLA4, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene CTLA4, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene CTLA4 protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene CTLA4 protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene CTLA4, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene CTLA4, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene CTLA4, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene CTLA4 protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene CTLA4, summarize transcription factor regulatory data. If CTLA4 is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate CTLA4 — names with evidence type (ChIP-seq / predicted / experimentally validated) If CTLA4 is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene CTLA4 protein as a drug target, summarize pharmacology data. If CTLA4 is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If CTLA4 is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene CTLA4, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene CTLA4, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in CTLA4: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
CTLA4 (cytotoxic T-lymphocyte associated protein 4) is a critical immune checkpoint receptor expressed predominantly on T cells, where it suppresses T cell activation by outcompeting CD28 for binding to B7 ligands (CD80/CD86) on antigen-presenting cells. Its central role in immune tolerance makes it one of the most therapeutically important genes in oncology and autoimmunity. Two FDA-approved monoclonal antibodies targeting CTLA4 — ipilimumab and tremelimumab — have collectively been evaluated in over 960 clinical trials, and 23 therapeutic antibodies (including bispecifics combining CTLA4 and PD-1/PD-L1 blockade) are in active development or clinical use. The gene carries approximately 285 ClinVar variants, with haploinsufficiency causing an autosomal dominant autoimmune lymphoproliferative syndrome (OMIM:616100); AlphaMissense flags cysteine residues (e.g., C129R at 0.994) among the most damaging missense changes. GWAS links the locus to a broad spectrum of autoimmune diseases including rheumatoid arthritis (p = 9e-25), autoimmune thyroid disease (p = 2e-74), type 1 diabetes, and alopecia areata, underscoring its central role in self-tolerance across multiple organ systems.
CTLA4 — Reference
Cross-database identifier and functional mapping reference for CTLA4.
Gene identifiers
CTLA4 (cytotoxic T-lymphocyte associated protein 4)
- HGNC ID: HGNC:2505
- Approved symbol: CTLA4
- Ensembl gene ID: ENSG00000163599
- NCBI Entrez Gene ID: 1493
- OMIM ID: 123890
- Genomic location (GRCh38):
- Chromosome: 2
- Start: 203,853,888
- End: 203,873,965
- Strand: +
Transcript identifiers
Ensembl transcripts
| ENST ID | Biotype | Exon Count |
|---|---|---|
| ENST00000295854 | protein_coding | 3 |
| ENST00000427473 | protein_coding_CDS_not_defined | 3 |
| ENST00000487393 | protein_coding | 2 |
| ENST00000648405 | protein_coding | 4 |
| ENST00000650075 | protein_coding_CDS_not_defined | 4 |
| ENST00000696049 | protein_coding | 4 |
| ENST00000696479 | protein_coding | 5 |
Total Ensembl transcripts: 7
RefSeq transcripts (NM_)
| Accession | Status | MANE Select |
|---|---|---|
| NM_001037631 | REVIEWED | — |
| NM_001281976 | REVIEWED | — |
| NM_005214 | REVIEWED | ✓ |
| NM_009843 | REVIEWED | — |
| NM_031674 | PROVISIONAL | — |
| NM_142824 | REVIEWED | — |
| XM_006245036 | PREDICTED | — |
| XM_036156357 | PREDICTED | — |
CCDS IDs
- CCDS2362
- CCDS42803
Canonical transcript exons (ENST00000295854)
| Exon ID | Start | End | Genomic Coordinates |
|---|---|---|---|
| ENSE00003664686 | 203867943 | 203868051 | chr2:203867943-203868051 |
| ENSE00003548810 | 203870586 | 203870933 | chr2:203870586-203870933 |
| ENSE00001857400 | 203872708 | 203872775 | chr2:203872708-203872775 |
Total exons in canonical transcript: 3
Protein identifiers
UniProt Accessions
- P16410 ✓ (Canonical reviewed entry) - Cytotoxic T-lymphocyte protein 4
- A0A8Q3SIR7 (Unreviewed)
- A0A8Q3WKZ2 (Unreviewed)
RefSeq Protein Accessions
- NP_005205 (MANE Select)
- NP_001032720
Protein Domains and Families
| ID | Name | Type |
|---|---|---|
| IPR008096 | Cytotoxic T-lymphocyte antigen 4 | Family |
| IPR040216 | Cytotoxic T-lymphocyte protein 4/CD28 | Family |
| IPR013106 | Immunoglobulin V-set domain | Domain |
| IPR003599 | Immunoglobulin domain subtype | Domain |
| IPR013783 | Immunoglobulin-like fold | Homologous_superfamily |
| IPR036179 | Immunoglobulin-like domain superfamily | Homologous_superfamily |
| PF07686 | Immunoglobulin domain | Pfam |
| SM00406 | Immunoglobulin domain | SMART |
| SM00409 | Immunoglobulin domain subtype | SMART |
| SSF48726 | Immunoglobulin-like | Superfamily |
Antibody Resources
23 therapeutic antibodies targeting CTLA4 are available, including:
Active clinical/approved:
- IPILIMUMAB (Whole mAb, IgG1) - FDA approved
- TREMELIMUMAB (Whole mAb, IgG2)
- BOTENSILIMAB (Whole mAb, IgG1)
- EVALSTOTUG (Whole mAb, IgG1)
- FIRASTOTUG (Whole mAb, IgG1)
- GOTISTOBART (Whole mAb, IgG1)
- MUZASTOTUG (Whole mAb, IgG1)
- QUAVONLIMAB (Whole mAb, IgG1)
- SOVIPOSTOBART (Whole mAb, IgG1)
- TAZLESTOBART (Whole mAb, IgG1)
- TUVONRALIMAB (Whole mAb, IgG1)
- VILASTOBART (Whole mAb, IgG1)
- PORUSTOBART (VH-CH2-CH3, IgG1)
Bispecific antibodies (active):
- CADONILIMAB (Bispecific mAb/scFv, IgG1) - targets PDCD1/PD1 + CTLA4
- LORIGERLIMAB (Bispecific scFv-CH2-CH3-scFv, IgG4) - targets PDCD1/PD1 + CTLA4
- ERFONRILIMAB (Bispecific VH-VH’-CH, IgG1) - targets PDL1 + CTLA4
- VOLRUSTOMIG (Bispecific mAb, IgG1) - targets CTLA4 + PDCD1/PD1
- VUDALIMAB (Bispecific mAb/scFv, IgG1) - targets CTLA4 + PDCD1/PD1
Discontinued:
- NURULIMAB (Whole mAb, IgG1)
- BAVUNALIMAB (Bispecific mAb/scFv, IgG1) - targeted LAG3 + CTLA4
- DANVILOSTOMIG (Bispecific mAb/scFv, IgG1)
Trial/TBC:
- FUTERMESTOTUG (Whole mAb, IgG1)
- ZALIFRELIMAB (Whole mAb, IgG1)
Structure
Experimental Structures: PDB
Total: 21 structures
X-ray Diffraction (20):
- 1H6E (3.6 Å) – AP2 adaptor complex with CTLA-4 internalization peptide
- 1I85 (3.2 Å) – CTLA-4/B7-2 complex
- 1I8L (3.0 Å) – B7-1/CTLA-4 co-stimulatory complex
- 2X44 (2.6 Å) – Strand-swapped dimeric form
- 3BX7 (2.1 Å) – Lipocalin 2 in complex with CTLA-4 ectodomain
- 3OSK (1.8 Å) – CTLA-4 apo homodimer
- 5GGV (1.998 Å) – CTLA-4 with tremelimumab Fab
- 5TRU (3.0 Å) – CTLA-4 with ipilimumab
- 5XJ3 (3.2 Å) – Ipilimumab-scFv/CTLA-4 complex
- 6RP8 (2.6 Å) – Ipilimumab Fab/CTLA-4
- 6RPJ (3.25 Å) – Non-blocking anti-CTLA-4 nanobody complex
- 6RQM (3.0 Å) – Blocking anti-CTLA-4 nanobody (KN044) complex
- 6XY2 (3.05 Å) – CTLA-4 with HL32 antibody Fab
- 7CIO (1.1 Å) – CTLA-4 cytoplasmic region with PI3K SH2 domains
- 7DV4 (2.38 Å) – Anti-CTLA-4 VH domain complex
- 7ELX (2.14 Å) – CTLA-4 with Fab
- 7SU0 (2.41 Å) – Acidic pH-selective ipilimumab variant (Ipi.105) complex
- 7SU1 (2.53 Å) – Acidic pH-selective ipilimumab variant (Ipi.106) complex
- 8GAB (2.72 Å) – CTLA-4 with high-affinity binder
- 8HIT (3.2 Å) – Humanized anti-CTLA-4 MAb JS007 complex
- 9DQ3 (1.64 Å) – Engineered ipilimumab (mipi.4) Fab complex
Solution NMR (1):
- 1AH1 – 20 NMR structures
Predicted Structure: AlphaFold
Model ID: AF-P16410-F1 (AlphaFold v4)
Confidence Metrics (pLDDT):
- Global pLDDT: 79.67
- Very high confidence (90–100): 48.5%
- Confident (70–90): 18.3%
- Low confidence (50–70): 24.4%
- Very low (<50): 8.9%
Additional Metrics:
- Sequence length: 1,728 residues
- Mean PAE: 17.73 Å
- Max PAE: 31.75 Å
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000026011 | Ctla4 |
| Rat (Rattus norvegicus) | ENSRNOG00000054129 | Ctla4 |
| Zebrafish (Danio rerio) | 127519330 | LOC127519330 |
| Fruit fly (Drosophila melanogaster) | none | none |
| Worm (C. elegans) | none | none |
| Yeast (S. cerevisiae) | none | none |
Clinical variants & AI predictions
ClinVar Summary
| Metric | Count |
|---|---|
| Total variants | ~285 |
ClinVar Classification Breakdown
Based on search results, high-confidence pathogenic/likely pathogenic variants identified:
| Classification | Representative Examples |
|---|---|
| Pathogenic/Likely Pathogenic | Nonsense, frameshift, splice site mutations; common p.Arg51Ter, p.Gln76Ter, p.Trp165Ter, p.Tyr150Ter |
| VUS | Missense variants with limited functional data |
| Benign/Likely Benign | Synonymous and common benign missense variants |
Top 30 Pathogenic/Likely Pathogenic ClinVar Variants
| HGVS (cDNA) | HGVS (Protein) | Variant Type | xref_count |
|---|---|---|---|
| c.151C>T | p.Arg51Ter | Nonsense | 31 |
| c.410C>T | p.Pro137Leu | Missense | 23 |
| c.49A>G | p.Thr17Ala | Missense | 18 |
| c.208C>T | p.Arg70Trp | Missense | 18 |
| c.109+1G>T | splice site | Splice donor | 12 |
| c.529dup | p.Tyr177fs | Frameshift | 11 |
| c.226C>T | p.Gln76Ter | Nonsense | 11 |
| c.494G>A | p.Trp165Ter | Nonsense | 11 |
| c.450T>G | p.Tyr150Ter | Nonsense | 10 |
| c.110-1G>A | splice site | Splice | 10 |
| c.110-3T>C | splice site | Splice | 9 |
| c.105C>A | p.Cys35Ter | Nonsense | 9 |
| c.75del | p.Leu24fs | Frameshift | 9 |
| c.567+5G>A | splice site | Splice | 9 |
| c.71_72del | p.Leu24fs | Frameshift | 9 |
| c.567+5G>C | splice site | Splice | 9 |
| c.238C>T | p.Gln80Ter | Nonsense | 9 |
| c.160G>C | p.Ala54Pro | Missense | 9 |
| c.451+14T>C | splice site | Splice intronic | 9 |
| c.16921 | c.49A>G | Missense | 18 |
| c.161109 | c.109+1G>T | Splice | 12 |
| c.161110 | c.75del | Frameshift | 9 |
| c.161111 | c.567+5G>C | Splice | 9 |
| c.161112 | c.105C>A | Nonsense | 9 |
| c.161113 | c.109+1G>T | Splice | 12 |
| c.1029948 | c.226C>T | Nonsense | 11 |
| c.1037921 | c.567G>A | Missense | 9 |
| c.1059071 | c.397C>A | Missense | 7 |
| c.1071971 | Large deletion | Deletion | 8 |
| c.432079 | c.410C>T | Missense | 23 |
AlphaMissense Predictions
| Metric | Count |
|---|---|
| Total predictions | 144+ |
Top 30 Likely Pathogenic Missense Variants (AlphaMissense)
| Protein Change | am_pathogenicity | am_class |
|---|---|---|
| C129R | 0.994 | likely_pathogenic |
| C129S | 0.993 | likely_pathogenic |
| R70P | 0.992 | likely_pathogenic |
| Y127D | 0.990 | likely_pathogenic |
| C129F | 0.972 | likely_pathogenic |
| C129Y | 0.991 | likely_pathogenic |
| L114P | 0.991 | likely_pathogenic |
| A54D | 0.980 | likely_pathogenic |
| C103S | 0.977 | likely_pathogenic |
| V73E | 0.975 | likely_pathogenic |
| C85S | 0.978 | likely_pathogenic |
| C85Y | 0.973 | likely_pathogenic |
| C58A | 0.984 | likely_pathogenic |
| C58Y | 0.984 | likely_pathogenic |
| Y127H | 0.939 | likely_pathogenic |
| I116N | 0.959 | likely_pathogenic |
| L119P | 0.978 | likely_pathogenic |
| L74P | 0.969 | likely_pathogenic |
| P137S | 0.941 | likely_pathogenic |
| Q42H | 0.963 | likely_pathogenic |
| Y127C | 0.969 | likely_pathogenic |
| T147I | 0.958 | likely_pathogenic |
| R75G | 0.672 | likely_pathogenic |
| G52V | 0.934 | likely_pathogenic |
| C85R | 0.983 | likely_pathogenic |
| V69D | 0.852 | likely_pathogenic |
| T72P | 0.913 | likely_pathogenic |
| G52T | 0.943 | likely_pathogenic |
| F56C | 0.946 | likely_pathogenic |
| C85W | 0.975 | likely_pathogenic |
SpliceAI Predictions
| Metric | Count |
|---|---|
| Total variants | 366 |
High-Impact Splice Effect Variants (top by score)
| Position | Variant | Effect Type | Score |
|---|---|---|---|
| 2:203871425 | GCA>G | donor_gain | 1.0000 |
| 2:203870930 | ATTG>A | donor_gain | 0.9700 |
| 2:203870932 | TGG>T | donor_loss | 0.9900 |
| 2:203870934 | G>GG | donor_gain | 0.9800 |
| 2:203870937 | AG>A | donor_loss | 0.9800 |
| 2:203870935 | T>A | donor_loss | 0.9900 |
| 2:203870936 | GA>G | donor_loss | 0.9900 |
| 2:203871376 | A>AG | acceptor_gain | 0.9800 |
| 2:203871377 | G>GG | acceptor_gain | 0.9800 |
| 2:203871371 | GTTGC>G | acceptor_loss | 0.9500 |
| 2:203871372 | TTGCA>T | acceptor_loss | 0.9800 |
| 2:203871373 | TGCA>T | acceptor_loss | 0.9800 |
| 2:203871374 | GCAGA>G | acceptor_loss | 0.9800 |
| 2:203871375 | CAGAT>C | acceptor_loss | 0.9800 |
| 2:203870932 | TGGTG>T | donor_gain | 0.3400 |
| 2:203870931 | TTG>T | donor_gain | 0.8900 |
| 2:203870927 | GG>G | donor_gain | 0.9100 |
| 2:203870908 | C>T | donor_gain | 0.9300 |
| 2:203871428 | G>GG | donor_gain | 0.9900 |
| 2:203871429 | T>G | donor_gain | 0.9400 |
| 2:203871430 | T>A | donor_gain | 0.9000 |
| 2:203871440 | T>TA | donor_gain | 0.9900 |
| 2:203871441 | T>TA | donor_gain | 0.8500 |
| 2:203870585 | GCA>G | acceptor_gain | 0.9900 |
| 2:203870587 | A>AG | acceptor_gain | 0.9500 |
| 2:203870588 | A>G | acceptor_gain | 0.8500 |
| 2:203870579 | A>AG | acceptor_gain | 0.9900 |
| 2:203870584 | A>AG | acceptor_gain | 0.9900 |
| 2:203870755 | TGA>T | acceptor_gain | 0.7800 |
| 2:203870756 | GAG>G | acceptor_gain | 0.7800 |
Pathways & Gene Ontology
Reactome Pathways
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-389356 | Co-stimulation by CD28 |
| R-HSA-389513 | Co-inhibition by CTLA4 |
| R-HSA-8877330 | RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) |
Total Reactome pathways: 3
MSigDB Gene Sets
CTLA4 is a member of 100 MSigDB gene sets, including:
- REACTOME_ADAPTIVE_IMMUNE_SYSTEM
- REACTOME_CO_STIMULATION_BY_CD28
- REACTOME_REGULATION_OF_T_CELL_ACTIVATION_BY_CD28_FAMILY
- REACTOME_RUNX1_AND_FOXP3_CONTROL_THE_DEVELOPMENT_OF_REGULATORY_T_LYMPHOCYTES_TREGS
- BIOCARTA_CTLA4_PATHWAY
- KEGG_AUTOIMMUNE_THYROID_DISEASE
- KEGG_CELL_ADHESION_MOLECULES_CAMS
- Multiple Gene Ontology-derived sets (GO biological processes, molecular functions, cellular components)
- Multiple transcription factor and microRNA target sets
Gene Ontology Annotations
Biological Process (11 terms)
| GO ID | Term |
|---|---|
| GO:0002250 | Adaptive immune response |
| GO:0006955 | Immune response |
| GO:0006974 | DNA damage response |
| GO:0030889 | Negative regulation of B cell proliferation |
| GO:0042130 | Negative regulation of T cell proliferation |
| GO:0043065 | Positive regulation of apoptotic process |
| GO:0045590 | Negative regulation of regulatory T cell differentiation |
| GO:0050852 | T cell receptor signaling pathway |
| GO:0050853 | B cell receptor signaling pathway |
| GO:0050860 | Negative regulation of T cell receptor signaling pathway |
| GO:0050868 | Negative regulation of T cell activation |
Molecular Function (1 term)
| GO ID | Term |
|---|---|
| GO:0140319 | Receptor decoy activity |
Cellular Component (6 terms)
| GO ID | Term |
|---|---|
| GO:0005794 | Golgi apparatus |
| GO:0005886 | Plasma membrane |
| GO:0009897 | External side of plasma membrane |
| GO:0045334 | Clathrin-coated endocytic vesicle |
| GO:0048471 | Perinuclear region of cytoplasm |
| GO:0098636 | Protein complex involved in cell adhesion |
Total Gene Ontology annotations: 18 (11 BP + 1 MF + 6 CC)
Protein interactions & networks
Protein-Protein Interactions
Interaction Summary:
- STRING: ~3,692 interactions
- BioGRID: 118 interactions
- IntAct: 53 interactions
Top 30 STRING Interacting Proteins (by network prominence):
| Rank | Gene Symbol | Protein Name | UniProt ID |
|---|---|---|---|
| 1 | CD80 | T-lymphocyte activation antigen CD80 | P33681 |
| 2 | CD86 | T-lymphocyte activation antigen CD86 | P42081 |
| 3 | CD274 | Programmed cell death 1 ligand 1 (PD-L1) | Q9NZQ7 |
| 4 | PDCD1LG2 | Programmed cell death 1 ligand 2 (PD-L2) | Q9BQ51 |
| 5 | ICOS | Inducible T-cell costimulator | Q9Y6W8 |
| 6 | ICOSLG | ICOS ligand | O75144 |
| 7 | LGALS9 | Galectin-9 | O00182 |
| 8 | PDCD1 | Programmed cell death protein 1 (PD-1) | Q15116 |
| 9 | CD28 | T-cell-specific surface glycoprotein CD28 | P10747 |
| 10 | CD276 | CD276 antigen (B7-H3) | Q5ZPR3 |
| 11 | PTPN11 | Protein tyrosine phosphatase SHP2 | Q06124 |
| 12 | LGALS9B | Galectin-9B isoform | Q3B8N2 |
| 13 | LGALS9C | Galectin-9C isoform | Q6DKI2 |
| 14 | CD40 | TNF receptor superfamily member 5 | P25942 |
| 15 | LAG3 | Lymphocyte activation gene 3 | P18627 |
| 16 | VTCN1 | V-set domain-containing T-cell activation inhibitor 1 (B7-H4) | Q7Z7D3 |
| 17 | CD155 | Poliovirus receptor (PVR) | P15151 |
| 18 | CD4 | T-cell surface glycoprotein CD4 | P01730 |
| 19 | FOXP3 | Forkhead box protein P3 | Q9BZS1 |
| 20 | IL2 | Interleukin-2 | P01585 |
| 21 | IFNG | Interferon gamma | P01579 |
| 22 | PVRL2 | Nectin-2 | Q92692 |
| 23 | CD8A | T-cell surface glycoprotein CD8 alpha chain | P01732 |
| 24 | TNFRSF18 | TNF receptor superfamily member 18 (GITR) | Q9Y5U5 |
| 25 | MTUS2 | Microtubule-associated tumor suppressor candidate 2 | Q5JR59 |
| 26 | MTUS1 | Microtubule-associated tumor suppressor 1 | Q9ULD2 |
| 27 | IL10 | Interleukin-10 | P22301 |
| 28 | IDO1 | Indoleamine 2,3-dioxygenase 1 | P14902 |
| 29 | HAR2 | Hepatitis A virus cellular receptor 2 | Q8TDQ0 |
| 30 | CD8B | B-cell antigen receptor complex-associated protein alpha chain | P11912 |
Protein Similarity
Structural/Embedding Similarity (ESM2, top 20):
| Rank | UniProt ID | Protein Description |
|---|---|---|
| 1 | P16410 | CTLA4 (query protein) |
| 2 | O95944 | Natural cytotoxicity triggering receptor 2 (NCR2) |
| 3 | P11912 | B-cell antigen receptor complex-associated protein alpha chain (Ig-α/CD79A) |
| 4 | P12318 | Low affinity immunoglobulin gamma Fc region receptor II-a (CD32A) |
| 5 | P31785 | Cytokine receptor common subunit gamma (IL2RG/γc) |
| 6 | P31994 | Low affinity immunoglobulin gamma Fc region receptor II-b (CD32B) |
| 7 | P31995 | Low affinity immunoglobulin gamma Fc region receptor II-c (CD32C) |
| 8 | P40259 | B-cell antigen receptor complex-associated protein beta chain (Ig-β/CD79B) |
| 9 | Q5T2D2 | Trem-like transcript 2 protein (TREML2) |
| 10 | Q6UXG3 | CMRF35-like molecule 9 (CMRF35L9) |
| 11 | Q6UXN2 | Trem-like transcript 4 protein (TREML4) |
| 12 | Q86YW5 | Trem-like transcript 1 protein (TREML1) |
| 13 | Q8TDQ1 | CMRF35-like molecule 1 (CMRF35L1) |
| 14 | Q96A28 | SLAM family member 9 (SLAMF9) |
| 15 | Q96BF3 | Transmembrane and immunoglobulin domain-containing protein 2 (TMIGD2) |
| 16 | Q9NQ25 | SLAM family member 7 (SLAMF7) |
| 17 | Q9NYZ4 | Sialic acid-binding Ig-like lectin 8 (SIGLEC8) |
| 18 | Q9UGN4 | CMRF35-like molecule 8 (CMRF35L8) |
| 19 | Q9UIB8 | SLAM family member 5 (SLAMF5/CD84) |
| 20 | Q9UKJ0 | Paired immunoglobulin-like type 2 receptor beta (PILRB) |
Sequence Homology (Diamond BLAST, 12 total):
CTLA4 shows limited high-identity sequence matches. The homologous proteins identified are primarily:
- P16410: CTLA4 (query)
- P10747: CD28 (T-cell costimulatory receptor, ~40% identity) — closest structural paralogue
- Other matches: Primarily non-human orthologs and isoforms with moderate sequence identity to CTLA4’s immunoglobulin domain
Note: CTLA4 and CD28 are functional homologs sharing the B7 ligand-binding interface despite modest sequence identity, representing an important paralogous relationship in T cell costimulation.
Transcription factor regulatory data
Status: CTLA4 is not a transcription factor. It encodes cytotoxic T-lymphocyte protein 4, an immune checkpoint receptor protein. Downstream targets and DNA binding motif sections are not applicable.
Upstream regulators of CTLA4
15 transcription factors regulate CTLA4 expression:
| Transcription Factor | Regulation Type | Evidence Type | Source Database(s) |
|---|---|---|---|
| FOXP3 | Unknown | Experimentally validated / Predicted | ExTRI, NTNU Curated |
| RUNX1 | Repression | Literature-based | Pavlidis2021 |
| NFATC2 | Unknown | Predicted | ExTRI, HTRI |
| AP1 | Unknown | Predicted | ExTRI |
| GATA3 | Unknown | Predicted | ExTRI |
| IRF8 | Unknown | Predicted | ExTRI |
| NR5A1 | Unknown | Predicted | ExTRI |
| ESR1 | Unknown | Predicted | ExTRI |
| AR | Unknown | Predicted | ExTRI |
| FOXO1 | Repression | Experimentally validated / Predicted | ExTRI, NTNU Curated |
| MSC | Activation | Literature-based | TRRUST |
| LEF1 | Unknown | Literature-based / Predicted | ExTRI, TRRUST, NTNU Curated |
| USF1 | Unknown | Predicted (Low confidence) | ExTRI |
| USF2 | Unknown | Predicted (Low confidence) | ExTRI |
| NR3C1 | Unknown | Literature-based | GEREDB |
Key findings: The regulatory landscape of CTLA4 is primarily defined by immune-related transcription factors (FOXP3, GATA3, IRF8, NFATC2) with high-confidence predicted or curated interactions. RUNX1 and FOXO1 repress CTLA4, while MSC activates it. Most regulatory interactions are classified as unknown directionality, indicating that the primary outcome (activation vs. repression) requires experimental validation.
Drug & pharmacology data
CTLA4 is a well-established drug target, particularly for immunotherapy against cancer.
Targeting Molecules: Total Count & Top Molecules
ChEMBL/DrugBank: 2 approved therapeutic molecules
CTLA4-targeting drugs are limited to two FDA-approved monoclonal antibodies (Phase 4):
| ID | Name | Mechanism | Phase | Clinical Trials |
|---|---|---|---|---|
| CHEMBL1789844 | Ipilimumab (Yervoy) | CTLA4 inhibitor | 4 | 739 |
| CHEMBL2108658 | Tremelimumab (Imjudo) | CTLA4 inhibitor | 4 | 229 |
Total CTLA4-targeting molecules in clinical development: 2
Top 20 Clinical Trials (CTLA4-Targeting Drugs)
Ipilimumab (selected Phase 3/4 trials):
- NCT01844505 - Nivolumab + Ipilimumab vs Ipilimumab in Advanced Melanoma (CheckMate 067) | PHASE3 | COMPLETED
- NCT02231749 - Nivolumab + Ipilimumab vs Sunitinib in Renal Cell Carcinoma (CheckMate 214) | PHASE3 | COMPLETED
- NCT02388906 - Nivolumab vs Ipilimumab in Melanoma Prevention | PHASE3 | COMPLETED
- NCT02599402 - Nivolumab + Ipilimumab as First-Line for Advanced Melanoma | PHASE3 | COMPLETED
- NCT03215706 - Nivolumab + Ipilimumab + Chemotherapy vs Chemotherapy in NSCLC | PHASE3 | COMPLETED
Tremelimumab (selected Phase 3 trials): 6. NCT02352948 - Durvalumab ± Tremelimumab vs SOC in NSCLC | PHASE3 | COMPLETED 7. NCT02453282 - Durvalumab ± Tremelimumab in NSCLC (NEPTUNE) | PHASE3 | ACTIVE_NOT_RECRUITING 8. NCT03043872 - Durvalumab ± Tremelimumab + Chemotherapy in Small Cell Lung Cancer (CASPIAN) | PHASE3 | ACTIVE_NOT_RECRUITING 9. NCT03164616 - Durvalumab + Tremelimumab + Chemotherapy in Lung Cancer (POSEIDON) | PHASE3 | ACTIVE_NOT_RECRUITING 10. NCT05883644 - Durvalumab + Tremelimumab in Advanced Hepatocellular Carcinoma | PHASE3 | ACTIVE_NOT_RECRUITING
(Additional trials span melanoma, renal cell carcinoma, NSCLC, mesothelioma, gastric cancer, pancreatic cancer, and bladder cancer across phases 1-4)
Pharmacogenomics & Drug Response Data
PharmGKB Status:
- VIP Gene Status: Yes (Very Important Pharmacogene)
- CPIC Guidelines: None established for CTLA4
- Variant Annotations: Present in PharmGKB
Known Drug-Gene Interactions:
- No published dosing guidelines or FDA-recognized pharmacogenomic biomarkers specifically for CTLA4 polymorphisms affecting ipilimumab/tremelimumab response
- CTLA4 genetic polymorphisms (e.g., rs3087243, rs5742909) have been investigated in research settings for association with treatment response and immune-related adverse events (irAE), but clinical guidelines remain lacking
- No routine pharmacogenomic testing recommended for CTLA4-targeted immunotherapy
Clinical Considerations:
- Response to CTLA4 blockade is influenced by tumor microenvironment, PD-L1 expression, and T-cell phenotype rather than patient CTLA4 genotype
- Adverse event monitoring (autoimmune/inflammatory) is standard; no genotype-based dose adjustments established
Expression profiles
Tissue Expression (Bgee)
CTLA4 shows ubiquitous expression across multiple tissues with a maximum expression score of 87.62 (on a 0-100 scale).
| Tissue/Cell Type | Expression Score | Quality | Status |
|---|---|---|---|
| Lymph node | 87.62 | Gold | Present |
| Vermiform appendix | 84.08 | Gold | Present |
| Buccal mucosa cell | 83.44 | Silver | Present |
| Primordial germ cell in gonad | 82.82 | Gold | Present |
| Epithelial cell of pancreas | 80.77 | Silver | Present |
| Caecum | 80.12 | Gold | Present |
| Male germ line stem cell (testis) | 79.21 | Gold | Present |
| Granulocyte | 77.13 | Gold | Present |
| Pancreatic ductal cell | 75.87 | Gold | Present |
| Superficial temporal artery | 74.64 | Gold | Present |
| Gall bladder | 74.43 | Gold | Present |
| Tonsil | 73.71 | Gold | Present |
| Rectum | 73.08 | Gold | Present |
| Spleen | 72.07 | Gold | Present |
| Blood | 71.38 | Gold | Present |
| Epithelium of nasopharynx | 70.89 | Gold | Present |
| Small intestine Peyer’s patch | 70.22 | Gold | Present |
| Right lung | 68.56 | Gold | Present |
| Small intestine | 67.64 | Gold | Present |
| Mucosa of transverse colon | 67.50 | Gold | Present |
| Left lung (upper lobe) | 66.32 | Gold | Present |
| Lung (upper lobe) | 65.83 | Gold | Present |
| Tibialis anterior | 65.76 | Silver | Present |
Summary: CTLA4 shows highest expression in immune tissues (lymph nodes, spleen, blood, tonsils, appendix) and mucosal tissues, consistent with its known role as an immune checkpoint inhibitor on T cells. Notably absent from skeletal muscle, vena cava, and paranasal sinus mucosa.
Single-Cell Expression (SCXA datasets)
| Dataset ID | Description | Organism | Cell Count |
|---|---|---|---|
| E-CURD-89 | Immune cells from colon lamina propria & mesenteric lymph nodes | Homo sapiens | 1,526 |
| E-CURD-95 | EOMES+ Tr1-like cells in primary and metastatic tumors | Homo sapiens | 87,767 |
| E-HCAD-29 | GM-CSF-producing T helper cells | Homo sapiens | 78,686 |
Cell-type specific pattern: CTLA4 expression is predominantly enriched in T cell populations, particularly in:
- Regulatory T cells (Tregs)
- Clonally expanded tumor-infiltrating T cells (Tr1-like cells)
- Activated T helper cells (GM-CSF-producing Th1 cells)
This reflects CTLA4’s canonical role as a surface receptor on T lymphocytes.
Disease associations
Mendelian/Monogenic Diseases
| Disease | Disease ID | Inheritance | Evidence |
|---|---|---|---|
| Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency | OMIM:616100, Orphanet:436159, MONDO:0014493 | Autosomal dominant | Strong |
| Congenital microcephaly-severe encephalopathy-progressive cerebral atrophy syndrome | Orphanet:391376, MONDO:0014258 | Unknown | Supportive |
| Systemic lupus erythematosus | Orphanet:536, MONDO:0007915 | Unknown | Supportive |
| Immunodeficiency, common variable 1 | MONDO:0011864 | Unknown | - |
Phenotype Associations (Clinical HPO Terms, Top 30)
| HPO ID | Phenotype |
|---|---|
| HP:0000006 | Autosomal dominant inheritance |
| HP:0002960 | Autoimmunity |
| HP:0001973 | Autoimmune thrombocytopenia |
| HP:0001890 | Autoimmune hemolytic anemia |
| HP:0001904 | Autoimmune neutropenia |
| HP:0002721 | Immunodeficiency |
| HP:0001744 | Splenomegaly |
| HP:0002716 | Lymphadenopathy |
| HP:0002725 | Systemic lupus erythematosus |
| HP:0001369 | Arthritis |
| HP:0001701 | Pericarditis |
| HP:0002090 | Pneumonia |
| HP:0002206 | Pulmonary fibrosis |
| HP:0000872 | Hashimoto thyroiditis |
| HP:0100651 | Type I diabetes mellitus |
| HP:0000083 | Renal insufficiency |
| HP:0000099 | Glomerulonephritis |
| HP:0000093 | Proteinuria |
| HP:0002665 | Lymphoma |
| HP:0000988 | Skin rash |
| HP:0000979 | Purpura |
| HP:0001047 | Atopic dermatitis |
| HP:0003493 | Antinuclear antibody positivity |
| HP:0003613 | Antiphospholipid antibody positivity |
| HP:0020151 | Anti-dsDNA antibody positivity |
| HP:0001945 | Fever |
| HP:0001250 | Seizure |
| HP:0003565 | Elevated erythrocyte sedimentation rate |
| HP:0012378 | Fatigue |
| HP:0045073 | Serositis |
Complex Disease / GWAS Associations (Top 30)
| Trait | P-value | Mapped Gene/Locus | Study ID |
|---|---|---|---|
| Medication use (thyroid preparations) | 5e-85 | CTLA4 - ICOS | GCST007932_67 |
| Autoimmune thyroid disease | 2e-74 | CTLA4 | GCST010571_58 |
| Type 1 diabetes | 2e-17 | CTLA4 - ICOS | GCST001191_10 |
| Graves’ disease | 2e-17 | CTLA4 | GCST001200_2 |
| Rheumatoid arthritis | 9e-25 | CTLA4 - ICOS | GCST002318_144 |
| Rheumatoid arthritis | 4e-22 | CTLA4 - ICOS | GCST002318_42 |
| Rheumatoid arthritis | 1e-23 | CTLA4 - ICOS | GCST006959_29 |
| Rheumatoid arthritis | 9e-20 | CTLA4 - ICOS | GCST006959_145 |
| Celiac disease | 5e-10 | CTLA4 - ICOS | GCST009874_11 |
| Type 1 diabetes | 7e-21 | CTLA4 - ICOS | GCST005536_8 |
| Celiac disease | 1e-15 | CD28 - KRT18P39 | GCST005523_17 |
| Basal cell carcinoma | 3e-16 | CTLA4 - ICOS | GCST008871_68 |
| Basal cell carcinoma | 2e-18 | CTLA4 - ICOS | GCST90013410_33 |
| Keratinocyte cancer (MTAG) | 1e-14 | CTLA4 | GCST008870_84 |
| Hypothyroidism | 1e-15 | CTLA4 - ICOS | GCST003988_8 |
| Type 1 diabetes | 2e-16 | CTLA4 - ICOS | GCST009875_7 |
| Alopecia areata | 2e-20 | CTLA4 | GCST004866_12 |
| Alopecia areata | 4e-13 | CTLA4 | GCST000719_1 |
| Vitiligo | 1e-10 | CTLA4 - ICOS | GCST004785_49 |
| Rheumatoid arthritis (ACPA-positive) | 4e-11 | CTLA4 - ICOS | GCST005568_31 |
| Rheumatoid arthritis (ACPA-positive) | 9e-15 | CTLA4 - ICOS | GCST006048_48 |
| Myasthenia gravis | 9e-11 | CTLA4 | GCST002838_1 |
| Systemic lupus erythematosus | 2e-08 | CTLA4 - ICOS | GCST011096_17 |
| Systemic lupus erythematosus | 6e-06 | CTLA4 - ICOS | GCST90011866_9 |
| Multiple sclerosis | 1e-07 | CD28 - KRT18P39 | GCST005531_64 |
| Type 1 diabetes | 8e-11 | CTLA4 - ICOS | GCST000258_7 |
| Type 1 diabetes | 1e-15 | CTLA4 - ICOS | GCST000392_23 |
| Addison’s disease | 5e-11 | RNU6-474P - CTLA4 | GCST90011871_2 |
| Celiac disease | 2e-08 | RNU6-474P - CTLA4 | GCST008489_12 |
| Autoimmune traits (pleiotropy) | 5e-16 | CTLA4 - ICOS | GCST009873_35 |