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GeneE
50 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
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CTLA4
cytotoxic T-lymphocyte associated protein 4
Chromosome 2 Β· 2q33.2
NCBI Gene: 1493Ensembl: ENSG00000163599.18HGNC: HGNC:2505UniProt: P16410
1,338PubMed Papers
24Diseases
6Drugs
62Pathogenic Variants
FUNCTIONAL ROLE
Highly ConstrainedHub Gene
RESEARCH IMPACT
Highly StudiedVariant-Rich
CLINICAL
FDA Approved TargetOMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
protein bindingreceptor decoy activityexternal side of plasma membraneGolgi apparatusautoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiencysystemic lupus erythematosusmelanomaHashimoto's thyroiditis
✦AI Summary

CTLA4 is an inhibitory immune checkpoint receptor that functions as a major negative regulator of T cell responses 1. It acts as a decoy receptor with substantially higher affinity for B7 family ligands (CD80 and CD86) compared to the stimulatory coreceptor CD28, allowing it to competitively suppress T cell activation 12. This inhibitory function is critical for maintaining immune homeostasis; dysregulation of CTLA4 is implicated in both autoimmunity and cancer. In cancer immunotherapy, CTLA4-blocking monoclonal antibodies (ipilimumab, tremelimumab) enhance anti-tumor T cell responses and are approved for melanoma, non-small-cell lung cancer, and renal cell carcinoma 34. Conversely, in autoimmune diseases including systemic lupus erythematosus, type 1 diabetes, and celiac disease, CTLA4 genetic variants are associated with disease susceptibility, suggesting insufficient inhibitory signaling contributes to pathogenesis 5. CTLA4 polymorphisms affecting receptor structure and function have been identified as disease-associated variants 6. Furthermore, CTLA4-CD28 fusion mutations in T cell lymphomas convert inhibitory to activating signals, promoting malignant T cell proliferation 7. Thus, CTLA4 represents a critical immune checkpoint with therapeutic relevance in both enhancing anti-tumor immunity and restraining autoimmune responses.

Sources cited
1
CTLA4 is an inhibitory receptor and major negative regulator of T cell responses; acts as decoy receptor with higher affinity for CD80/CD86 than CD28
PMID: 11279501
2
CTLA4 decoy receptor activity with stronger affinity for B7 ligands compared to CD28
PMID: 16551244
3
Ipilimumab is an anti-CTLA4 monoclonal antibody in clinical development for melanoma, prostate cancer, lymphoma, and lung cancer
PMID: 20698719
4
Tremelimumab is a fully human anti-CTLA4 antibody in phase III development for melanoma and phase II for multiple other cancers
PMID: 20698721
5
CTLA4 is an essential inhibitor of T cell responses; polymorphisms are associated with autoimmune disease susceptibility
PMID: 15790353
6
CTLA4 polymorphisms are associated with rheumatoid arthritis, autosomal dominant immune dysregulation syndrome, and autoimmune diseases
PMID: 36443461
7
CTLA4-CD28 fusion converts inhibitory to activating signals, promoting T cell proliferation and lymphoma development
PMID: 35003894
Disease Associationsβ“˜24
autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiencyOpen Targets
0.79Strong
systemic lupus erythematosusOpen Targets
0.62Moderate
melanomaOpen Targets
0.61Moderate
Hashimoto's thyroiditisOpen Targets
0.60Moderate
non-small cell lung carcinomaOpen Targets
0.60Moderate
hepatocellular carcinomaOpen Targets
0.60Moderate
type 1 diabetes mellitusOpen Targets
0.56Moderate
renal cell carcinomaOpen Targets
0.56Moderate
rheumatoid arthritisOpen Targets
0.55Moderate
metastatic melanomaOpen Targets
0.55Moderate
hypothyroidismOpen Targets
0.54Moderate
Graves diseaseOpen Targets
0.53Moderate
neoplasmOpen Targets
0.52Moderate
thyroid diseaseOpen Targets
0.50Moderate
autoimmune diseaseOpen Targets
0.49Moderate
myxedemaOpen Targets
0.49Moderate
ThyrotoxicosisOpen Targets
0.48Moderate
common variable immunodeficiencyOpen Targets
0.48Moderate
hyperthyroidismOpen Targets
0.48Moderate
autoimmune thyroid diseaseOpen Targets
0.47Moderate
Celiac disease 3UniProt
Immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferationUniProt
Systemic lupus erythematosusUniProt
Type 1 diabetes mellitus 12UniProt
Pathogenic Variants62
NM_005214.5(CTLA4):c.105C>A (p.Cys35Ter)Pathogenic
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
β˜…β˜…β˜…β˜†2025β†’ Residue 35
NM_005214.5(CTLA4):c.410C>T (p.Pro137Leu)Likely pathogenic
not provided|Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency|Celiac disease, susceptibility to, 3;Type 1 diabetes mellitus 12;Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency;Hashimoto thyroiditis;Systemic lupus erythematosus
β˜…β˜…β˜…β˜†2025β†’ Residue 137
NM_005214.5(CTLA4):c.416A>G (p.Tyr139Cys)Likely pathogenic
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency|not provided
β˜…β˜…β˜…β˜†2025β†’ Residue 139
NM_005214.5(CTLA4):c.94_101delinsTTCTCTTCATCA (p.Pro32fs)Pathogenic
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
β˜…β˜…β˜…β˜†2025β†’ Residue 32
NM_005214.5(CTLA4):c.457G>A (p.Asp153Asn)Pathogenic
not provided|Celiac disease, susceptibility to, 3;Hashimoto thyroiditis;Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency;Type 1 diabetes mellitus 12;Systemic lupus erythematosus|Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
β˜…β˜…β˜…β˜†2025β†’ Residue 153
NM_005214.5(CTLA4):c.223C>T (p.Arg75Trp)Pathogenic
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency|not provided
β˜…β˜…β˜…β˜†2025β†’ Residue 75
NM_005214.5(CTLA4):c.406C>T (p.Pro136Ser)Likely pathogenic
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
β˜…β˜…β˜…β˜†2025β†’ Residue 136
NM_005214.5(CTLA4):c.406C>G (p.Pro136Ala)Likely pathogenic
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
β˜…β˜…β˜…β˜†2025β†’ Residue 136
NM_005214.5(CTLA4):c.151C>T (p.Arg51Ter)Pathogenic
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency|not provided|Inborn genetic diseases|Type 1 diabetes mellitus 12;Systemic lupus erythematosus;Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency;Celiac disease, susceptibility to, 3;Hashimoto thyroiditis
β˜…β˜…β˜…β˜†2025β†’ Residue 51
NM_005214.5(CTLA4):c.75del (p.Leu28fs)Pathogenic
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
β˜…β˜…β˜…β˜†2025β†’ Residue 28
NM_005214.5(CTLA4):c.71_72del (p.Leu24fs)Pathogenic
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
β˜…β˜…β˜…β˜†2025β†’ Residue 24
NM_005214.5(CTLA4):c.410C>G (p.Pro137Arg)Likely pathogenic
Inherited Immunodeficiency Diseases|Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
β˜…β˜…β˜…β˜†2025β†’ Residue 137
NM_005214.5(CTLA4):c.407C>T (p.Pro136Leu)Likely pathogenic
not provided|Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
β˜…β˜…β˜…β˜†2025β†’ Residue 136
NM_005214.5(CTLA4):c.81dup (p.Leu28fs)Pathogenic
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency|not provided
β˜…β˜…β˜…β˜†2025β†’ Residue 28
NM_005214.5(CTLA4):c.361del (p.Ala121fs)Pathogenic
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
β˜…β˜…β˜…β˜†2025β†’ Residue 121
NM_005214.5(CTLA4):c.209G>A (p.Arg70Gln)Likely pathogenic
Inherited Immunodeficiency Diseases|Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 70
NM_005214.5(CTLA4):c.208C>T (p.Arg70Trp)Pathogenic
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 70
NM_005214.5(CTLA4):c.436G>A (p.Gly146Arg)Pathogenic
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency|Inborn genetic diseases|CTLA4-related disorder
β˜…β˜…β˜†β˜†2025β†’ Residue 146
NM_005214.5(CTLA4):c.60G>A (p.Trp20Ter)Pathogenic
not provided|Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
β˜…β˜…β˜†β˜†2024β†’ Residue 20
NM_005214.5(CTLA4):c.226C>T (p.Gln76Ter)Pathogenic
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency
β˜…β˜…β˜†β˜†2022β†’ Residue 76
View on ClinVar β†—
Drug Targets6
CADONILIMABPhase III
Programmed cell death protein 1 inhibitor
cervical cancer
ERFONRILIMABPhase III
Cytotoxic T-lymphocyte protein 4 inhibitor
non-small cell lung carcinoma
IPILIMUMABApproved
Cytotoxic T-lymphocyte protein 4 inhibitor
melanoma
QUAVONLIMABPhase III
Cytotoxic T-lymphocyte protein 4 inhibitor
renal cell carcinoma
TREMELIMUMABApproved
Cytotoxic T-lymphocyte protein 4 inhibitor
non-small cell lung carcinoma
ZALIFRELIMABPhase II
Cytotoxic T-lymphocyte protein 4 inhibitor
non-small cell lung carcinoma
Related Genes
CD58Protein interaction100%CD70Protein interaction100%LCKProtein interaction100%TMIGD2Protein interaction100%IFNGProtein interaction99%LGALS9CProtein interaction99%
Tissue Expression6 tissues
Bone Marrow
100%
Lung
26%
Heart
6%
Liver
3%
Ovary
1%
Brain
0%
Gene Interaction Network
Click a node to explore
CTLA4CD58CD70LCKTMIGD2IFNGLGALS9C
PROTEIN STRUCTURE
Preparing viewer…
PDB7CIO Β· 1.10 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.21Highly Constrained
pLIβ“˜
1.00Intolerant
Observed/Expected LoF0.00 [0.00–0.21]
RankingsWhere CTLA4 stands among ~20K protein-coding genes
  • #102of 20,598
    Most Researched1,338 Β· top 1%
  • #493of 1,025
    FDA-Approved Drug Targets2
  • #1,138of 5,498
    Most Pathogenic Variants62 Β· top quartile
  • #506of 17,882
    Most Constrained (LOEUF)0.21 Β· top 5%
Genes detectedCTLA4
Sources retrieved50 papers
Response timeβ€”
πŸ“„ Sources
50β–Ό
1
Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy.
PMID: 27079802
Nat Rev Cancer Β· 2016
1.00
2
Ipilimumab.
PMID: 20698719
Drugs R D Β· 2010
0.90
3
[Immunotherapy and cancer: towards 2020.].
PMID: 30667385
Recenti Prog Med Β· 2018
0.86
4
CTLA4-related primary immune dysregulatory disorders.
PMID: 41158012
Curr Opin Allergy Clin Immunol Β· 2025
0.80
5
Targeting co-stimulatory molecules in autoimmune disease.
PMID: 32939077
Nat Rev Drug Discov Β· 2020
0.80