CTLA4

Summary

CTLA4 (cytotoxic T-lymphocyte associated protein 4, HGNC:2505) is a protein-coding gene on chromosome 2q33.2, encoding Cytotoxic T-lymphocyte protein 4 (P16410). Inhibitory receptor acting as a major negative regulator of T-cell responses.

This gene is a member of the immunoglobulin superfamily and encodes a protein which transmits an inhibitory signal to T cells. The protein contains a V domain, a transmembrane domain, and a cytoplasmic tail. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. Mutations in this gene have been associated with insulin-dependent diabetes mellitus, Graves disease, Hashimoto thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, and other autoimmune diseases.

Source: NCBI Gene 1493 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 46 (top 2% of genes corpus-wide)
• Clinical variants (ClinVar): 315 total — 43 pathogenic, 25 likely-pathogenic (top 10% of genes corpus-wide)
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈6% of expected missense variation)
• GTEx eGene: eQTL in 7 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 181
• Drug target: yes — 6 curated mechanism-of-action drugs
• Approved drugs (ChEMBL mechanism of action): 2 — Ipilimumab, Tremelimumab
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.21 (highly constrained)
• MANE Select transcript: NM_005214
• Interaction hub: 4,126 STRING partners (top 1% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2505
Approved symbol	CTLA4
Name	cytotoxic T-lymphocyte associated protein 4
Location	2q33.2
Locus type	gene with protein product
Status	Approved
Aliases	CD152, CD, GSE, CTLA-4
Ensembl gene	ENSG00000163599
Ensembl biotype	protein_coding
OMIM	123890
Entrez	1493

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000648405

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 5: 2

ENST00000648405, ENST00000295854, ENST00000427473, ENST00000487393, ENST00000650075, ENST00000696049, ENST00000696479

RefSeq mRNA: 2 — MANE Select: NM_005214 NM_001037631, NM_005214

CCDS: CCDS2362, CCDS42803

Canonical transcript exons

ENST00000648405 — 4 exons

Exon	Start	End
ENSE00003548810	203870586	203870933
ENSE00003965892	203872708	203873965
ENSE00003965893	203871378	203871487
ENSE00003967479	203867771	203868051

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 87.62.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 5.9324 / max 1232.3727, expressed in 169 samples.

Highest expression (Bgee): lymph node, vermiform appendix, buccal mucosa cell, primordial germ cell in gonad, epithelial cell of pancreas.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CTLA4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 7 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

7 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	1.6e-10	+0.33	2:203874196:G:A
Adipose Subcutaneous	eqtl	1.1e-04	+0.27	2:203712200:C:A
Nerve Tibial	eqtl	2.3e-03	-0.45	2:203827021:A:G
Lung	eqtl	6.0e-03	+0.18	2:204437462:G:C
Whole Blood	eqtl	3.2e-02	+0.26	2:204806897:A:T
Artery Tibial	eqtl	4.0e-02	-0.28	2:203822795:G:A
Artery Aorta	eqtl	4.1e-02	-0.19	2:203875100:A:G

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
24779	3.0857	121
24781	2.1789	108
24780	0.4781	60
24782	0.1897	48

Top tissues by expression

showing 100 of 261 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lymph node	UBERON:0000029	87.62	gold quality
vermiform appendix	UBERON:0001154	84.08	gold quality
buccal mucosa cell	CL:0002336	83.44	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.82	gold quality
epithelial cell of pancreas	CL:0000083	80.77	silver quality
caecum	UBERON:0001153	80.12	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.21	gold quality
granulocyte	CL:0000094	77.13	gold quality
pancreatic ductal cell	CL:0002079	75.87	gold quality
superficial temporal artery	UBERON:0001614	74.64	gold quality
gall bladder	UBERON:0002110	74.43	gold quality
tonsil	UBERON:0002372	73.71	gold quality
rectum	UBERON:0001052	73.08	gold quality
spleen	UBERON:0002106	72.07	gold quality
blood	UBERON:0000178	71.38	gold quality
epithelium of nasopharynx	UBERON:0001951	70.89	gold quality
myocardium	UBERON:0002349	70.71	gold quality
small intestine Peyer’s patch	UBERON:0003454	70.22	gold quality
oocyte	CL:0000023	69.07	gold quality
right lung	UBERON:0002167	68.56	gold quality
small intestine	UBERON:0002108	67.64	gold quality
mucosa of paranasal sinus	UBERON:0005030	67.52	gold quality
mucosa of transverse colon	UBERON:0004991	67.50	gold quality
nasal cavity epithelium	UBERON:0005384	67.44	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	67.42	gold quality
vena cava	UBERON:0004087	66.91	gold quality
upper lobe of left lung	UBERON:0008952	66.32	gold quality
quadriceps femoris	UBERON:0001377	66.01	gold quality
upper lobe of lung	UBERON:0008948	65.83	gold quality
tibialis anterior	UBERON:0001385	65.76	silver quality
left ventricle myocardium	UBERON:0006566	65.46	gold quality
secondary oocyte	CL:0000655	65.36	gold quality
vastus lateralis	UBERON:0001379	65.30	gold quality
cardiac muscle of right atrium	UBERON:0003379	64.85	gold quality
upper arm skin	UBERON:0004263	64.66	gold quality
cerebellar vermis	UBERON:0004720	64.48	gold quality
bone marrow	UBERON:0002371	64.15	gold quality
mammary duct	UBERON:0001765	63.60	gold quality
epithelium of mammary gland	UBERON:0003244	63.34	gold quality
layer of synovial tissue	UBERON:0007616	63.04	gold quality
smooth muscle tissue	UBERON:0001135	62.65	gold quality
thymus	UBERON:0002370	62.56	silver quality
parotid gland	UBERON:0001831	61.95	gold quality
lung	UBERON:0002048	61.25	gold quality
left uterine tube	UBERON:0001303	61.11	gold quality
ileal mucosa	UBERON:0000331	61.07	gold quality
cartilage tissue	UBERON:0002418	61.04	gold quality
superior surface of tongue	UBERON:0007371	60.45	gold quality
peritoneum	UBERON:0002358	60.41	gold quality
omental fat pad	UBERON:0010414	60.41	gold quality
adipose tissue of abdominal region	UBERON:0007808	60.26	gold quality
esophagus mucosa	UBERON:0002469	60.16	gold quality
postcentral gyrus	UBERON:0002581	59.63	gold quality
tongue	UBERON:0001723	59.57	silver quality
bone marrow cell	CL:0002092	59.53	silver quality
body of tongue	UBERON:0011876	59.52	gold quality
colonic mucosa	UBERON:0000317	59.51	gold quality
decidua	UBERON:0002450	59.46	silver quality
saphenous vein	UBERON:0007318	59.42	gold quality
parietal lobe	UBERON:0001872	59.41	gold quality
transverse colon	UBERON:0001157	59.15	gold quality
oral cavity	UBERON:0000167	59.10	silver quality
intestine	UBERON:0000160	59.09	gold quality
heart right ventricle	UBERON:0002080	59.08	gold quality
pericardium	UBERON:0002407	59.06	gold quality
inferior vagus X ganglion	UBERON:0005363	59.01	gold quality
lower lobe of lung	UBERON:0008949	58.96	silver quality
subthalamic nucleus	UBERON:0001906	58.84	gold quality
colonic epithelium	UBERON:0000397	58.81	silver quality
nipple	UBERON:0002030	58.78	gold quality
synovial joint	UBERON:0002217	58.75	gold quality
dorsal plus ventral thalamus	UBERON:0001897	58.67	gold quality
substantia nigra pars compacta	UBERON:0001965	58.58	gold quality
muscle tissue	UBERON:0002385	58.54	gold quality
trigeminal ganglion	UBERON:0001675	58.51	gold quality
pons	UBERON:0000988	58.47	gold quality
renal medulla	UBERON:0000362	58.40	gold quality
cardia of stomach	UBERON:0001162	58.40	gold quality
calcaneal tendon	UBERON:0003701	58.40	gold quality
superior vestibular nucleus	UBERON:0007227	58.40	gold quality
substantia nigra pars reticulata	UBERON:0001966	58.35	gold quality
ventral tegmental area	UBERON:0002691	58.29	gold quality
lateral nuclear group of thalamus	UBERON:0002736	58.28	gold quality
trachea	UBERON:0003126	58.20	gold quality
lateral globus pallidus	UBERON:0002476	58.13	gold quality
urinary bladder	UBERON:0001255	57.95	gold quality
globus pallidus	UBERON:0001875	57.95	gold quality
esophagus squamous epithelium	UBERON:0006920	57.94	silver quality
upper leg skin	UBERON:0004262	57.88	gold quality
mucosa of sigmoid colon	UBERON:0004993	57.68	gold quality
medial globus pallidus	UBERON:0002477	57.66	gold quality
dorsal root ganglion	UBERON:0000044	57.58	gold quality
biceps brachii	UBERON:0001507	57.58	gold quality
vagina	UBERON:0000996	57.28	gold quality
medulla oblongata	UBERON:0001896	57.25	gold quality
superior frontal gyrus	UBERON:0002661	57.02	silver quality
mammalian vulva	UBERON:0000997	56.88	gold quality
right coronary artery	UBERON:0001625	56.84	gold quality
large intestine	UBERON:0000059	56.72	gold quality
urethra	UBERON:0000057	56.58	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-29	yes	2750.29
E-CURD-89	yes	525.47
E-CURD-88	yes	374.45
E-CURD-122	yes	340.29
E-CURD-120	yes	51.21
E-CURD-46	yes	25.51
E-ANND-3	yes	5.98
E-CURD-112	no	3.24

HPA expression

RNA tissue specificity: Tissue enriched

58 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Lymph node	tissue	35.1
Appendix	tissue	17.5
Tonsil	tissue	16.0
Thymus	tissue	9.5
Bone marrow	tissue	5.8
Urinary bladder	tissue	5.4
Gallbladder	tissue	4.9
Spleen	tissue	3.3
Rectum	tissue	3.0
Stomach 1	tissue	2.8
Lung	tissue	2.2
Esophagus	tissue	1.5
Prostate	tissue	1.5
Small intestine	tissue	1.3
Breast	tissue	1.0
Adipose tissue	tissue	1.0
Colon	tissue	1.0
Seminal vesicle	tissue	0.9
Testis	tissue	0.8
Smooth muscle	tissue	0.8
Choroid plexus	tissue	0.8
Heart muscle	tissue	0.7
Vagina	tissue	0.7
Liver	tissue	0.7
Cervix	tissue	0.6
Skin 1	tissue	0.6
Salivary gland	tissue	0.5
Parathyroid gland	tissue	0.4
Pancreas	tissue	0.4
Nucleus accumbens	tissue	0.4
Thyroid gland	tissue	0.4
Periaqueductal gray	tissue	0.4
Pituitary gland	tissue	0.3
Endometrium 1	tissue	0.3
Hypothalamus	tissue	0.3
Placenta	tissue	0.3
Substantia nigra	tissue	0.3
Kidney	tissue	0.3
Duodenum	tissue	0.3
Locus coeruleus	tissue	0.3
Spinal cord	tissue	0.3
Adrenal gland	tissue	0.3
Fallopian tube	tissue	0.3
Pons	tissue	0.2
Midbrain	tissue	0.2
Medulla oblongata	tissue	0.2
Hippocampus	tissue	0.2
Cerebral cortex	tissue	0.1
Ovary	tissue	0.1
Tongue	tissue	0.1
Basal ganglia	tissue	0.1
Amygdala	tissue	0.1
Thalamus	tissue	0.1
Superior colliculi	tissue	0.1
Hippocampal formation	tissue	0.1
Postcentral gyrus	tissue	0.1
Septum	tissue	0.1
Insular cortex	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 185; highest nTPM — Area postrema (2.2), Kolliker-Fuse nucleus (1.8), Nucleus tractus solitarii (1.3), Motor hypoglossal nucleus (1.0), Periaquaductal grey, lateral (1.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, ESR1, FOXO1, FOXP3, GATA3, IRF8, LEF1, MSC, NFATC2, NR3C1, NR5A1, RUNX1, USF1, USF2

miRNA regulators (miRDB)

Targeting CTLA4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 69 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3910	99.95	71.13	2227
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-154-3P	99.50	70.05	831

Functional genomics

gnomAD constraint: pLI 0.998, LOEUF 0.211, missense Z 2.09 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000648405 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈6% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:203,867,943–203,868,039	35 / 36.6	0.96	no
2:203,868,040–203,870,610	2 / 16.8	0.12	yes (p 3.1e-04)
2:203,870,611–203,872,809	147 / 223.4	0.66	no

Literature-anchored findings (GeneRIF, showing 40)

• CTLA4 gene polymorphisms are associated with, and linked to, insulin-dependent diabetes mellitus in a Russian population. (PMID:11286636)
• effect on cytokine production by antigen-stimulated T cells (PMID:11751964)
• CTLA4 gene region is associated with genetic susceptibility to celiac disease in UK families. (PMID:11826026)
• The B7-CD28/CTLA-4 costimulatory pathway has a dominant role in regulating T-cell activation. Antagonists enable graft survival and suppress autoimmunity. (PMID:11826754)
• results suggest that the CTLA-4 gene region on chromosome 2q33 is a susceptibility locus for autoimmune hypothyroidism in the United Kingdom (PMID:11842815)
• The CTLA-4 49 Ala allele confers an increased risk of type 1 diabetes, independent of age and HLA-DQ genetic markers (PMID:11900275)
• the strongest association between CTLA4 gene polymorphisms and RA susceptibility occurs with the 3’ UTR polymorphism (PMID:11916172)
• results support the concept that CTLA-4 plays a critical role in the autoimmune process in Graves’ disease (PMID:11936461)
• polymorphism in type 1 diabetics in a Romanian population (PMID:12003670)
• CTLA-4 gene polymorphism contributes to the genetic risk for latent autoimmune diabetes in adults. (PMID:12021137)
• Surface cytotoxic T lymphocyte-associated antigen 4 partitions within lipid rafts and relocates to the immunological synapse under conditions of inhibition of T cell activation. (PMID:12021313)
• association of Wegener’s granulomatosis (WG) with 2 single nucleotide polymorphisms (SNP), a +49 A/G polymorphism in coding sequence (CDS) 1 and a C/T base exchange in the promoter region at position -318. (PMID:12022356)
• Long-term therapy with recombinant human erythropoietin decreases percentage of T-cells in primary glomerulonephritis haemodialysis patients. (PMID:12032199)
• evidence against the +49 A/G transition as the aetiological polymorphism within the CTLA4 gene (PMID:12047357)
• segregation analysis supports the hypothesis of a modulation by CTLA-4 49 G/A dimorphism of the susceptibility to type 1 diabetes conferred by maternal HLA-DRB1*03 inheritance (PMID:12047362)
• Remission of Graves’ hyperthyroidism and A/G polymorphism at position 49 in exon 1 of cytotoxic T lymphocyte-associated molecule-4 gene. (PMID:12050220)
• The -318T allele is associated with a higher promoter activity than the -318C allele. (PMID:12058260)
• Cell surface expression of the HIV-1 envelope glycoproteins is directed from intracellular CTLA-4-containing regulated secretory granules. (CTLA-4) (PMID:12060749)
• exon 1 polymorphism of the cytotoxic T lymphocyte antigen 4 gene influences on thyroid antibody production in patients with newly diagnosed Graves’ disease. (PMID:12097196)
• Reduced expression of CTLA-4 may contribute to favorable umbilical cord blood T lymphocyte allogeneic responses (PMID:12135671)
• The results showed that the CTLA4 dimorphism does not affect susceptibility to MS in ethnic Russians, be these stratified or not with regard to DRB1 alleles corresponding to serologic specificities DR1 to DR16. (PMID:12173468)
• Among Filipinos, the CTLA-4 genotypes are associated with type I diabetes only in the presence of the predisposing DR3, 4, and 9 haplotypes (P=0.012). (PMID:12185534)
• role of ligation in modulating TCR-induced transcriptional profiles (PMID:12195015)
• Results suggest that the linkage of the CTLA-4 A49G single nucleotide polymorphism to autoimmune thyroid disease is most likely secondary to linkage disequilibrium. (PMID:12202150)
• HTLV-1 infection is not associated with CTLA-4 polymorphisms in patients with Hashimoto’s thyroiditis (PMID:12225635)
• Levels of sCTLA-4 increase with the serum concentration of antibodies against the acetylcholine receptor. The (AT)(n) polymorphism in the 3’-untranslated region causes decreased mRNA stability and reduced levels of CTLA-4. (PMID:12225905)
• common autoimmunity predisposing signal peptide variant of the cytotoxic T-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele (PMID:12244107)
• CTLA-4 upregulation during aging (PMID:12297345)
• CD80 and CD86 differ in their interactions with CTLA-4 and that CD80 appears to be the preferential inhibitory ligand for CTLA-4 working via a population of CD4(+) CD25(+) CTLA-4(+) regulatory T cells. (PMID:12355442)
• role of genotypes at the -1722 locus in susceptibility to systemic lupus erythematosus (PMID:12384790)
• analysis of expression on leukocytes, hematopoietic cell lines, and a variety of myeloid and lymphoid leukemias (PMID:12393538)
• at least two novel signal pathways regulate CTLA-4 gene expression and CD152 molecule up-regulation in human CD4(+) T lymphocytes, in the absence of full T cell activation (PMID:12444128)
• CTLA4 exon 1 dimorphism is associated with primary progressive multiple sclerosis. (PMID:12458055)
• C-318T and A+49G CTLA4 gene polymorphisms and their haplotypes are not associated in Dutch Caucasian patients with IBD and in Chinese patients with UC. (PMID:12465728)
• In Japanese patients, the +49A allele of CTLA-4 increased in the presence of systemic sclerosis with the anti-RNP antibody. (PMID:12508774)
• Allele G and G/G genotype confer genetic susceptibility to Grave’s disease; (ii) CTLA-4 A49G polymorphism is not associated with the development of Grave’s ophthalmopathy; (iii) different non-genetic factors may contribute to GO in different populations. (PMID:12534352)
• prevalence of the A and G alleles of the CTLA-4 gene in autoimmune hemolytic anemia, AIHA and CLL, and immune thrombocytopenic purpura indicate that the G allele predisposes to the development of AIHA, particularly among patients with CLL (PMID:12555221)
• CTLA-4 is a predisposing gene for celiac disease in an Italian population with a prominent role in patients not carrying the high-risk human leukocyte antigen-DQ2 molecules. (PMID:12559633)
• Length of exposure and microfilarial antigen status are both important factors in determining the level of CTLA-4 expression in filarial infections and may provide insight into its role in diminished parasite antigen-specific T cell responsiveness. (PMID:12574361)
• distinct association exists between the G allele of CTLA-4 and high values of GAD Ab, residual beta-cell function, and the absence of HLA-DRB1*0405. (PMID:12610047)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:dkey-1h24.6	ENSDARG00000092653
mus_musculus	Ctla4	ENSMUSG00000026011
rattus_norvegicus	Ctla4	ENSRNOG00000054129

Paralogs (1): CD28 (ENSG00000178562)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88556) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 44 distinct phenotype terms.

Mouse phenotype (MP)	Records
premature death	5
myocarditis	2
lung inflammation	2
salivary gland inflammation	2
abnormal regulatory T cell physiology	2
increased double-negative T cell number	2
decreased double-positive T cell number	2
abnormal splenic cell ratio	2
enlarged heart	1
abnormal liver morphology	1
enlarged spleen	1
spleen hyperplasia	1
enlarged lymph nodes	1
abnormal thymus morphology	1
autoimmune response	1
increased inflammatory response	1
vascular inflammation	1
pancreas inflammation	1
stomach inflammation	1
abnormal T cell differentiation	1
abnormal T cell physiology	1
abnormal immunoglobulin level	1
increased IgG level	1
increased IgE level	1
joint inflammation	1

+19 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Sus scrofa	Q9MYX7	90.1%	Diamond
Canis lupus familiaris	Q9XSI1	90.1%	Diamond
Oryctolagus cuniculus	P42072	86.5%	Diamond
Felis catus	O02757	83.3%	Diamond
Bos taurus	Q28071	82.2%	Diamond
Gallus gallus	P31043	53.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CD28	protein-coding	940
ICOS	protein-coding	29851

Protein

Protein identifiers

Cytotoxic T-lymphocyte protein 4 — P16410 (reviewed: P16410)

Alternative names: Cytotoxic T-lymphocyte-associated antigen 4

All UniProt accessions (3): P16410, A0A8Q3SIR7, A0A8Q3WKZ2

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitory receptor acting as a major negative regulator of T-cell responses. Acts as a decoy receptor: the affinity of CTLA4 for its natural B7 family ligands, CD80 and CD86, is considerably stronger than the affinity of their cognate stimulatory coreceptor CD28.

Subunit / interactions. Homodimer; disulfide-linked (PubMed:11279501, PubMed:11279502, PubMed:21156796, PubMed:28484017, Ref.24). Interacts with ICOSLG.

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed with highest levels in lymphoid tissues. Detected in activated T-cells where expression levels are 30- to 50-fold less than CD28, the stimulatory coreceptor, on the cell surface following activation.

Post-translational modifications. N-glycosylation is important for dimerization. Phosphorylation at Tyr-201 prevents binding to the AP-2 adapter complex, blocks endocytosis, and leads to retention of CTLA4 on the cell surface.

Disease relevance. Immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL) [MIM:616100] An autosomal dominant primary immunodeficiency characterized by severe autoimmunity, infiltration of non-lymphoid organs, such as the intestine, lungs and brain, by hyperactive T cells and B cells, autoimmune cytopenias, and hypogammaglobulinemia in early childhood. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. Genetic variations in CTLA4 might influence susceptibility to celiac disease and autoimmune disorders including Graves disease and systemic lupus erythematosus.

Miscellaneous. The therapeutic antibody Ipilimumab competes for the binding site of the endogenous ligands CD80/B7-1, CD86/B7-2 and ICOSLG.

Isoforms (5)

UniProt ID	Names	Canonical?
P16410-1	1	yes
P16410-2	2, ss-CTLA-4
P16410-3	3
P16410-4	4
P16410-5	5

RefSeq proteins (2): NP_001032720, NP_005205* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR008096	CTLA4	Family
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR040216	CTLA4/CD28	Family

Pfam: PF07686

UniProt features (51 total): strand 13, mutagenesis site 8, splice variant 6, helix 5, disulfide bond 3, region of interest 3, glycosylation site 2, topological domain 2, sequence variant 2, sequence conflict 2, signal peptide 1, chain 1, transmembrane region 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

22 structures by resolution:

PDB	Title	Method	Resolution (Å)
7CIO	Molecular interactions of cytoplasmic region of CTLA-4 with SH2 domains of PI3-kinase	X-RAY DIFFRACTION	1.1
9DQ3	Crystal structure of engineered Ipilimumab (mipi.4) Fab in complex with human CTLA-4	X-RAY DIFFRACTION	1.64
3OSK	Crystal structure of human CTLA-4 apo homodimer	X-RAY DIFFRACTION	1.8
5GGV	CTLA-4 in complex with tremelimumab Fab	X-RAY DIFFRACTION	2
3BX7	Engineered Human Lipocalin 2 (LCN2) in Complex with the Extracellular Domain of Human …	X-RAY DIFFRACTION	2.1
7ELX	The crystal structure of CTLA-4 and Fab	X-RAY DIFFRACTION	2.14
7DV4	Crystal structure of anti-CTLA-4 VH domain in complex with human CTLA-4	X-RAY DIFFRACTION	2.38
7SU0	Crystal structure of an acidic pH-selective Ipilimumab variant Ipi.105 in complex with …	X-RAY DIFFRACTION	2.41
7SU1	Crystal structure of an acidic pH-selective Ipilimumab variant Ipi.106 in complex with …	X-RAY DIFFRACTION	2.53
2X44	Structure of a strand-swapped dimeric form of CTLA-4	X-RAY DIFFRACTION	2.6
6RP8	Crystal Structure of Ipilimumab Fab complexed with CTLA-4 at 2.6A resolution	X-RAY DIFFRACTION	2.6
8GAB	Crystal structure of CTLA-4 in complex with a high affinity CTLA-4 binder	X-RAY DIFFRACTION	2.72
1I8L	HUMAN B7-1/CTLA-4 CO-STIMULATORY COMPLEX	X-RAY DIFFRACTION	3
5TRU	Structure of the first-in-class checkpoint inhibitor Ipilimumab bound to human CTLA-4	X-RAY DIFFRACTION	3
6RQM	A blocking anti-CTLA-4 Nanobody (KN044) complexed with CTLA-4	X-RAY DIFFRACTION	3
6XY2	Crystal structure of CTLA-4 complexed with the Fab of HL32 antibody	X-RAY DIFFRACTION	3.05
1I85	CRYSTAL STRUCTURE OF THE CTLA-4/B7-2 COMPLEX	X-RAY DIFFRACTION	3.2
5XJ3	Complex structure of ipilimumab-scFv and CTLA-4	X-RAY DIFFRACTION	3.2
8HIT	Crystal structure of anti-CTLA-4 humanized IgG1 MAb–JS007 in complex with human CTLA-4	X-RAY DIFFRACTION	3.2
6RPJ	A Non-blocking anti-CTLA-4 Nanobody complexed with CTLA-4	X-RAY DIFFRACTION	3.25
1H6E	MU2 ADAPTIN SUBUNIT (AP50) OF AP2 ADAPTOR (SECOND DOMAIN), COMPLEXED WITH CTLA-4 …	X-RAY DIFFRACTION	3.6
1AH1	CTLA-4, NMR, 20 STRUCTURES	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16410-F1	79.67	0.48

Antibody-complex structures (SAbDab)

23 antibodies co-crystallized with this protein: 5GGV, 5TRU, 5XJ3, 6RP8, 6RPJ, 6RQM, 6XY2, 7DV4, 7ELX, 7SU0, 7SU1, 8HIT, 9DQ3, DANVILOSTOMIG, ERFONRILIMAB, GOTISTOBART, IPILIMUMAB, LORIGERLIMAB, NURULIMAB, PORUSTOBART, SOVIPOSTOBART, TAZLESTOBART, VUDALIMAB

Human Protein Atlas

Protein class: CD markers, Predicted membrane proteins, Predicted intracellular proteins, Disease related genes, FDA approved drug targets, Biotech drugs, Human disease related genes, Diabetes, Primary immunodeficiency

Protein evidence: Evidence at protein level

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1)

Type	Positions
Phosphotyrosine	201

Disulfide bonds (3)

Type	Positions
Disulfide bond	58–129, 85–103
Interchain	157

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	113, 145

Mutagenesis-validated functional residues (8)

Position	Phenotype
45	strongly reduced interaction with cd80, cd86 and icoslg.
47	strongly reduced interaction with cd80, cd86 and icoslg.
49	strongly reduced interaction with cd80, cd86 and icoslg.
70	strongly reduced interaction with cd80, cd86 and icoslg.
130	strongly reduced interaction with cd80, cd86 and icoslg.
132	strongly reduced interaction with cd80, cd86 and icoslg.
139	strongly reduced interaction with cd80, cd86 and icoslg.
143	strongly reduced interaction with cd80, cd86 and icoslg.

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 10; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

10 pathways:

ID	Pathway	Evidence
R-HSA-389513	Co-inhibition by CTLA4	curated
R-HSA-389356	Co-stimulation by CD28	curated
R-HSA-8877330	RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	curated
R-HSA-1280218	Adaptive Immune System	—
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-168256	Immune System	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-388841	Regulation of T cell activation by CD28 family	—
R-HSA-8878171	Transcriptional regulation by RUNX1	—

MSigDB gene sets: 647 (showing top): GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, AAGCAAT_MIR137, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_B_CELL_ACTIVATION, NKX25_02, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_B_CELL_ACTIVATION, GOCC_CELL_SURFACE, GOBP_B_CELL_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION

GO Biological Process (13): adaptive immune response (GO:0002250), immune response (GO:0006955), DNA damage response (GO:0006974), negative regulation of B cell proliferation (GO:0030889), negative regulation of T cell proliferation (GO:0042130), positive regulation of apoptotic process (GO:0043065), negative regulation of regulatory T cell differentiation (GO:0045590), T cell receptor signaling pathway (GO:0050852), B cell receptor signaling pathway (GO:0050853), negative regulation of T cell receptor signaling pathway (GO:0050860), negative regulation of T cell activation (GO:0050868), immune system process (GO:0002376), regulation of T cell proliferation (GO:0042129)

GO Molecular Function (2): receptor decoy activity (GO:0140319), protein binding (GO:0005515)

GO Cellular Component (7): Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), clathrin-coated endocytic vesicle (GO:0045334), perinuclear region of cytoplasm (GO:0048471), protein complex involved in cell adhesion (GO:0098636), membrane (GO:0016020)

Reactome top-level categories

7 top-level categories:

Category	Pathways
Regulation of T cell activation by CD28 family	2
Transcriptional regulation by RUNX1	1
Immune System	1
RNA Polymerase II Transcription	1
Adaptive Immune System	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1

GO top-level categories

41 GO namespaces:

Category	Terms
negative regulation of lymphocyte proliferation	2
T cell proliferation	2
antigen receptor-mediated signaling pathway	2
regulation of T cell activation	2
cytoplasm	2
cellular anatomical structure	2
immune response	1
immune system process	1
response to stimulus	1
cellular response to stress	1
regulation of B cell proliferation	1
B cell proliferation	1
negative regulation of B cell activation	1
regulation of T cell proliferation	1
negative regulation of T cell activation	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
regulatory T cell differentiation	1
negative regulation of T cell differentiation	1
regulation of regulatory T cell differentiation	1
T cell receptor signaling pathway	1
regulation of T cell receptor signaling pathway	1
negative regulation of antigen receptor-mediated signaling pathway	1
T cell activation	1
negative regulation of lymphocyte activation	1
negative regulation of leukocyte cell-cell adhesion	1
biological_process	1
regulation of lymphocyte proliferation	1
molecular sequestering activity	1
binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
clathrin-coated vesicle	1
endocytic vesicle	1
protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 14 of 22 annotations. The rest are phylogenetic / computational / electronic (IEA).

14 experimentally-supported GO terms:

GO term	NS	Evidence
B cell receptor signaling pathway	BP	mutant phenotype
DNA damage response	BP	mutant phenotype
negative regulation of B cell proliferation	BP	mutant phenotype
negative regulation of T cell activation	BP	direct assay
negative regulation of T cell receptor signaling pathway	BP	direct assay
negative regulation of regulatory T cell differentiation	BP	direct assay
positive regulation of apoptotic process	BP	mutant phenotype
Golgi apparatus	CC	direct assay
clathrin-coated endocytic vesicle	CC	direct assay
external side of plasma membrane	CC	direct assay
perinuclear region of cytoplasm	CC	direct assay
plasma membrane	CC	direct assay
protein complex involved in cell adhesion	CC	direct assay
receptor decoy activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 4,126 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTLA4	PDCD1	Q15116	968
CTLA4	CD274	Q9NZQ7	966
CTLA4	CD80	P33681	962
CTLA4	CD86	P42081	954
CTLA4	ICOS	Q9Y6W8	952
CTLA4	CD4	P01730	942
CTLA4	IL2	P01585	941
CTLA4	FOXP3	Q9BZS1	939
CTLA4	IFNG	P01579	930
CTLA4	LAG3	P18627	927
CTLA4	CD8A	P01732	926
CTLA4	IL10	P22301	919
CTLA4	TNFRSF18	Q9Y5U5	916
CTLA4	PDCD1LG2	Q9BQ51	916
CTLA4	IDO1	P14902	909

IntAct

Human interaction partners of CTLA4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

24 partners by confidence:

Partner	Interaction type	MIscore	Records
CD80	direct interaction	0.880	10
CD86	direct interaction	0.840	6
LRBA	physical association	0.670	1
PIK3R1	association	0.640	3
CTXN3	physical association	0.560	3
MALL	physical association	0.560	3
TMEM218	physical association	0.560	3
B4GALT5	association	0.530	1
CD274	physical association	0.400	1
ICOSLG	physical association	0.400	1
RAPGEF1	physical association	0.400	1
SIGLEC10	physical association	0.400	1
TMEM120B	association	0.350	1
SMARCA4	proximity	0.270	4
SPOP	proximity	0.270	3
TRIM25	colocalization	0.270	2
AKT1	proximity	0.270	1
BRAF	proximity	0.270	1
EGFR	proximity	0.270	1
FYN	proximity	0.270	1
LAX1	colocalization	0.270	1
RAB8A	colocalization	0.270	1
STAT5A	proximity	0.270	1
STAT5B	proximity	0.270	1

BioGRID (119 interactions; top human partners by supporting records): AP2M1 (Co-crystal Structure; 5 records), CD80 (Reconstituted Complex; 4 records), CD86 (Co-localization; 3 records), FYN (Co-localization; 2 records), PPP2R5A (Affinity Capture-Western; 2 records), ABCD1 (Affinity Capture-MS), AGPAT3 (Affinity Capture-MS), AGPAT5 (Affinity Capture-MS), B4GALT5 (Affinity Capture-MS), BCAM (Affinity Capture-MS), BLZF1 (Affinity Capture-MS), BMPR1A (Affinity Capture-MS), C15orf61 (Affinity Capture-MS), CAPN15 (Affinity Capture-MS), CDON (Affinity Capture-MS)

SIGNOR signaling

10 signaling interactions:

A	Effect	B	Mechanism
FYN	unknown	CTLA4	phosphorylation
FYN	“up-regulates quantity by stabilization”	CTLA4	phosphorylation
JAK2	“up-regulates quantity by stabilization”	CTLA4	phosphorylation
LCK	“up-regulates quantity by stabilization”	CTLA4	phosphorylation
LCK	unknown	CTLA4	phosphorylation
ipilimumab	“down-regulates activity”	CTLA4	binding
CTLA4	“down-regulates activity”	AKT
CTLA4	up-regulates	“T cell exhaustion”
TXK	“up-regulates quantity by stabilization”	CTLA4	phosphorylation
hsa-miR-138-5p	“down-regulates quantity by repression”	CTLA4	“post transcriptional regulation”

Ligand–receptor pairs (CellPhoneDB) (2)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

2 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
CD80	receptor
CD86	receptor

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
CD28 dependent PI3K/Akt signaling	5	109.4×	2e-07
Constitutive Signaling by Aberrant PI3K in Cancer	5	35.2×	7e-06
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	6	32.3×	2e-06
Signaling by Interleukins	7	24.9×	1e-06
PIP3 activates AKT signaling	6	22.3×	6e-06
Diseases of signal transduction by growth factor receptors and second messengers	6	18.9×	1e-05
Cytokine Signaling in Immune system	7	15.9×	6e-06
Signaling by Receptor Tyrosine Kinases	5	14.3×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of T cell activation	5	119.7×	2e-07
T cell costimulation	5	85.1×	6e-07
adaptive immune response	6	23.0×	2e-05
immune response	5	10.7×	1e-03

Disease & clinical

Genetic variants

Variant evidence for CTLA4: 315 ClinVar records (68 pathogenic / likely pathogenic); 41 ClinGen expert-panel interpretations; 5 PharmGKB clinical annotations; 46 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

315 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	43
Likely pathogenic	25
Uncertain significance	140
Likely benign	69
Benign	21

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 68 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
161109	NM_005214.5(CTLA4):c.151C>T (p.Arg51Ter)	Pathogenic	reviewed by expert panel	10
945024	NM_005214.5(CTLA4):c.223C>T (p.Arg75Trp)	Pathogenic	reviewed by expert panel	6
644629	NM_005214.5(CTLA4):c.81dup (p.Leu28fs)	Pathogenic	reviewed by expert panel	3
161110	NM_005214.5(CTLA4):c.75del (p.Leu28fs)	Pathogenic	reviewed by expert panel	2
161112	NM_005214.5(CTLA4):c.105C>A (p.Cys35Ter)	Pathogenic	reviewed by expert panel	2
636389	NM_005214.5(CTLA4):c.457G>A (p.Asp153Asn)	Pathogenic	reviewed by expert panel	2
1439020	NM_005214.5(CTLA4):c.71_72del (p.Leu24fs)	Pathogenic	reviewed by expert panel	2
4683125	NM_005214.5(CTLA4):c.94_101delinsTTCTCTTCATCA (p.Pro32fs)	Pathogenic	reviewed by expert panel	1
4683126	NM_005214.5(CTLA4):c.361del (p.Ala121fs)	Pathogenic	reviewed by expert panel	1
432079	NM_005214.5(CTLA4):c.410C>T (p.Pro137Leu)	Likely pathogenic	reviewed by expert panel	6
623475	NM_005214.5(CTLA4):c.416A>G (p.Tyr139Cys)	Likely pathogenic	reviewed by expert panel	6
1711524	NM_005214.5(CTLA4):c.407C>T (p.Pro136Leu)	Likely pathogenic	reviewed by expert panel	3
827701	NM_005214.5(CTLA4):c.410C>G (p.Pro137Arg)	Likely pathogenic	reviewed by expert panel	2
4683129	NM_005214.5(CTLA4):c.406C>T (p.Pro136Ser)	Likely pathogenic	reviewed by expert panel	1
4683130	NM_005214.5(CTLA4):c.406C>G (p.Pro136Ala)	Likely pathogenic	reviewed by expert panel	1

Per-variant reference — Sugi Variant

Explore CTLA4’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

ClinGen expert-panel interpretations (41)

Expert ACMG interpretations from Antibody Deficiencies VCEP for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency; autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency — a higher-authority tier than individual ClinVar submissions.

Assertion	Variants
Pathogenic	11
Likely Pathogenic	7
Uncertain Significance	6
Likely Benign	2
Benign	15

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 30 predictions of 171):

Position(s)	Effect	Δscore	Sites
2:203868052	donor_loss	1.0000
2:203868052–203868053	donor_loss	0.9900	4
2:203870580	acceptor_gain	0.9900
2:203870934–203870935	donor_loss	0.9900	5
2:203870584–203870585	acceptor_loss	0.9800	4
2:203870935	donor_loss	0.9800
2:203870585	acceptor_loss	0.9700	2
2:203871376–203871377	acceptor_loss	0.9700	6
2:203871488–203871489	donor_loss	0.9700	5
2:203871489	donor_loss	0.9600

AlphaMissense

362 missense substitutions predicted likely pathogenic (of 1,460 scored), across 97 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M204	9	0.923	0.987
C129	7	0.985	0.994
C58	7	0.973	0.987
C85	7	0.957	0.983
C103	7	0.952	0.977
F215	7	0.885	0.982
C157	7	0.794	0.897
D123	7	0.767	0.933
P136	6	0.905	0.941
G144	6	0.903	0.973
G199	6	0.899	0.960
K203	6	0.897	0.961
P138	6	0.895	0.936
F56	6	0.860	0.968
F219	6	0.850	0.956
Q42	6	0.838	0.963
P217	6	0.826	0.886
E132	6	0.814	0.886
T147	6	0.809	0.958
V202	6	0.787	0.923

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Head and Neck Squamous Cell Carcinoma (TCGA)	favorable	0.000113
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	0.000259
Skin Cutaneous Melanoma (TCGA)	favorable	0.000873

Disease associations

OMIM: gene MIM:123890 | disease phenotypes: MIM:616100, MIM:140300, MIM:152700, MIM:601744, MIM:601388, MIM:609755, MIM:607594

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency	Strong	Autosomal dominant	3
systemic lupus erythematosus	Supportive	Unknown

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (5 panels, 5 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

5 panels:

Panel	Rating
COVID-19 research	green
Gastrointestinal epithelial barrier disorders	green
Infantile enterocolitis & monogenic inflammatory bowel disease	green
Intestinal failure or congenital diarrhoea	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green

Mondo (6): autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (MONDO:0014493), Hashimoto thyroiditis (MONDO:0007699), systemic lupus erythematosus (MONDO:0007915), type 1 diabetes mellitus 12 (MONDO:0011068), celiac disease, susceptibility to, 3 (MONDO:0012341), immunodeficiency, common variable, 1 (MONDO:0011864)

Orphanet (5): Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (Orphanet:436159), Systemic lupus erythematosus (Orphanet:536), OBSOLETE: Common variable immunodeficiency (Orphanet:1572), Late-onset combined immunodeficiency due to ICOS deficiency (Orphanet:695183), NON RARE IN EUROPE: Hashimoto thyroiditis (Orphanet:855)

HPO phenotypes

showing 60 of 181 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000024	Prostatitis
HP:0000071	Ureteral stenosis
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000099	Glomerulonephritis
HP:0000126	Hydronephrosis
HP:0000155	Oral ulcer
HP:0000163	Abnormal oral cavity morphology
HP:0000246	Sinusitis
HP:0000366	Abnormality of the nose
HP:0000388	Otitis media
HP:0000389	Chronic otitis media
HP:0000407	Sensorineural hearing impairment
HP:0000421	Epistaxis
HP:0000488	Retinopathy
HP:0000491	Keratitis
HP:0000492	Abnormal eyelid morphology
HP:0000505	Visual impairment
HP:0000520	Proptosis
HP:0000579	Nasolacrimal duct obstruction
HP:0000656	Ectropion
HP:0000716	Depression
HP:0000763	Sensory neuropathy
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000864	Abnormality of the hypothalamus-pituitary axis
HP:0000873	Diabetes insipidus
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000964	Eczematoid dermatitis
HP:0000969	Edema
HP:0000979	Purpura
HP:0000982	Palmoplantar keratoderma
HP:0000988	Skin rash
HP:0000989	Pruritus
HP:0000992	Cutaneous photosensitivity
HP:0001019	Erythroderma
HP:0001029	Poikiloderma
HP:0001047	Atopic dermatitis
HP:0001053	Hypopigmented skin patches
HP:0001250	Seizure
HP:0001287	Meningitis
HP:0001337	Tremor
HP:0001369	Arthritis
HP:0001510	Growth delay
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0001607	Subglottic stenosis
HP:0001681	Angina pectoris
HP:0001701	Pericarditis
HP:0001733	Pancreatitis
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001878	Hemolytic anemia
HP:0001882	Decreased total leukocyte count
HP:0001888	Decreased total lymphocyte count
HP:0001890	Autoimmune hemolytic anemia
HP:0001904	Autoimmune neutropenia

GWAS associations

showing 30 of 46 associations:

Study	Trait	p-value
GCST007932_85	Medication use (thyroid preparations)	5e-85
GCST010571_83	Autoimmune thyroid disease	2e-74
GCST002318_16	Rheumatoid arthritis	3e-25
GCST006959_29	Rheumatoid arthritis	1e-23
GCST002318_47	Rheumatoid arthritis	4e-22
GCST005536_40	Type 1 diabetes	7e-21
GCST004866_12	Alopecia areata	2e-20
GCST006959_121	Rheumatoid arthritis	9e-20
GCST90013410_36	Basal cell carcinoma	2e-18
GCST001191_10	Type 1 diabetes	2e-17
GCST001200_2	Graves’ disease	2e-17
GCST008644_10	Celiac disease and Rheumatoid arthritis	2e-17
GCST009875_7	Type 1 diabetes	2e-16
GCST008871_19	Basal cell carcinoma	3e-16
GCST009873_28	Autoimmune traits (pleiotropy)	5e-16
GCST000392_23	Type 1 diabetes	1e-15
GCST003988_11	Hypothyroidism	1e-15
GCST005523_12	Celiac disease	1e-15
GCST006048_22	Rheumatoid arthritis (ACPA-positive)	9e-15
GCST008870_33	Keratinocyte cancer (MTAG)	1e-14
GCST004302_16	Primary biliary cholangitis	1e-13
GCST000719_1	Alopecia areata	4e-13
GCST009877_5	Rheumatoid arthritis	1e-11
GCST005568_6	Rheumatoid arthritis (ACPA-positive)	4e-11
GCST90011871_2	Addison’s disease	5e-11
GCST005569_8	Rheumatoid arthritis	7e-11
GCST000258_7	Type 1 diabetes	8e-11
GCST002838_1	Myasthenia gravis	9e-11
GCST004785_49	Vitiligo	1e-10
GCST006979_285	Heel bone mineral density	3e-10

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0009933	Thyroid preparation use measurement
EFO:0010176	keratinocyte carcinoma

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
D050031	Hashimoto Disease	C19.874.871.102.500; C20.111.809.500
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590
C563326	Diabetes Mellitus, Insulin-Dependent, 12 *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2364164 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the CTLA4 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

6 curated-mechanism drugs:

Drug	Modality	Max phase
IPILIMUMAB	Antibody	4
TREMELIMUMAB	Antibody	4
CADONILIMAB	Antibody	3
ERFONRILIMAB	Antibody	3
QUAVONLIMAB	Antibody	3
ZALIFRELIMAB	Antibody	2

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

5 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs231775	Toxicity	3	cyclosporine	Kidney Transplantation
rs231775	Toxicity	3	Antiinflammatory agents;non-steroids
rs3087243	Toxicity	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Psoriasis
rs4553808	Toxicity	3	bortezomib;dexamethasone;melphalan;prednisone
rs4553808	Metabolism/PK	3	tacrolimus	Kidney Transplantation

PharmGKB variants

3 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs231775	CTLA4	3	2.25	2	Antiinflammatory agents;non-steroids;cyclosporine
rs3087243	CTLA4	3	2.50	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs4553808	CTLA4	3	4.00	2	bortezomib;dexamethasone;melphalan;prednisone;tacrolimus

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

9 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs3087243	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Toxicity	Genotypes AG + GG is associated with decreased risk of Psoriasis when treated with Tumor necrosis factor alpha (TNF-alpha) inhibitors in people with Psoriasis as compared to genotype AA.	PMID:26194362
rs4553808	tacrolimus	Metabolism/PK	Genotypes AG + GG is associated with increased exposure to tacrolimus in people with Kidney Transplantation as compared to genotype AA.	PMID:28112181
rs4553808	tacrolimus	Metabolism/PK	Genotype AA is associated with increased exposure to tacrolimus in people with Kidney Transplantation as compared to genotypes AG + GG.	PMID:28112181
rs231775	Antiinflammatory agents, non-steroids	Toxicity	Allele G is associated with decreased risk of Drug Hypersensitivity due to Antiinflammatory agents, non-steroids as compared to allele A.	PMID:28750137
rs3087243		Other	Allele A is associated with decreased risk of Arthritis, Rheumatoid as compared to allele G.	PMID:21120996
rs4553808	bortezomib, melphalan, prednisone	Toxicity	Genotype GG is associated with earlier onset of bortezomib-induced peripheral neuropathy when treated with bortezomib, melphalan and prednisone in people with Multiple Myeloma as compared to genotypes AA + AG.	PMID:21228734
rs231775	cyclosporine	Toxicity	Allele A is associated with increased likelihood of Gingival Overgrowth when treated with cyclosporine in people with Kidney Transplantation as compared to allele G.	PMID:18021981
rs231775	peginterferon alfa-2a, peginterferon alfa-2b, ribavirin	Efficacy	Allele A is associated with increased rapid virological response (RVR) in HCV-HIV coinfected patients when treated with peginterferon alfa-2a, peginterferon alfa-2b and ribavirin as compared to allele G.	PMID:23133602
rs231775	peginterferon alfa-2a, peginterferon alfa-2b, ribavirin	Toxicity	Genotype AG is associated with decreased risk of Anemia when treated with peginterferon alfa-2a, peginterferon alfa-2b and ribavirin as compared to genotype GG.	PMID:23133602

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
lorigerlimab	Binding	10.85	pEC50
cadonilimab	Binding	10.1	pEC50
tremelimumab	Binding	8.91	pKd
quavonlimab	Binding	8.44	pKd
ipilimumab	Binding	8.07	pKd

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5291170	KD	31 nM

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation, affects response to substance	3
Arsenic	increases expression, affects cotreatment, affects expression	2
triphenyl phosphate	affects expression	1
trichostatin A	affects cotreatment, increases expression	1
glucuronoxylomannan	increases expression	1
fumonisin B1	increases expression	1
di-n-butylphosphoric acid	affects expression	1
ON 01910	increases expression	1
Indirubin E804	affects cotreatment, decreases expression	1
7-bromoindirubin-3’-oxime	affects cotreatment, decreases expression	1
6,2’,4’-trimethoxyflavone	decreases expression, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
Arsenic Trioxide	increases expression	1
Amiodarone	increases expression	1
Benzene	increases expression	1
Hydroxychloroquine	affects cotreatment, decreases expression	1
Methotrexate	affects cotreatment, decreases expression	1
Sulfasalazine	decreases expression, affects cotreatment	1
Valproic Acid	decreases methylation	1
Zearalenone	increases expression	1
Simvastatin	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5256856	Binding	Binding affinity to recombinant human CTLA4 assessed as binding constant at 150 to 200 micromol/L measured for 600 sec bio-layer interferometry assay	Computational design of a cyclic peptide that inhibits the CTLA4 immune checkpoint. — *RSC Med Chem*

Cellosaurus cell lines

15 cell lines: 6 cancer cell line, 5 transformed cell line, 4 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_6384	CHO-DXB11 CTLA4 Ig-24	Transformed cell line	Female
CVCL_A7ZW	Raji-hCTLA4	Cancer cell line	Male
CVCL_B8E8	Abcam HCT 116 CTLA4 KO	Cancer cell line	Male
CVCL_B8UF	Abcam MCF-7 CTLA4 KO	Cancer cell line	Female
CVCL_B9GG	Abcam A-549 CTLA4 KO	Cancer cell line	Male
CVCL_D7BF	Abeomics CHO-K1 CTLA4	Spontaneously immortalized cell line	Female
CVCL_E6AS	CHO-CTLA4	Spontaneously immortalized cell line	Female
CVCL_E6AT	HEK293-CTLA4	Transformed cell line	Female
CVCL_E6Q4	Genomeditech CHO-K1 H_CTLA4	Spontaneously immortalized cell line	Female
CVCL_E6TU	Genomeditech HEK-293 H_CTLA4	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 339 trials:

NCT	Phase	Status	Title
NCT00120887	Phase 4	COMPLETED	Lupus Atherosclerosis Prevention Study
NCT00125307	Phase 4	COMPLETED	Tacrolimus for the Treatment of Systemic Lupus Erythematosus With Membranous Nephritis
NCT00188188	Phase 4	UNKNOWN	Study of Endothelial Dysfunction in Systemic Lupus and Its Role in Heart Disease
NCT00371501	Phase 4	COMPLETED	Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus
NCT00392093	Phase 4	COMPLETED	Effect of Hormone Replacement Therapy on Lupus Activity
NCT00413361	Phase 4	COMPLETED	The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS
NCT00508898	Phase 4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00668330	Phase 4	COMPLETED	Steroid Induced Osteoporosis in Patients With Systemic Lupus Erythematosus
NCT00739050	Phase 4	TERMINATED	Effect of Simvastatin on Endothelial Function in Premenopausal Women With Systemic Lupus Erythematosus (0733-271)(TERMINATED)
NCT00815282	Phase 4	COMPLETED	Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
NCT00828178	Phase 4	COMPLETED	Efficacy of Fish Oil in Lupus Patients
NCT00866229	Phase 4	UNKNOWN	Efficacy and Adverse Effect of Simvastatin Compare to Rosuvastatin in Systemic Lupus Erythematosus (SLE) Patients With Corticosteroid Therapy and High Low-Density Lipoprotein (LDL) Cholesterol Level
NCT00911521	Phase 4	COMPLETED	Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled Study
NCT01101802	Phase 4	COMPLETED	Mycophenolate Mofetil in Systemic Lupus Erythematosus (MISSILE)
NCT01112215	Phase 4	COMPLETED	Enteric-coated Mycophenolate Sodium Versus Azathioprine for the Extra-renal Lupus Manifestations
NCT01151644	Phase 4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01276782	Phase 4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01322308	Phase 4	COMPLETED	Effect of Pioglitazone on Endothelial Function in Premenopausal Women With Uncomplicated Systemic Lupus Erythematosus
NCT01359826	Phase 4	WITHDRAWN	The Effect of Milnacipran on Fatigue and Quality of Life in Lupus Patients
NCT01597492	Phase 4	COMPLETED	A Study to Evaluate the Effect of Belimumab on Vaccine Responses in Subjects With Systemic Lupus Erythematosus (SLE)
NCT01632241	Phase 4	COMPLETED	Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
NCT01705977	Phase 4	COMPLETED	Belimumab Assessment of Safety in SLE
NCT01753401	Phase 4	COMPLETED	Acthar for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients With a History of Persistently Active Disease
NCT02270970	Phase 4	UNKNOWN	Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy
NCT02477150	Phase 4	COMPLETED	Safety and Immunogenicity of a Zoster Vaccine in SLE
NCT02741960	Phase 4	COMPLETED	The Effect of Metformin on Reducing Lupus Flares
NCT02779153	Phase 4	WITHDRAWN	Acthar SLE (Systemic Lupus Erythematosus)
NCT02953821	Phase 4	COMPLETED	Acthar Gel for Active Systemic Lupus Erythematosus (SLE)
NCT03042260	Phase 4	UNKNOWN	Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous
NCT03098823	Phase 4	COMPLETED	A Crossover Study to Compare RAYOS to IR Prednisone to Improve Fatigue and Morning Symptoms for SLE
NCT03122431	Phase 4	COMPLETED	Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
NCT03543839	Phase 4	RECRUITING	Trial of Belimumab in Early Lupus
NCT04447053	Phase 4	UNKNOWN	Sequential Belimumab and T-cell Based Therapy in SLE
NCT04515719	Phase 4	COMPLETED	Efficacy and Safety of Belimumab in SLE Patients
NCT04893161	Phase 4	UNKNOWN	A Model About the Response of Belimumab in SLE
NCT04908865	Phase 4	COMPLETED	Open-label Study of Belimumab Plus Standard Therapy in Chinese Pediatric Participants With Active Systemic Lupus Erythematosus (SLE)
NCT04956484	Phase 4	COMPLETED	Belimumab In Early Systemic Lupus Erythematosus
NCT05559671	Phase 4	RECRUITING	Safety of the Herpes Zoster Subunit Vaccine in Lupus
NCT05666336	Phase 4	UNKNOWN	Multi-omics Studies on the Efficacy of Telitacicept in Chinese SLE Patients
NCT05748925	Phase 4	COMPLETED	Cardio Renal Effects of SGLT2 Inhibitors Among Lupus Nephritis Patients
NCT05828147	Phase 4	UNKNOWN	Anti-CD20 Antibodies for Treatment of SLE-PAH
NCT05879419	Phase 4	ACTIVE_NOT_RECRUITING	Recombinant Herpes Zoster Vaccine in Patients With Autoimmune Rheumatic Diseases
NCT05899907	Phase 4	UNKNOWN	Efficacy and Safety of Telitacicept in Early SLE
NCT05916781	Phase 4	UNKNOWN	Effectiveness of Mycophenolate Mofetil Combined With Tacrolimus for Steroid Tapering in Systemic Lupus Erythematosus
NCT06411249	Phase 4	ACTIVE_NOT_RECRUITING	A Study Describing the Efficacy and Safety of Belimumab Administered in Adult Participants With Early Systemic Lupus Erythematosus (SLE)
NCT06594068	Phase 4	RECRUITING	Prospective Registry Investigating Maternal, Infant, and Lactation Outcomes in Anifrolumab Users
NCT06677801	Phase 4	ACTIVE_NOT_RECRUITING	Immune Cell Subsets in SLE Patients Treated with Telitacicept
NCT06763783	Phase 4	ENROLLING_BY_INVITATION	Vaccination Against Herpes Zoster in Patients With Inflammatory Rheumatic Diseases
NCT06875960	Phase 4	RECRUITING	A Study to Continue the Administration of Deucravacitinib in Participants With Systemic Lupus Erythematosus (SLE) or Discoid and/or Subacute Cutaneous Lupus Erythematosus (DLE/SCLE) Who Have Completed Study IM011074 or Study IM011132
NCT07077486	Phase 4	RECRUITING	Effects of Telitacicept vs Cyclophosphamide on Lupus Related Interstitial Lung Disease
NCT07087912	Phase 4	RECRUITING	Safety and Immunogenicity of the Live Attenuated Tetravalent Butantan-Dengue Vaccine in Autoimmune Rheumatic Diseases
NCT07381465	Phase 4	ACTIVE_NOT_RECRUITING	Efficacy and Safety of IL-1 Inhibitors in Mild to Moderate Systemic Lupus Erythematosus
NCT07611747	Phase 4	RECRUITING	Carotid Ultrasound-Based Strategy for Primary Prevention of Cardiovascular Events in Inflammatory Rheumatic Disease (PREVENER)
NCT07760480	Phase 4	RECRUITING	Assessing Residual Inflammation and Macrophage Presence in Lupus Nephritis After 3 Months of Intensified Treatment With Prednisolone, Mycofenolate Mofetil and Voclosporin as Compared to Mycofenolate Mofetil and Prednisolone
NCT05435547	Phase 4	RECRUITING	Preoperative Corticosteroids in Autoimmune Thyroid Disease
NCT00000419	Phase 3	TERMINATED	Safety of Estrogens in Lupus: Hormone Replacement Therapy
NCT00000420	Phase 3	COMPLETED	Safety of Estrogens in Lupus: Birth Control Pills
NCT00004662	Phase 3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Dehydroepiandrosterone in Women With Active Systemic Lupus Erythematosus
NCT00005778	Phase 3	COMPLETED	High-Dose Intravenous (IV) Cyclophosphamide Versus Monthly IV Cyclophosphamide
NCT00025818	Phase 3	COMPLETED	Six Month Clinical Research Study for Patients With Moderate or Severe Dry Eye Syndrome