CTLA4

Chr 2AD

cytotoxic T-lymphocyte associated protein 4

Also known as: ALPS5, CD, CD152, CELIAC3, CTLA-4, GRD4, GSE, IDDM12

NCBI Gene: 1493ENSG00000163599OMIM: 123890

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. [provided by RefSeq, Jul 2008]

GeneReviewsOMIMResearchGenerating clinical summary…
MultiplemechanismADLOEUF 0.331 OMIM phenotype
Clinical Summary— CTLA4
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Gene-Disease Validity (ClinGen)
autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.94). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
68 unique Pathogenic / Likely Pathogenic· 139 VUS of 307 total submissions
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Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — CTLA4
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?
0.33LOEUF
pLI 0.941
Z-score 2.77
OE 0.00 (0.00–0.33)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?
1.69Z-score
OE missense 0.58 (0.48–0.70)
74 obs / 127.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.00 (0.00–0.33)
0≤0.351.4
Missense OE?0.58 (0.48–0.70)
0≤0.61.4
Synonymous OE?0.88
0≤1.21.6
LoF obs/exp: 0 / 9.0Missense obs/exp: 74 / 127.6Syn Z: 0.65

This gene — mechanism propensity

DN
0.4884th %ile
GOF
0.6540th %ile
LOF
0.51top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 57% of P/LP variants are LoF · LOEUF 0.33
GOFprediction above median
DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNAs CTLA-4 forms homodimers and clusters with its ligands, these mutants may exert a dominant negative effect.1
LOFTaken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

  1. 1.PMID 25329329 ↗

ClinVar Variant Classifications

307 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45
Likely Pathogenic23
VUS139
Likely Benign67
Benign21
Conflicting10
45
Pathogenic
23
Likely Pathogenic
139
VUS
67
Likely Benign
21
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
32
7
6
0
45
Likely Pathogenic
7
15
1
0
23
VUS
4
121
10
4
139
Likely Benign
0
8
15
44
67
Benign
0
10
9
2
21
Conflicting
—10
Total431614150305

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

30 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap CTLA4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

CTLA4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Lung Adenocarcinoma

PHOENIX: QL1706 Plus Chemotherapy and Bevacizumab in AGA-Resistant, PD-L1 ≥50% Non-Squamous NSCLC

NOT YET RECRUITING
NCT07416058Phase PHASE2Guangdong Association of Clinical TrialsStarted 2026-01-31
QL1706 (bispecific antibody targeting PD-1 and CLTA-4)
ALK Gene RearrangementEGFR Gene MutationLocally Advanced Lung Non-Small Cell Carcinoma

Ipilimumab and Nivolumab in Combination With Radiation Therapy in Treating Patients With Stage 2-3 Non-small Lung Cancer

ACTIVE NOT RECRUITING
NCT04013542Phase PHASE1M.D. Anderson Cancer CenterStarted 2019-09-13
IpilimumabNivolumabRadiation Therapy
Biliary Tract CancerDNA Damage Repair Deficiency

Olaparib With or Without Durvalumab for DDR Gene Mutated Biliary Tract Cancer Following Platinum-based Chemotherapy

RECRUITING
NCT05222971Phase PHASE2Asan Medical CenterStarted 2022-04-01
DurvalumabOlaparib
BCLC Stage B Hepatocellular CarcinomaBCLC Stage C Hepatocellular CarcinomaLocally Advanced Hepatocellular Carcinoma

Durvalumab and Tremelimumab After Radioembolization for the Treatment of Unresectable, Locally Advanced Liver Cancer

ACTIVE NOT RECRUITING
NCT04605731Phase PHASE1City of Hope Medical CenterStarted 2021-08-03
DurvalumabTremelimumab
Clinical Stage III Cutaneous Melanoma AJCC v8Clinical Stage IV Cutaneous Melanoma AJCC v8Metastatic Melanoma

Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAFV600 Melanoma

ACTIVE NOT RECRUITING
NCT02224781Phase PHASE3National Cancer Institute (NCI)Started 2015-09-08
Biospecimen CollectionComputed TomographyDabrafenib Mesylate
Melanoma Stage IIIMelanoma Stage IVAdvanced Melanoma

Neoadjuvant and Adjuvant Anti-PD1 or Combinations for Locoregionally Advanced Melanoma

RECRUITING
NCT06295159Phase PHASE2H. Lee Moffitt Cancer Center and Research InstituteStarted 2024-05-17
NivolumabNivolumab + RelatlimabIpilimumab
PI3KCDCTLA4STAT3GOF

Novel Genetic Disorders of the Immune System

RECRUITING
NCT02257892National Institute of Allergy and Infectious Diseases (NIAID)Started 2014-10-22
Ovary Cancer

RC48 in Combination With AK104 and Bevacizumab in OCCC

RECRUITING
NCT06540729Phase PHASE2Sun Yat-Sen Memorial Hospital of Sun Yat-Sen UniversityStarted 2024-09-24
Disitamab vedotin in combination with AK104 and bevacizumab for the treatment of recurrent and persistent clear cell ovarian cancer
Advanced Clear Cell Renal Cell CarcinomaMetastatic Clear Cell Renal Cell CarcinomaStage III Renal Cell Cancer AJCC v8

Genetic Testing to Select Therapy for the Treatment of Advanced or Metastatic Kidney Cancer, OPTIC RCC Study

RECRUITING
NCT05361720Phase PHASE2Vanderbilt-Ingram Cancer CenterStarted 2022-12-06
CabozantinibIpilimumabNivolumab
Vascular Complications

Prospective Exploration of Vascular Complications Associated With the Use of Immune Checkpoint Inhibitors

NOT YET RECRUITING
NCT07535944University Hospital, RouenStarted 2026-06-01
Evaluation of the vascular impact of ICIs (Immune Checkpoint Inhibitors)
Meningiomas

An Open-Label Phase II Study of Nivolumab or Nivolumab/Ipilimumab in Adult Participants With Progessive/ Recurrent Meningioma

ACTIVE NOT RECRUITING
NCT02648997Phase PHASE2Dana-Farber Cancer InstituteStarted 2016-03
Nivolumab - 240 mgIpilimumab - 1 mg/kgNivolumab - 480 mg
Recurrent Squamous Cell Lung CarcinomaStage IV Squamous Cell Lung Carcinoma AJCC v7

Lung-MAP: Nivolumab With or Without Ipilimumab as Second-Line Therapy in Treating Patients With Recurrent Stage IV Squamous Cell Lung Cancer and No Matching Biomarkers

ACTIVE NOT RECRUITING
NCT02785952Phase PHASE3SWOG Cancer Research NetworkStarted 2015-12-29
IpilimumabLaboratory Biomarker AnalysisNivolumab

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients