CD28

Chr 2AR

CD28 molecule

Also known as: IMD123, Tp44

NCBI Gene: 940ENSG00000178562UniProt: P10747

The protein encoded by this gene is essential for T-cell proliferation and survival, cytokine production, and T-helper type-2 development. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2011]

Primary Disease Associations & Inheritance

?Immunodeficiency 123 with HPV-related verrucosisMIM #620901
AR
55
ClinVar variants
32
Pathogenic / LP
0.36
pLI score
12
Active trials
Clinical Summary— CD28
🧬
Gene-Disease Validity (ClinGen)
immunodeficiency 123 with HPV-related verrucosis · ARModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
📋
ClinVar Variants
32 Pathogenic / Likely Pathogenic· 20 VUS of 55 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.71LOEUF
pLI 0.358
Z-score 2.13
OE 0.23 (0.09–0.71)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.80Z-score
OE missense 0.80 (0.68–0.94)
103 obs / 128.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.23 (0.09–0.71)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.80 (0.68–0.94)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.07
0≤1.21.6
LoF obs/exp: 2 / 8.9Missense obs/exp: 103 / 128.4Syn Z: -0.39

ClinVar Variant Classifications

55 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31
Likely Pathogenic1
VUS20
Likely Benign1
Benign2
31
Pathogenic
1
Likely Pathogenic
20
VUS
1
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
30
0
31
Likely Pathogenic
0
0
1
0
1
VUS
0
15
5
0
20
Likely Benign
0
1
0
0
1
Benign
0
0
1
1
2
Total01737155

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

View in ClinVar →

Protein Context — Lollipop Plot

CD28 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
ANTIGEN CD28; CD28
MIM #186760 · *

?Immunodeficiency 123 with HPV-related verrucosis

MIM #620901

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
CD28 Costimulation: From Mechanism to Therapy.
Esensten JH et al.·Immunity
2016Review
CD28 co-stimulation: novel insights and applications in cancer immunotherapy.
Lotze MT et al.·Nat Rev Immunol
2024Review
A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains.
Cappell KM et al.·Nat Rev Clin Oncol
2021Review
Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
Lévy R et al.·J Exp Med
2023
OMIP-099: 31-color spectral flow cytometry panel to investigate the steady-state phenotype of human T cells.
Zacharias ZR et al.·Cytometry A
2024
4-1BB and optimized CD28 co-stimulation enhances function of human mono-specific and bi-specific third-generation CAR T cells.
Roselli E et al.·J Immunother Cancer
2021
CD19-CD28: an affinity-optimized CD28 agonist for combination with glofitamab (CD20-TCB) as off-the-shelf immunotherapy.
Sam J et al.·Blood
2024
Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function.
Salter AI et al.·Sci Signal
2018
CAR-T cells containing CD28 versus 4-1BB co-stimulatory domains show distinct metabolic profiles in patients.
Cook MS et al.·Cell Rep
2025Cohort
T2-high asthma phenotypes across lifespan.
Maison N et al.·Eur Respir J
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Mantle Cell LymphomaFollicular LymphomaSplenic Marginal Zone Lymphoma

Study of Kappa Chimeric Antigen Receptor (CAR) T Lymphocytes Co-Expressing the Kappa and CD28 CARs for Relapsed/Refractory Kappa+ Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

RECRUITING
NCT04223765Phase PHASE1UNC Lineberger Comprehensive Cancer CenterStarted 2020-11-12
CAR.k.28FludarabineCyclophosphamide
Recurrent GlioblastomaRecurrent Malignant GliomaRecurrent WHO Grade II Glioma

Chimeric Antigen Receptor (CAR) T Cells With a Chlorotoxin Tumor-Targeting Domain for the Treatment of MMP2+ Recurrent or Progressive Glioblastoma

ACTIVE NOT RECRUITING
NCT04214392Phase PHASE1City of Hope Medical CenterStarted 2020-02-26
Chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes (via ICT delivery)Chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes (via ICT/ICV dual delivery)
Sarcoma

Her2 Chimeric Antigen Receptor Expressing T Cells in Advanced Sarcoma

ACTIVE NOT RECRUITING
NCT00902044Phase PHASE1Baylor College of MedicineStarted 2010-02-11
Autologous HER2-specific T cellsFludarabineCyclophosphamide
T-cell Acute Lymphoblastic LymphomaT-non-Hodgkin LymphomaT-cell Acute Lymphoblastic Leukemia

Autologous T-Cells Expressing a Second Generation CAR for Treatment of T-Cell Malignancies Expressing CD5 Antigen

RECRUITING
NCT03081910Phase PHASE1Baylor College of MedicineStarted 2017-11-01
Autologous CD5.CAR/28zeta CAR T cellsAllogeneic CD5.CAR/28zeta CAR T cells
Adult Acute Myeloid Leukemia in RemissionAcute Biphenotypic LeukemiaEarly Relapse of Acute Myeloid Leukemia

Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed/Refractory Acute Myeloid Leukemia and Persistent/Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm

ACTIVE NOT RECRUITING
NCT02159495Phase PHASE1City of Hope Medical CenterStarted 2015-12-15
cyclophosphamideAutologous CD123CAR-CD28-CD3zeta-EGFRt-expressing T Lymphocyteslaboratory biomarker analysis
RhA - Rheumatoid Arthritis

Adversity and Its Association With the Development and Expression of Rheumatic Diseases

NOT YET RECRUITING
NCT06386380National Institute of Medical Sciences and Nutrition, Salvador ZubiranStarted 2024-06-01
Rheumatic diseases Mistreatment Scale (RDMS)Routine assessment of patient index data 3 (RAPID-3)Health Assessment Questionnaire (HAQ)
Cutaneous Squamous Cell Carcinoma (CSCC)

Next-gen Flow Cytometry to Find Immune Profiles, Treatment Response, and Toxicity Markers in Skin Cancer Patients Treated With Cemiplimab.

RECRUITING
NCT07064330Instituto de Investigación Biomédica de SalamancaStarted 2025-07-17
Cemiplimab
Acute Myeloid Leukemia

Chimeric Antigen Receptor T Cell Redirected to Target CD4 Positive Relapsed Refractory Acute Myeloid Leukemia (AML ) as a Bridge to Allogeneic Stem Cell Transplant

RECRUITING
NCT06197672Phase PHASE1Huda SalmanStarted 2024-03-19
CD4CAR
Refractory B-Cell Non-Hodgkin LymphomaRefractory B-Cell Small Lymphocytic LymphomaRelapsed Adult ALL

CD19.CAR Allogeneic NKT for Patients With Relapsed or Refractory B-Cell Malignancies (ANCHOR)

ACTIVE NOT RECRUITING
NCT03774654Phase PHASE1Baylor College of MedicineStarted 2020-06-22
CD19.CAR-aNKT cells
LymphomaMyelomaLeukemia

Kappa-CD28 T Lymphocytes, Chronic Lymphocytic Leukemia, B-cell Lymphoma or Multiple Myeloma, CHARKALL

ACTIVE NOT RECRUITING
NCT00881920Phase PHASE1Baylor College of MedicineStarted 2009-07
Kappa CD28 T cells
B Acute Lymphoblastic LeukemiaRecurrent Acute Lymphoblastic LeukemiaRefractory Acute Lymphoblastic Leukemia

Cellular Immunotherapy in Treating Patients With High-Risk Acute Lymphoblastic Leukemia

ACTIVE NOT RECRUITING
NCT02146924Phase PHASE1City of Hope Medical CenterStarted 2014-10-16
CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytesCD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytesLaboratory Biomarker Analysis
Recurrent Acute Lymphoblastic LeukemiaRefractory Acute Lymphoblastic Leukemia

Humanized CD19-Specific CAR T Cells for the Treatment of Patients With Positive Relapsed or Refractory CD19 Positive B-Cell Acute Lymphoblastic Leukemia

RECRUITING
NCT06447987Phase PHASE1City of Hope Medical CenterStarted 2024-11-06
Allogeneic Hematopoietic Stem Cell TransplantationBiospecimen CollectionBone Marrow Aspiration

External Resources

Links to major genomics databases and tools