ICOS

Chr 2AR

inducible T cell costimulator

Also known as: AILIM, CD278, CVID1

NCBI Gene: 29851ENSG00000163600UniProt: Q9Y6W8

The protein encoded by this gene belongs to the CD28 and CTLA-4 cell-surface receptor family. It forms homodimers and plays an important role in cell-cell signaling, immune responses, and regulation of cell proliferation. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Immunodeficiency, common variable, 1MIM #607594
AR
231
ClinVar variants
46
Pathogenic / LP
0.03
pLI score
2
Active trials
Clinical Summary— ICOS
🧬
Gene-Disease Validity (ClinGen)
common variable immunodeficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
46 Pathogenic / Likely Pathogenic· 84 VUS of 231 total submissions
💊
Clinical Trials
2 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.
0.91LOEUF
pLI 0.031
Z-score 1.78
OE 0.40 (0.19–0.91)
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.
1.21Z-score
OE missense 0.67 (0.55–0.81)
69 obs / 103.6 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.0.40 (0.19–0.91)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.55–0.81)
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.1.12
0≤1.21.6
LoF obs/exp: 4 / 10.1Missense obs/exp: 69 / 103.6Syn Z: -0.55

ClinVar Variant Classifications

231 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42
Likely Pathogenic4
VUS84
Likely Benign63
Benign27
Conflicting11
42
Pathogenic
4
Likely Pathogenic
84
VUS
63
Likely Benign
27
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
0
37
0
42
Likely Pathogenic
3
0
1
0
4
VUS
1
45
38
0
84
Likely Benign
0
2
27
34
63
Benign
0
1
25
1
27
Conflicting
—11
Total94812835231

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

View in ClinVar →

Protein Context — Lollipop Plot

ICOS · protein map & ClinVar variants

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

Gene2Phenotype Curations

ICOS-related combined immunodeficiency with recurrent sinopulmonary infections and recalcitrant warts

moderate
ARUndeterminedAbsent Gene Product
Skin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Immunodeficiency, common variable, 1

MIM #607594

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.
Guttman-Yassky E et al.·J Allergy Clin Immunol
2019Clinical trial
Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways.
Kraehenbuehl L et al.·Nat Rev Clin Oncol
2022Review
Novel targets for immune-checkpoint inhibition in cancer.
Borgeaud M et al.·Cancer Treat Rev
2023Review
Integrated analysis of single-cell RNA-seq, bulk RNA-seq, Mendelian randomization, and eQTL reveals T cell-related nomogram model and subtype classification in rheumatoid arthritis.
Ding Q et al.·Front Immunol
2024Functional
T follicular helper cells in autoimmune diseases.
Wei X et al.·J Autoimmun
2023Review
Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement.
Herrmann J et al.·Eur Heart J
2022
T follicular helper cells and T follicular regulatory cells in autoimmune diseases.
Qi J et al.·Front Immunol
2023Review
Interferon subverts an AHR-JUN axis to promote CXCL13(+) T cells in lupus.
Law C et al.·Nature
2024
IFNγ causes mitochondrial dysfunction and oxidative stress in myositis.
Abad C et al.·Nat Commun
2024
Autoimmune Hepatitis: Pathophysiology.
Yuming Z et al.·Clin Liver Dis
2024Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Integrative analysis of T cell subset-specific ICOS expression and tumor HLA class I/II expression in lung adenocarcinoma: implications for their interaction and clinical outcome.
Yamada H et al.·Cancer Immunol Immunother
2026🔓 Open Access
Elemental Analyzer-Interface-Off-Axis Integrated Cavity Output Spectroscopy (EA-OA-ICOS): A Universal Coupling for Carbon Stable Isotope Analysis of Organic Materials.
Ferrant M et al.·Anal Chem
2026
Novel OA-ICOS Sensor for Real-Time Quantification of Enteric Methane from Ruminants.
Sun Y et al.·Sensors (Basel)
2026
Analysis of CCR9, CXCR5 and ICOS in Circulating Follicular Helper T Cell-like Populations in Sjögren's Disease.
Garcia-Espinoza JA et al.·Int J Mol Sci
2026
Advancing ICOS agonism in solid tumors: lessons from INDUCE-1.
Habibzadeh P et al.·J Immunother Cancer
2026🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Recurrent Classic Hodgkin LymphomaRefractory Classic Hodgkin Lymphoma

Brentuximab Vedotin and Nivolumab With or Without Ipilimumab in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma

ACTIVE NOT RECRUITING
NCT01896999Phase PHASE1, PHASE2National Cancer Institute (NCI)Started 2014-03-07
Biopsy ProcedureBiospecimen CollectionBrentuximab Vedotin
Bladder Cancer

Antitumor T Cell Responses in Patients With Bladder Cancer

NOT YET RECRUITING
NCT06334406Centre Hospitalier Universitaire de BesanconStarted 2024-04-02
Biological samples

External Resources

Links to major genomics databases and tools