ICOS

Chr 2AR

inducible T cell costimulator

Also known as: AILIM, CD278, CVID1

NCBI Gene: 29851 ENSG00000163600 UniProt: Q9Y6W8 OMIM: 604558

The ICOS protein is a costimulatory receptor on activated T-cells that enhances T-cell responses to antigens, promotes T-cell and B-cell interactions, and is essential for normal antibody production and immune responses. Mutations cause common variable immunodeficiency, resulting in recurrent infections, hypogammaglobulinemia, and impaired antibody responses, with autosomal recessive inheritance. The gene shows low constraint to loss-of-function variants, which is consistent with the recessive inheritance pattern observed in affected patients.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.911 OMIM phenotype

Clinical Summary— ICOS

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Gene-Disease Validity (ClinGen)

common variable immunodeficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 82 VUS of 202 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.91LOEUF

pLI 0.031

Z-score 1.78

OE 0.40 (0.19–0.91)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.21Z-score

OE missense 0.67 (0.55–0.81)

69 obs / 103.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.40 (0.19–0.91)

0≤0.351.4

Missense OE?0.67 (0.55–0.81)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 4 / 10.1Missense obs/exp: 69 / 103.6Syn Z: -0.55

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateICOS-related combined immunodeficiency with recurrent sinopulmonary infections and recalcitrant wartsOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.76top 25%

GOF

0.6541th %ile

LOF

0.2288th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

202 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic3

VUS82

Likely Benign63

Benign27

Conflicting11

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	0	3	0	12
Likely Pathogenic	3	0	0	0	3
VUS	1	47	34	0	82
Likely Benign	0	2	27	34	63
Benign	0	1	25	1	27
Conflicting	—				11
Total	13	50	89	35	198

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

View in ClinVar →

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