ICOS

Summary

ICOS (inducible T cell costimulator, HGNC:5351) is a protein-coding gene on chromosome 2q33.2, encoding Inducible T-cell costimulator (Q9Y6W8). Stimulatory receptor expressed in activated or antigen-experienced T-cells that plays an important role in the immune response.

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.

Source: NCBI Gene 29851 — RefSeq curated summary.

At a glance

• Gene–disease (curated): common variable immunodeficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 17
• Clinical variants (ClinVar): 200 total — 10 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 32
• Druggable target: yes
• MANE Select transcript: NM_012092

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5351
Approved symbol	ICOS
Name	inducible T cell costimulator
Location	2q33.2
Locus type	gene with protein product
Status	Approved
Aliases	AILIM, CD278
Ensembl gene	ENSG00000163600
Ensembl biotype	protein_coding
OMIM	604558
Entrez	29851

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000316386, ENST00000435193, ENST00000897354

RefSeq mRNA: 1 — MANE Select: NM_012092 NM_012092

CCDS: CCDS2363

Canonical transcript exons

ENST00000316386 — 5 exons

Exon	Start	End
ENSE00001076433	203957799	203957883
ENSE00001076434	203936763	203936872
ENSE00001076436	203955636	203955971
ENSE00001076437	203956659	203956765
ENSE00003507544	203959586	203961577

Expression profiles

Bgee: expression breadth ubiquitous, 110 present calls, max score 79.37.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 7.1984 / max 718.3986, expressed in 181 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24785	6.5113	177
24786	0.4788	69
24784	0.2082	65

Top tissues by expression

266 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lymph node	UBERON:0000029	79.37	gold quality
vermiform appendix	UBERON:0001154	76.97	gold quality
thymus	UBERON:0002370	75.66	silver quality
granulocyte	CL:0000094	75.36	gold quality
epithelium of nasopharynx	UBERON:0001951	73.47	gold quality
blood	UBERON:0000178	72.48	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	71.18	gold quality
caecum	UBERON:0001153	70.66	gold quality
superficial temporal artery	UBERON:0001614	67.54	gold quality
bone marrow	UBERON:0002371	66.27	gold quality
tonsil	UBERON:0002372	65.23	gold quality
spleen	UBERON:0002106	65.17	gold quality
gall bladder	UBERON:0002110	64.88	gold quality
palpebral conjunctiva	UBERON:0001812	63.07	gold quality
rectum	UBERON:0001052	62.64	gold quality
colonic epithelium	UBERON:0000397	60.97	silver quality
right lung	UBERON:0002167	60.58	gold quality
small intestine Peyer’s patch	UBERON:0003454	59.07	gold quality
upper lobe of left lung	UBERON:0008952	59.06	gold quality
upper lobe of lung	UBERON:0008948	58.63	gold quality
bone marrow cell	CL:0002092	58.40	silver quality
small intestine	UBERON:0002108	57.34	gold quality
epithelial cell of pancreas	CL:0000083	57.33	gold quality
gluteal muscle	UBERON:0002000	57.26	gold quality
lung	UBERON:0002048	56.92	gold quality
tendon of biceps brachii	UBERON:0008188	56.68	gold quality
visceral pleura	UBERON:0002401	56.57	silver quality
oral cavity	UBERON:0000167	56.41	silver quality
triceps brachii	UBERON:0001509	56.16	gold quality
esophagus squamous epithelium	UBERON:0006920	54.95	silver quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-89	yes	1677.44
E-CURD-122	yes	40.30
E-CURD-88	yes	36.73
E-CURD-46	yes	16.04
E-ANND-3	yes	7.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, GATA3, HAND1, NFATC2, STAT3, STAT6, TBX21

miRNA regulators (miRDB)

117 targeting ICOS, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-548AR-3P	99.85	71.26	3889

Literature-anchored findings (GeneRIF, showing 40)

• its polymorphism may contributes to the pathogenesis of spondyloarthropathy (PMID:11771526)
• Genetic polymorphism of the human ICOS gene. (PMID:11904679)
• role of ligation in modulating TCR-induced transcriptional profiles (PMID:12195015)
• ICOS reversely regulates IL-10 on re-activation of human effector T cells with mature dendritic cells. Interaction of ICOS with ICOS-L strongly promoted IL-10 secretion. (PMID:12207353)
• ICOS provides co-stimulation to memory t-cells [review] (PMID:12456021)
• Analysis of the upstream region of ICOS revealed an additional eight single nucleotide polymorphism (PMID:12753665)
• local immune responses may be modulated by H4/ICOS expressed on T cells in the joints of patients with rheumatoid arthritis, and thus it may be involved in the pathogenetic mechanism of rheumatoid arthritis. (PMID:12784384)
• ICOS is upregulated on human T cells after stimulation and can modulate both Th1 and Th2 cytokine production in the absence and presence of B7-1 (CD80) and B7-2 (CD86)costimulation. (PMID:12864987)
• Targeting of specific chemokine and chemokine receptor pathways and/or ICOS may have clinical application in the prevention and treatment of chronic allograft nephropathy. (PMID:12919091)
• AILIM has a role in regulating the signaling cascades for T-cell proliferation and IL-10 production (PMID:14550257)
• ICOS does not belong to the group of genes that, if mutated, present clinically as the hyper-IgM syndrome. (PMID:14610488)
• Highly expressed ICOS in activated CD4(+) lamina propria T cells of inflammatory bowel (IBD) contributes to dysregulated immune responses. Hyperexpression limited to inflammatory sites in IBD. Feasible therapeutic target for treatment of IBD. (PMID:14988837)
• A subtype of regulatory T cells in human blood can be identified by expression of ICOS after activation; these ICOS-expressing cells block the capacity of reciprocal ICOS-negative cells to proliferate and to produce cytokines. (PMID:15100277)
• ICOS expression on activated Th cells may provide a powerful means to amplify effector T cell responses in peripheral tissues, independently of the polarized state of the Th cells (PMID:15265908)
• AILIM/ICOS-B7h interactions play an important role in the endothelium in controlling the entry of memory/effector T-cells into inflamed tissues in the periphery. (PMID:15339883)
• The incidence of ICOS deficiency among patients with Common variable immunodeficiency is less than 5% (PMID:15507387)
• invariant NKT cell activation is regulated by CD28 and IOCS independently (PMID:15629449)
• A predominant effect of ICOS-mediated costimulation on T helper type 2 (Th2) cell differentiation in transgenic ICOS-deficient mice may be achieved by the enhancement of IL-4 receptor-mediated signaling. (PMID:15699127)
• ICOS is an influential costimulatory pathway in atherosclerosis & may play a protective role. It localizes with T cells in human aortic plaque. (PMID:15941568)
• This study could not confirm association with the CD28/CTLA4/ICOS gene region in multiple sclerosis. (PMID:16005527)
• Two variants in the ICOS promoter region are significantly associated with allergic sensitization and production of type 2 T helper (Th2) cell cytokines (PMID:16081771)
• ICOS is involved in abnormal T cell activation in systsemic lupus erythematosus (SLE) and blockade of the interaction between ICOS and its receptor may have therapeutic value in the treatment of this intractable disease. (PMID:16563187)
• There are no major effects of the CD28/CTLA4/ICOS gene region on susceptibility to primary sclerosing cholangitis but minor contributions cannot be excluded. (PMID:16638702)
• ICOS activation is associated with T helper type 1 (Th1) cell responses in human intracellular tuberculosis infection and may contribute to the amplification of those responses. (PMID:16670305)
• This review summarizes the evidence that ICOS expression regulates T-cell-dependent B cell responses and proposes a model for the role of ICOS in diseases characterized by dysregulated humoral immunity. (PMID:16790364)
• genetic variation in ICOS gene regulates the expression of both CTLA4 and ICOS and not only the splicing of sCTLA4 as suggested earlier. (PMID:16996590)
• Both the PI3-kinase/Akt and Rho family cascades operate coordinately to induce the forward migration of activated T cells by AILIM/ICOS signaling. (PMID:17077177)
• With multiethnic DNA panels that represent a wide spectrum of ethnic groups, we demonstrate long-range linkage disequilibrium among CD28, CTLA4, and ICOS costimulatory genes. (PMID:17197413)
• ICOS may be relevant in inducing an acute immune response and may be critically involved in perpetuating inflammation in chronically immune-mediated disorders of the peripheral nervous system. (PMID:17242332)
• These results define elevated populations of memory T-lymphocytes expressing B7 molecules in rheumatoid arthritis (RA) synovial fluid that either stimulate T cells through ICOS, or down-regulate RA synovial tissue T-lymphocytes through B7H1 and B7H2. (PMID:17323353)
• The whole blood gene expression quantities of costimulatory molecules CD154 and ICOS reasonably robustly differentiated rejection patients from control patients. (PMID:17414714)
• ICOS gene haplotypes correlate with IL10 secretion and multiple sclerosis. (PMID:17481737)
• Of 9 CVID patients…No mutations of SAP, ICOS, TACI, BAFFR, and CD19 were identified (PMID:18051214)
• definition of a newly discovered pathway that prevents autoimmunity by limiting the levels on T lymphocytes of aco-stimulatory receptor, the inducible T-cell co-stimulator(ICOS) (PMID:18172933)
• Modulation of immune responses by ICOS-expressing naturally occurring T regulatory cells present in melanoma tissue depends upon costimulatory signals delivered to the CD4-positive CD25-negative responder cells and the cytokine milieu. (PMID:18292519)
• p50alpha is likely a determining factor in ICOS-mediated PI3K activity in T cells (PMID:18641334)
• Children with type 1 diabetes show decreased inducrion of ICOS in T cells. (PMID:18973208)
• The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency. (PMID:19020530)
• ICOS-induced T cell spreading and filopodia/microspike formation may promote antigen recognition by enhancing a T cell’s scanning potential of an adherent APC surface. (PMID:19095735)
• ICOS variants do not play a major role in the development of atopy in European children. (PMID:19175887)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Icos	ENSMUSG00000026009
rattus_norvegicus	Icos	ENSRNOG00000046196

Protein

Protein identifiers

Inducible T-cell costimulator — Q9Y6W8 (reviewed: Q9Y6W8)

Alternative names: Activation-inducible lymphocyte immunomediatory molecule

All UniProt accessions (2): Q9Y6W8, Q53QY6

UniProt curated annotations — full annotation on UniProt →

Function. Stimulatory receptor expressed in activated or antigen-experienced T-cells that plays an important role in the immune response. Upon binding to its ligand ICOSL expressed on antigen presenting cells (APCs), delivers costimulatory signals that enhances all basic T-cell responses to a foreign antigen, namely proliferation, secretion of lymphokines including IL10, up-regulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B-cells. Also acts as a costimulatory receptor critical for the differentiation of T follicular regulatory cells upon immune challenges such as viral infection. Mechanistically, potentiates TCR-induced calcium flux by augmenting PLCG1 activation and actin remodeling. In addition, activates PI3K signaling pathways independently of calcium flux. Essential both for efficient interaction between T and B-cells and for normal antibody responses to T-cell dependent antigens. Prevents the apoptosis of pre-activated T-cells. Plays a critical role in CD40-mediated class switching of immunoglobin isotypes.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with ICOSLG. Interacts with PIK3R1. Interacts with TBK1; this interaction is critical for the maturation of T follicular regulatory cells.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Activated T-cells. Highly expressed on tonsillar T-cells, which are closely associated with B-cells in the apical light zone of germinal centers, the site of terminal B-cell maturation. Expressed at lower levels in thymus, lung, lymph node and peripheral blood leukocytes. Expressed in the medulla of fetal and newborn thymus.

Post-translational modifications. N-glycosylated.

Disease relevance. Immunodeficiency, common variable, 1 (CVID1) [MIM:607594] A primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low. The disease is caused by variants affecting the gene represented in this entry.

Induction. By phorbol myristate acetate (PMA) and ionomycin. Up-regulated early on T-cells and continues to be expressed into the later phases of T-cell activation.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y6W8-1	1	yes
Q9Y6W8-2	2

RefSeq proteins (1): NP_036224* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR039943	ICOS	Family

Pfam: PF15910

UniProt features (22 total): strand 9, topological domain 2, glycosylation site 2, disulfide bond 2, signal peptide 1, chain 1, splice variant 1, mutagenesis site 1, helix 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7JOO	X-RAY DIFFRACTION	2.4
6X4G	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6W8-F1	74.24	0.22

Antibody-complex structures (SAbDab): 2 — 6X4G, 7JOO

Functional residue map

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

Disulfide bonds (2): 42–109, 63–83

Glycosylation sites (2): 89, 110

Mutagenesis-validated functional residues (1):

Position	Phenotype
110	about 4.3-fold improvement in binding affinity to icoslg.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9725371	Nuclear events stimulated by ALK signaling in cancer
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-9927354	Co-stimulation by ICOS

MSigDB gene sets: 385 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_TOLERANCE_INDUCTION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, CHIARETTI_T_ALL_REFRACTORY_TO_THERAPY, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_LYMPHOCYTE_COSTIMULATION, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_CELL_CELL_ADHESION, GOBP_CD4_POSITIVE_ALPHA_BETA_T_CELL_ACTIVATION, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, GOBP_T_CELL_DIFFERENTIATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CELL_ACTIVATION, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_AND_BRAIN_QTL_TRANS

GO Biological Process (5): T cell tolerance induction (GO:0002517), immune response (GO:0006955), T cell costimulation (GO:0031295), T follicular helper cell differentiation (GO:0061470), cell-cell adhesion (GO:0098609)

GO Molecular Function (2): signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by ALK fusions and activated point mutants	1
Intracellular signaling by second messengers	1
PI3K/AKT Signaling in Cancer	1
Negative regulation of the PI3K/AKT network	1
Regulation of T cell activation by CD28 family	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
tolerance induction	1
immune system process	1
response to stimulus	1
lymphocyte costimulation	1
positive regulation of T cell activation	1
T-helper cell differentiation	1
cell adhesion	1
molecular transducer activity	1
binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

2156 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ICOS	A0A087X1L8	A0A087X1L8	999
ICOS	ICOSLG	O75144	999
ICOS	CD80	P33681	997
ICOS	CD86	P42081	996
ICOS	CD274	Q9NZQ7	995
ICOS	CTLA4	P16410	994
ICOS	CD40LG	P29965	990
ICOS	CD40	P25942	987
ICOS	PDCD1LG2	Q9BQ51	971
ICOS	CD28	P10747	954
ICOS	CXCR5	P32302	941
ICOS	TNFSF4	P23510	938
ICOS	PDCD1	Q15116	929
ICOS	CD4	P01730	909
ICOS	CD70	P32970	903
ICOS	TNFRSF9	Q07011	903

IntAct

23 interactions, top by confidence:

A	B	Type	Score
ICOS	ICOSLG	psi-mi:“MI:0915”(physical association)	0.850
ICOS	ICOSLG	psi-mi:“MI:0407”(direct interaction)	0.850
ICOSLG	ICOS	psi-mi:“MI:0915”(physical association)	0.850
ICOSLG	ICOS	psi-mi:“MI:0407”(direct interaction)	0.850
ICOS	PIK3R1	psi-mi:“MI:0914”(association)	0.620
ICOS	PIK3R1	psi-mi:“MI:0915”(physical association)	0.620
ICOS	TBK1	psi-mi:“MI:0915”(physical association)	0.500
PIK3R1	ICOS	psi-mi:“MI:0403”(colocalization)	0.430
WIF1	ICOS	psi-mi:“MI:0915”(physical association)	0.370
ICOS	GAK	psi-mi:“MI:0914”(association)	0.350
ICOS	TNF	psi-mi:“MI:0914”(association)	0.350
ICOS	TNFSF9	psi-mi:“MI:0914”(association)	0.350

BioGRID (20): ACY1 (Affinity Capture-MS), TNF (Affinity Capture-MS), ICOSLG (Affinity Capture-MS), MFI2 (Affinity Capture-MS), TBK1 (Affinity Capture-Western), PIK3R1 (Affinity Capture-Western), RC3H1 (Protein-RNA), NUFIP2 (Protein-RNA), CDC20B (Affinity Capture-MS), ICOS (Reconstituted Complex), TNF (Affinity Capture-MS), ACY1 (Affinity Capture-MS), TRHDE (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), ITFG3 (Affinity Capture-MS)

ESM2 similar proteins: A0A0E4BZH1, A4KWA1, A5D7V5, A7TZE6, D3W0D1, O35778, O54707, P15509, P27471, P27812, P27814, P78380, P79391, Q0VCS6, Q12918, Q13241, Q28110, Q38HS3, Q49BZ4, Q58DF9, Q5NKN2, Q5NKN4, Q5QGZ9, Q60653, Q60660, Q60682, Q63378, Q64329, Q6QLQ4, Q7YR73, Q80ZC8, Q863H3, Q8BWY2, Q8C567, Q8HZR8, Q8MHY9, Q8NC01, Q8VD98, Q92478, Q99JB4

Diamond homologs: Q58DF9, Q7YR73, Q9R1T7, Q9WVS0, Q9Y6W8

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ICOSLG	“up-regulates activity”	ICOS	binding
ICOS	“up-regulates activity”	PIK3R1	binding
hsa-mir-146a-5p	“down-regulates quantity by repression”	ICOS	“post transcriptional regulation”
hsa-mir-27a-3p	“down-regulates quantity by repression”	ICOS	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	3
Uncertain significance	82
Likely benign	63
Benign	27

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1359008	NM_012092.4(ICOS):c.61G>T (p.Glu21Ter)	Pathogenic
1449576	NM_012092.4(ICOS):c.318T>G (p.Tyr106Ter)	Pathogenic
2002817	NM_012092.4(ICOS):c.17G>A (p.Trp6Ter)	Pathogenic
2003841	NM_012092.4(ICOS):c.357del (p.Phe119fs)	Pathogenic
2872742	NM_012092.4(ICOS):c.294del (p.Leu99fs)	Pathogenic
2993769	NM_012092.4(ICOS):c.291C>A (p.Tyr97Ter)	Pathogenic
4728975	NM_012092.4(ICOS):c.272dup (p.Ser91fs)	Pathogenic
5501	NM_012092.4(ICOS):c.59-594_501+93del	Pathogenic
871366	GRCh37/hg19 2q33.2(chr2:204820359-204821488)x0	Pathogenic
940397	NM_012092.4(ICOS):c.181del (p.Ile61fs)	Pathogenic
2585218	NM_012092.4(ICOS):c.136_139del (p.Asp46fs)	Likely pathogenic
573877	NM_012092.4(ICOS):c.394+2T>C	Likely pathogenic
663980	NM_012092.4(ICOS):c.58+1G>A	Likely pathogenic

SpliceAI

608 predictions. Top by Δscore:

Variant	Effect	Δscore
2:203942270:T:G	donor_gain	1.0000
2:203955786:G:GT	donor_gain	1.0000
2:203956657:A:AG	acceptor_gain	1.0000
2:203956658:G:GG	acceptor_gain	1.0000
2:203956658:GA:G	acceptor_gain	1.0000
2:203957798:GAA:G	acceptor_gain	1.0000
2:203957798:GAAGT:G	acceptor_gain	1.0000
2:203936871:AGGTA:A	donor_loss	0.9900
2:203936872:GGT:G	donor_loss	0.9900
2:203936873:G:GC	donor_loss	0.9900
2:203942270:TTA:T	donor_gain	0.9900
2:203955631:T:G	acceptor_gain	0.9900
2:203955786:G:T	donor_gain	0.9900
2:203956652:A:AG	acceptor_gain	0.9900
2:203956654:TCCA:T	acceptor_loss	0.9900
2:203956655:CCA:C	acceptor_loss	0.9900
2:203956657:A:T	acceptor_loss	0.9900
2:203956658:GAAT:G	acceptor_gain	0.9900
2:203956763:AAGG:A	donor_loss	0.9900
2:203956764:AGGT:A	donor_loss	0.9900
2:203956765:GGTAA:G	donor_loss	0.9900
2:203956766:GT:G	donor_loss	0.9900
2:203956767:T:G	donor_loss	0.9900
2:203957879:CACAG:C	donor_loss	0.9900
2:203957880:ACAGG:A	donor_loss	0.9900
2:203957881:CAG:C	donor_loss	0.9900
2:203957882:AG:A	donor_loss	0.9900
2:203957883:GG:G	donor_loss	0.9900
2:203957884:GT:G	donor_loss	0.9900
2:203957885:T:G	donor_loss	0.9900

AlphaMissense

1313 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:203955741:T:C	L55S	0.952
2:203955902:T:A	C109S	0.908
2:203955903:G:C	C109S	0.908
2:203955701:T:A	C42S	0.901
2:203955702:G:C	C42S	0.901
2:203955932:T:C	F119L	0.899
2:203955934:T:A	F119L	0.899
2:203955934:T:G	F119L	0.899
2:203955701:T:C	C42R	0.879
2:203955729:T:C	F51S	0.879
2:203955696:T:C	I40T	0.877
2:203955902:T:C	C109R	0.874
2:203955909:T:C	L111P	0.873
2:203955960:T:C	L128S	0.869
2:203955903:G:A	C109Y	0.864
2:203955668:T:C	F31L	0.857
2:203955670:T:A	F31L	0.857
2:203955670:T:G	F31L	0.857
2:203955857:T:C	F94L	0.845
2:203955859:T:A	F94L	0.845
2:203955859:T:G	F94L	0.845
2:203955904:C:G	C109W	0.840
2:203955702:G:A	C42Y	0.835
2:203955735:T:C	M53T	0.832
2:203955917:T:C	F114L	0.817
2:203955919:T:A	F114L	0.817
2:203955919:T:G	F114L	0.817
2:203955860:T:C	F95L	0.816
2:203955862:T:A	F95L	0.816
2:203955862:T:G	F95L	0.816

dbSNP variants (sampled 300 via entrez): RS1000000534 (2:203940521 A>C,G), RS1000103908 (2:203939705 T>C), RS1000335106 (2:203946890 T>C), RS1000352120 (2:203959320 A>G), RS1000415941 (2:203953027 C>A), RS1000489516 (2:203953265 C>G), RS1000649714 (2:203958541 C>T), RS1000774112 (2:203951621 TGA>T), RS1000825184 (2:203951837 T>C), RS1000936031 (2:203934812 T>C), RS1001021849 (2:203958241 A>G), RS1001497612 (2:203941043 G>A), RS1001537375 (2:203947390 C>T), RS1001715443 (2:203953872 A>G), RS1001897493 (2:203959963 C>A)

Disease associations

OMIM: gene MIM:604558 | disease phenotypes: MIM:607594

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency, common variable, 1	Strong	Autosomal recessive
common variable immunodeficiency	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
common variable immunodeficiency	Definitive	AR

Mondo (2): immunodeficiency, common variable, 1 (MONDO:0011864), common variable immunodeficiency (MONDO:0015517)

Orphanet (2): OBSOLETE: Common variable immunodeficiency (Orphanet:1572), Late-onset combined immunodeficiency due to ICOS deficiency (Orphanet:695183)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000403	Recurrent otitis media
HP:0000509	Conjunctivitis
HP:0001287	Meningitis
HP:0001744	Splenomegaly
HP:0001904	Autoimmune neutropenia
HP:0002014	Diarrhea
HP:0002090	Pneumonia
HP:0002110	Bronchiectasis
HP:0002240	Hepatomegaly
HP:0002664	Neoplasm
HP:0002665	Lymphoma
HP:0002716	Lymphadenopathy
HP:0002718	Recurrent bacterial infections
HP:0002720	Decreased circulating IgA concentration
HP:0002721	Immunodeficiency
HP:0002729	Follicular hyperplasia
HP:0002837	Recurrent bronchitis
HP:0002850	Decreased circulating total IgM
HP:0002960	Autoimmunity
HP:0004315	Decreased circulating IgG concentration
HP:0005387	Combined immunodeficiency
HP:0006532	Recurrent pneumonia
HP:0010976	Decreased total B cell count
HP:0011108	Recurrent sinusitis
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0011839	Abnormal total T cell count
HP:0011840	Abnormal T cell physiology

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000612_31	Celiac disease	6.000000e-09
GCST000719_1	Alopecia areata	4.000000e-13
GCST001762_487	Obesity-related traits	1.000000e-06
GCST002931_9	Aluminium levels	3.000000e-07
GCST003043_183	Inflammatory bowel disease	5.000000e-07
GCST003045_68	Ulcerative colitis	1.000000e-07
GCST003988_11	Hypothyroidism	1.000000e-15
GCST004302_16	Primary biliary cholangitis	1.000000e-13
GCST004866_12	Alopecia areata	2.000000e-20
GCST004904_151	Body mass index	4.000000e-08
GCST005568_8	Rheumatoid arthritis (ACPA-positive)	4.000000e-08
GCST005569_29	Rheumatoid arthritis	5.000000e-07
GCST005588_17	Idiopathic dilated cardiomyopathy	5.000000e-06
GCST006627_31	Diastolic blood pressure	3.000000e-12
GCST009391_761	Metabolite levels	7.000000e-06
GCST009391_781	Metabolite levels	5.000000e-06
GCST009391_803	Metabolite levels	5.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004736	aspartate aminotransferase measurement
EFO:0004340	body mass index
EFO:0009094	idiopathic dilated cardiomyopathy
EFO:0006336	diastolic blood pressure
EFO:0010391	sphingomyelin 16:0 measurement
EFO:0010394	sphingomyelin 18:1 measurement
EFO:0010396	sphingomyelin 22:1 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D017074	Common Variable Immunodeficiency	C20.673.330

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3712953 (SINGLE PROTEIN), CHEMBL5482971 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — CD molecules

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
feladilimab	Binding	8.87	pKd

ChEMBL bioactivities

6 potent at pChembl≥5 of 19 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.73	IC50	1870	nM	CHEMBL5591374
5.43	IC50	3680	nM	CHEMBL5592269
5.35	IC50	4480	nM	CHEMBL5591374
5.35	Kd	4470	nM	CHEMBL5590462
5.33	IC50	4680	nM	CHEMBL2171562
5.25	IC50	5650	nM	CHEMBL5429501

PubChem BioAssay actives

6 with measured affinity, of 28 total; 5 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(3S,9S,12S,18S,21S,27S,30R,35R,38S,41S,44S,47S)-30-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-41,44-dibenzyl-9,27-bis[(4-hydroxyphenyl)methyl]-38-(2-methylpropyl)-2,8,11,17,20,26,29,37,40,43,46-undecaoxo-18-propan-2-yl-32,33-dithia-1,7,10,16,19,25,28,36,39,42,45-undecazapentacyclo[45.3.0.03,7.012,16.021,25]pentacontane-35-carbonyl]amino]-4-methylpentanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoic acid	2115250: Inhibition of ICOS/ICOSL (unknown origin) interaction by ELISA method	ic50	1.8700	uM
(1R,4S,10S,13S,19S,22S,28S,34S,37S,40S,43S,46R,49S,55S,58S,61S)-37,40,58-tribenzyl-4,22,61-tris[(4-hydroxyphenyl)methyl]-43,49-bis(2-methylpropyl)-13-propan-2-yl-65,66-dithia-3,6,12,15,21,24,30,36,39,42,45,48,51,57,60,63-hexadecazaheptacyclo[44.17.4.06,10.015,19.024,28.030,34.051,55]heptahexacontane-2,5,11,14,20,23,29,35,38,41,44,47,50,56,59,62-hexadecone	2115249: Inhibition of ICOS/ICOSL (unknown origin) interaction by TR-FRET assay	ic50	3.6800	uM
2-[3-[(1R,4S,7S,13S,19S,22S,25S,28S,31R,34S,40S,43S,49S)-40-benzyl-19-[(2S)-butan-2-yl]-22-(hydroxymethyl)-25,28-bis[(4-hydroxyphenyl)methyl]-4,49-bis(2-methylpropyl)-3,6,12,18,21,24,27,30,33,36,39,42,48,51-tetradecaoxo-53,54-dithia-2,5,11,17,20,23,26,29,32,35,38,41,47,50-tetradecazapentacyclo[29.20.4.07,11.013,17.043,47]pentapentacontan-34-yl]propyl]guanidine	2115251: Binding affinity to ICOS (unknown origin) assessed as dissociation constant	kd	4.4700	uM
N-[3-(benzylamino)-6-chloro-9H-pyrido[3,4-b]indol-8-yl]pyridine-3-carboxamide	1977233: Inhibition of C-terminal IgG1 Fc region fused human ICOS extracellular domain (1 to 141 residues)/C-terminal polyhistidine tagged human ICOSL extracellular domain (1 to 258 residues) interaction incubated for 1 hr by TR-FRET assay	ic50	4.6800	uM
N-(6-chloro-7-methoxy-9H-pyrido[3,4-b]indol-8-yl)-4-methylpyrimidine-5-carboxamide	1977233: Inhibition of C-terminal IgG1 Fc region fused human ICOS extracellular domain (1 to 141 residues)/C-terminal polyhistidine tagged human ICOSL extracellular domain (1 to 258 residues) interaction incubated for 1 hr by TR-FRET assay	ic50	5.6500	uM

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants, Occupational	affects expression, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Nickel	increases expression	2
(+)-JQ1 compound	decreases expression	1
Acetaminophen	increases expression	1
Dieldrin	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Aflatoxin B1	increases methylation	1
Sodium Selenite	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5580017	Binding	Binding affinity to ICOS (unknown origin) assessed as dissociation constant	Design of cyclic peptides as novel inhibitors of ICOS/ICOSL interaction. — Bioorg Med Chem Lett

Cellosaurus cell lines

6 cell lines: 4 cancer cell line, 2 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7ZZ	Raji-hICOS	Cancer cell line	Male
CVCL_B8HQ	Abcam HCT 116 ICOS KO	Cancer cell line	Male
CVCL_B8WZ	Abcam MCF-7 ICOS KO	Cancer cell line	Female
CVCL_B9K0	Abcam A-549 ICOS KO	Cancer cell line	Male
CVCL_D7BJ	Abeomics CHO-K1 ICOS	Spontaneously immortalized cell line	Female
CVCL_E5IS	CHO-K1/ICOS	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

42 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00520494	PHASE4	COMPLETED	Efficacy and Safety of Vivaglobin® in Previously Untreated Patients With Primary Immunodeficiency
NCT01289847	PHASE4	COMPLETED	A Study to Find Out How Safe and Effective Gammaplex® is in Young People With Primary Immunodeficiency
NCT01946906	PHASE4	COMPLETED	The Rifaximin Study in CVID
NCT05193552	PHASE4	RECRUITING	Usage of Spirometry in Managing IgG Therapy in CVID With Airway Disease
NCT00168012	PHASE3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IVIG-F10 in Patients With Primary Immunodeficiencies (PID)
NCT00168025	PHASE3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT00322556	PHASE3	COMPLETED	Safety and Efficacy of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00542997	PHASE3	COMPLETED	Study of Subcutaneous Immune Globulin in Patients Requiring IgG Replacement Therapy
NCT01884311	PHASE3	COMPLETED	Pharmacokinetics (PK) and Safety of Subgam-VF in Primary Immunodeficiency Diseases
NCT01963143	PHASE3	COMPLETED	Bioequivalence Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Gammaplex® 10 and Gammaplex® 5% in Primary Immunodeficiency Diseases
NCT02247141	PHASE3	COMPLETED	A Multi-centre Open Study to Assess the Safety and Efficacy of Subgam®
NCT01489618	PHASE2	TERMINATED	Prime Boost Vaccination Strategy Combining Conjugated Anti- Pneumococcal Vaccine (s0) and Polysaccharide Anti- Pneumococcal Vaccine (s4) Compared to Polysaccharide Anti- Pneumococcal Vaccine Alone (s4) In Patients With Common Variable Immunodeficiency
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02579967	PHASE2	RECRUITING	Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies
NCT03663933	PHASE2	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Cell Transplantation for Disorders of T-cell Proliferation and/or Dysregulation
NCT04339777	PHASE2	RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Inborn Errors of Immunity
NCT04925375	PHASE2	RECRUITING	Abatacept for the Treatment of Common Variable Immunodeficiency With Interstitial Lung Disease
NCT05593588	PHASE2	ENROLLING_BY_INVITATION	Senolytics Treatment of Interstitial Lung Disease in Common Variable Immunodeficiency
NCT06897358	PHASE2	ACTIVE_NOT_RECRUITING	Leniolisib for Immune Dysregulation in CVID
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT00263237	PHASE1	COMPLETED	STA-5326 Meslylate to Treat Gut Inflammation Associated With Common Variable Immunodeficiency
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT00004695	Not specified	COMPLETED	Randomized Study of Polyethylene-Glycol-Conjugated Interleukin 2 in Patients With Common Variable Immunodeficiency
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00015431	Not specified	COMPLETED	Immune System and Gut Abnormalities in Patients With Common Variable Immunodeficiency With and Without Gastrointestinal Symptoms
NCT00661401	Not specified	COMPLETED	Specific IgG Antibody in Patients With Primary Antibody Deficiencies Treated With Subcutaneous Immunoglobulin
NCT00943514	Not specified	RECRUITING	Natural History of Bronchiectasis
NCT01196702	Not specified	COMPLETED	Lymphocyte Immunophenotyping in Common Variable Immunodeficiency
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT01981785	Not specified	UNKNOWN	Investigation of Immune Disorders and Deficiencies
NCT02960399	Not specified	TERMINATED	Assessment of Immunogenicity of Zostavax® in Patients With Antibody Deficiency 60 Years of Age and Older
NCT03188419	Not specified	COMPLETED	Breadth of Donor Options for People With Inherited Diseases Requiring Allogeneic Hematopoietic Stem Cell Transplant in the Era of Alternative Donor Transplants Using Post-Transplantation Cyclophosphamide
NCT03211689	Not specified	COMPLETED	The Impact of Exercise on Stress, Fatigue, and Quality of Life in Individuals With Primary Immunodeficiency Disease
NCT03534479	Not specified	COMPLETED	Human IgGs and Endothelial Function in Vivo in Humans
NCT05310604	Not specified	COMPLETED	Early Detection of Primary Antibody Deficiencies in Primary Care Facilities by an Algorithm Driven Selection of Serologic Testing in Individuals at Risk.
NCT05321407	Not specified	ACTIVE_NOT_RECRUITING	COVID-19 Vaccine Responses in PIDD Subjects
NCT05481554	Not specified	UNKNOWN	Composition and Function of Gut Microbiota in Porto-sinusoidal Vascular Disease Associated With Variable Common Immunodeficiency
NCT06145100	Not specified	COMPLETED	Prediction of Portal Hypertension in Patients With CVID (CVID-pHT)