Immunodeficiency, common variable, 1

Summary

Immunodeficiency, common variable, 1 (MONDO:0011864) is a disease caused by ICOS (GenCC Strong), with 6 cohort genes.

At a glance

• Causal gene: ICOS (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 187

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency, common variable, 1
Mondo ID	MONDO:0011864
OMIM	607594
Orphanet	695183
DOID	DOID:0081144
UMLS	C3149378
MedGen	460728
GARD	0024829
Is cancer (heuristic)	no

Also known as: CVID1 · immunodeficiency, common variable, 1 · immunodeficiency, common variable, type 1

Data availability: 187 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic agammaglobulinemia › common variable immunodeficiency › immunodeficiency, common variable, 1

Related subtypes (15): immune deficiency, familial variable, immunodeficiency, common variable, 2, immunodeficiency, common variable, 3, immunodeficiency, common variable, 4, immunodeficiency, common variable, 5, immunodeficiency, common variable, 6, immunodeficiency, common variable, 7, combined immunodeficiency due to LRBA deficiency, immunodeficiency, common variable, 10, IL21-related infantile inflammatory bowel disease, immunodeficiency, common variable, 12, pancytopenia due to IKZF1 mutations, immunodeficiency, common variable, 14, immunodeficiency, common variable, due to APRIL deficiency, immunodeficiency, common variable, 15

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

187 retrieved; paginated sample, class counts are floors:

75 uncertain significance, 61 likely benign, 19 benign, 14 pathogenic, 12 conflicting classifications of pathogenicity, 4 likely pathogenic, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
3247378	NC_000002.11:g.(?204730944)(204824322_?)del	CTLA4	Pathogenic	criteria provided, single submitter
830454	NC_000002.12:g.(?203866796)(203959619_?)del	CTLA4	Pathogenic	criteria provided, single submitter
1359008	NM_012092.4(ICOS):c.61G>T (p.Glu21Ter)	ICOS	Pathogenic	criteria provided, single submitter
1449576	NM_012092.4(ICOS):c.318T>G (p.Tyr106Ter)	ICOS	Pathogenic	criteria provided, single submitter
2002817	NM_012092.4(ICOS):c.17G>A (p.Trp6Ter)	ICOS	Pathogenic	criteria provided, single submitter
2003841	NM_012092.4(ICOS):c.357del (p.Phe119fs)	ICOS	Pathogenic	criteria provided, single submitter
2872742	NM_012092.4(ICOS):c.294del (p.Leu99fs)	ICOS	Pathogenic	criteria provided, single submitter
2993769	NM_012092.4(ICOS):c.291C>A (p.Tyr97Ter)	ICOS	Pathogenic	criteria provided, single submitter
4728975	NM_012092.4(ICOS):c.272dup (p.Ser91fs)	ICOS	Pathogenic	criteria provided, single submitter
5501	NM_012092.4(ICOS):c.59-594_501+93del	ICOS	Pathogenic	no assertion criteria provided
940397	NM_012092.4(ICOS):c.181del (p.Ile61fs)	ICOS	Pathogenic	criteria provided, single submitter
65386	NM_001322934.2(NFKB2):c.2564del (p.Lys855fs)	NFKB2	Pathogenic	no assertion criteria provided
1456057	NC_000002.11:g.(?201943606)(204824322_?)del	STRADB	Pathogenic	criteria provided, single submitter
265340	NM_012452.3(TNFRSF13B):c.431C>G (p.Ser144Ter)	TNFRSF13B	Pathogenic	criteria provided, multiple submitters, no conflicts
322029	NM_012452.3(TNFRSF13B):c.204dup (p.Leu69fs)	TNFRSF13B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1801487	NM_005214.5(CTLA4):c.231_297delinsA (p.Gln80_Ser101del)	CTLA4	Likely pathogenic	criteria provided, single submitter
2585218	NM_012092.4(ICOS):c.136_139del (p.Asp46fs)	ICOS	Likely pathogenic	criteria provided, single submitter
573877	NM_012092.4(ICOS):c.394+2T>C	ICOS	Likely pathogenic	criteria provided, single submitter
663980	NM_012092.4(ICOS):c.58+1G>A	ICOS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
282569	NM_012092.4(ICOS):c.105C>T (p.Asn35=)	ICOS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333732	NM_012092.4(ICOS):c.58+9T>G	ICOS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333737	NM_012092.4(ICOS):c.591G>A (p.Val197=)	ICOS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333738	NM_012092.4(ICOS):c.597A>G (p.Leu199=)	ICOS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
497910	NM_012092.4(ICOS):c.451G>C (p.Val151Leu)	ICOS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
666602	NM_012092.4(ICOS):c.189C>A (p.Cys63Ter)	ICOS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
784704	NM_012092.4(ICOS):c.375A>G (p.Gly125=)	ICOS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
827707	NM_012092.4(ICOS):c.356T>C (p.Phe119Ser)	ICOS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895773	NM_012092.4(ICOS):c.495A>C (p.Thr165=)	ICOS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896052	NM_012092.4(ICOS):c.510A>G (p.Ser170=)	ICOS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898739	NM_012092.4(ICOS):c.42C>A (p.Arg14=)	ICOS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ICOS	Strong	Autosomal recessive	immunodeficiency, common variable, 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ICOS	Orphanet:695183	Late-onset combined immunodeficiency due to ICOS deficiency
CD28	Orphanet:2584	Classic mycosis fungoides
CD28	Orphanet:3162	Sézary syndrome
TNFRSF13B	Orphanet:696907	Common variable immunodeficiency phenotype due to homozygous TACI deficiency
CTLA4	Orphanet:2584	Classic mycosis fungoides
CTLA4	Orphanet:3162	Sézary syndrome
CTLA4	Orphanet:391490	Adult-onset myasthenia gravis
CTLA4	Orphanet:436159	Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency
CTLA4	Orphanet:536	Systemic lupus erythematosus
CTLA4	Orphanet:900	Granulomatosis with polyangiitis
NFKB2	Orphanet:293978	Deficiency in anterior pituitary function-variable immunodeficiency syndrome

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ICOS	HGNC:5351	ENSG00000163600	Q9Y6W8	Inducible T-cell costimulator	gencc,clinvar
STRADB	HGNC:13205	ENSG00000082146	Q9C0K7	STE20-related kinase adapter protein beta	clinvar
CD28	HGNC:1653	ENSG00000178562	P10747	T-cell-specific surface glycoprotein CD28	clinvar
TNFRSF13B	HGNC:18153	ENSG00000240505	O14836	Tumor necrosis factor receptor superfamily member 13B	clinvar
CTLA4	HGNC:2505	ENSG00000163599	P16410	Cytotoxic T-lymphocyte protein 4	clinvar
NFKB2	HGNC:7795	ENSG00000077150	Q00653	Nuclear factor NF-kappa-B p100 subunit	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ICOS	Inducible T-cell costimulator	Stimulatory receptor expressed in activated or antigen-experienced T-cells that plays an important role in the immune response.
STRADB	STE20-related kinase adapter protein beta	Pseudokinase which, in complex with CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta), binds to and activates STK11/LKB1.
CD28	T-cell-specific surface glycoprotein CD28	Receptor that plays a role in T-cell activation, proliferation, survival and the maintenance of immune homeostasis.
TNFRSF13B	Tumor necrosis factor receptor superfamily member 13B	Receptor for TNFSF13/APRIL and TNFSF13B/TALL1/BAFF/BLYS that binds both ligands with similar high affinity.
CTLA4	Cytotoxic T-lymphocyte protein 4	Inhibitory receptor acting as a major negative regulator of T-cell responses.
NFKB2	Nuclear factor NF-kappa-B p100 subunit	NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as infl…

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	3	14.6×	0.003
Kinase	1	4.6×	0.396
Transcription factor	1	1.4×	0.719
Other/Unknown	1	0.3×	0.993

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ICOS	Antibody/Immunoglobulin	yes		Ig_V-set, Ig-like_fold, ICOS
STRADB	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, STRAD_A/B-like
CD28	Antibody/Immunoglobulin	yes		CD28, Ig_V-set, Ig-like_fold
TNFRSF13B	Other/Unknown	no		TACI_Cys-rich-dom, TNFR_13B
CTLA4	Antibody/Immunoglobulin	yes		Ig_sub, CTLA4, Ig_V-set
NFKB2	Transcription factor	no		NFkB/Dor, Death_dom, Ankyrin_rpt

Expression context

Cohort genes with no expression data: 0.

6 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lymph node	3
vermiform appendix	3
spleen	2
thymus	1
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1
blood	1
olfactory bulb	1
type B pancreatic cell	1
buccal mucosa cell	1
granulocyte	1
muscle layer of sigmoid colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ICOS	110	tissue_specific	marker	lymph node, vermiform appendix, thymus
STRADB	140	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
CD28	154	broad	marker	lymph node, vermiform appendix, blood
TNFRSF13B	158	tissue_specific	marker	type B pancreatic cell, olfactory bulb, spleen
CTLA4	164	tissue_specific	marker	lymph node, vermiform appendix, buccal mucosa cell
NFKB2	221	ubiquitous	marker	granulocyte, muscle layer of sigmoid colon, spleen

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NFKB2	4,041
CTLA4	3,863
CD28	2,958
ICOS	2,199
TNFRSF13B	1,333
STRADB	882

Intra-cohort edges

A	B	Sources
CD28	CTLA4	intact, string_interaction
CD28	ICOS	string_interaction
CTLA4	ICOS	string_interaction
ICOS	TNFRSF13B	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CTLA4	P16410	22
NFKB2	Q00653	11
CD28	P10747	10
ICOS	Q9Y6W8	2
TNFRSF13B	O14836	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
STRADB	Q9C0K7	74.39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 42. Enrichment computed across 6 evidence-associated genes (6 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Co-stimulation by CD28	2	126.9×	0.004	CD28, CTLA4
Nef mediated downregulation of CD28 cell surface expression	1	951.7×	0.015	CD28
Constitutive Signaling by Aberrant PI3K in Cancer	2	42.3×	0.015	ICOS, CD28
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	2	32.3×	0.016	ICOS, CD28
DEx/H-box helicases activate type I IFN and inflammatory cytokines production	1	271.9×	0.022	NFKB2
IkBA variant leads to EDA-ID	1	271.9×	0.022	NFKB2
PIP3 activates AKT signaling	2	22.3×	0.022	ICOS, CD28
Interleukin-1 processing	1	211.5×	0.024	NFKB2
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	1	190.3×	0.024	CTLA4
Co-stimulation by ICOS	1	173.0×	0.024	ICOS
SUMOylation of immune response proteins	1	158.6×	0.024	NFKB2
CD28 dependent Vav1 pathway	1	146.4×	0.024	CD28
RIP-mediated NFkB activation via ZBP1	1	112.0×	0.025	NFKB2
The NLRP3 inflammasome	1	112.0×	0.025	NFKB2
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1	105.7×	0.025	CD28
The role of Nef in HIV-1 replication and disease pathogenesis	1	105.7×	0.025	CD28
Co-inhibition by CTLA4	1	86.5×	0.028	CTLA4
TRAF6 mediated NF-kB activation	1	76.1×	0.028	NFKB2
Regulation of T cell activation by CD28 family	1	70.5×	0.028	CD28
Purinergic signaling in leishmaniasis infection	1	70.5×	0.028	NFKB2
Energy dependent regulation of mTOR by LKB1-AMPK	1	65.6×	0.028	STRADB
CD28 dependent PI3K/Akt signaling	1	65.6×	0.028	CD28
TNFs bind their physiological receptors	1	65.6×	0.028	TNFRSF13B
PI3K/AKT Signaling in Cancer	1	61.4×	0.028	CD28
Host Interactions of HIV factors	1	56.0×	0.029	CD28
Nuclear events stimulated by ALK signaling in cancer	1	54.4×	0.029	ICOS
TAK1-dependent IKK and NF-kappa-B activation	1	50.1×	0.031	NFKB2
Negative regulation of the PI3K/AKT network	1	46.4×	0.032	CD28
MTOR signalling	1	44.3×	0.032	STRADB
NIK–>noncanonical NF-kB signaling	1	38.1×	0.036	NFKB2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of B cell proliferation	2	312.1×	1e-03	TNFRSF13B, CTLA4
T cell costimulation	2	124.8×	0.003	ICOS, CD28
T cell tolerance induction	1	2808.7×	0.007	ICOS
follicular dendritic cell differentiation	1	1404.3×	0.008	NFKB2
T cell receptor signaling pathway	2	50.6×	0.008	CD28, CTLA4
positive regulation of inflammatory response to antigenic stimulus	1	936.2×	0.011	CD28
negative regulation of regulatory T cell differentiation	1	561.7×	0.014	CTLA4
regulatory T cell differentiation	1	351.1×	0.014	CD28
CD4-positive, alpha-beta T cell proliferation	1	312.1×	0.014	CD28
regulation of regulatory T cell differentiation	1	312.1×	0.014	CD28
germinal center formation	1	280.9×	0.014	NFKB2
positive regulation of CD4-positive, alpha-beta T cell proliferation	1	280.9×	0.014	CD28
activation of protein kinase activity	1	255.3×	0.014	STRADB
positive regulation of isotype switching to IgG isotypes	1	255.3×	0.014	CD28
negative thymic T cell selection	1	234.1×	0.014	CD28
T follicular helper cell differentiation	1	234.1×	0.014	ICOS
adaptive immune response	2	28.1×	0.014	TNFRSF13B, CTLA4
cell surface receptor signaling pathway	2	21.4×	0.014	CD28, TNFRSF13B
immune response	2	15.7×	0.020	ICOS, CTLA4
non-canonical NF-kappaB signal transduction	1	140.4×	0.021	NFKB2
positive regulation of T cell receptor signaling pathway	1	127.7×	0.022	CD28
positive regulation of viral genome replication	1	96.8×	0.026	CD28
B cell homeostasis	1	93.6×	0.026	TNFRSF13B
positive regulation of interleukin-4 production	1	93.6×	0.026	CD28
positive regulation of mitotic nuclear division	1	90.6×	0.026	CD28
negative regulation of T cell activation	1	87.8×	0.026	CTLA4
protein export from nucleus	1	85.1×	0.026	STRADB
positive regulation of interleukin-2 production	1	78.0×	0.027	CD28
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	68.5×	0.027	STRADB
positive regulation of interleukin-10 production	1	66.9×	0.027	CD28

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 5 of 6 evidence-associated genes (83%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
NFKB2	INDOPROFEN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NFKB2	15	4
ICOS	0	0
STRADB	0	0
CD28	0	0
TNFRSF13B	0	0
CTLA4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INDOPROFEN	4	NFKB2
VAMOROLONE	4	NFKB2
BORTEZOMIB	4	NFKB2
DEXAMETHASONE	4	NFKB2
SULFASALAZINE	4	NFKB2
CURCUMIN	3	NFKB2
RESVERATROL	3	NFKB2
IXAZOMIB	3	NFKB2
WITHANOLIDE D	3	NFKB2
TRIPTOLIDE	3	NFKB2
FRENTIZOLE	2	NFKB2
LAPACHONE	2	NFKB2
SANGUINARIUM	2	NFKB2
AS-602868	1	NFKB2
WITHAFERIN A	1	NFKB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NFKB2	230	Binding:226, Functional:4
STRADB	20	Binding:20
ICOS	7	Binding:7
CD28	1	Functional:1
CTLA4	1	Binding:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
NFKB2	230

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

15 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
INDOPROFEN	4	NFKB2
VAMOROLONE	4	NFKB2
BORTEZOMIB	4	NFKB2
DEXAMETHASONE	4	NFKB2
SULFASALAZINE	4	NFKB2
CURCUMIN	3	NFKB2
RESVERATROL	3	NFKB2
IXAZOMIB	3	NFKB2
WITHANOLIDE D	3	NFKB2
TRIPTOLIDE	3	NFKB2
FRENTIZOLE	2	NFKB2
LAPACHONE	2	NFKB2
SANGUINARIUM	2	NFKB2
AS-602868	1	NFKB2
WITHAFERIN A	1	NFKB2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NFKB2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	ICOS, CD28, CTLA4
D	Druggable family + AlphaFold only, no drug	1	STRADB
E	Difficult family or no structure, no drug	1	TNFRSF13B

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ICOS	7	—
STRADB	20	—
CD28	1	—
TNFRSF13B	0	—
CTLA4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.