Immunodeficiency, common variable, 7

Summary

Immunodeficiency, common variable, 7 (MONDO:0013862) is a disease caused by CR2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: CR2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 772

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency, common variable, 7
Mondo ID	MONDO:0013862
OMIM	614699
Orphanet	696894
DOID	DOID:0081150
UMLS	C3542922
MedGen	762276
GARD	0015836
Is cancer (heuristic)	no

Also known as: CVID7 · immunodeficiency, common variable, 7 · immunodeficiency, common variable, type 7

Data availability: 772 ClinVar variants · 3 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, 7

Related subtypes (15): immune deficiency, familial variable, immunodeficiency, common variable, 2, immunodeficiency, common variable, 1, immunodeficiency, common variable, 3, immunodeficiency, common variable, 4, immunodeficiency, common variable, 5, immunodeficiency, common variable, 6, 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

600 retrieved; paginated sample, class counts are floors:

271 likely benign, 246 uncertain significance, 31 pathogenic, 15 benign, 13 conflicting classifications of pathogenicity, 11 likely pathogenic, 9 benign/likely benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1005385	NM_001006658.3(CR2):c.623_624del (p.Pro208fs)	CR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1017238	NM_001006658.3(CR2):c.592_595del (p.Ser199fs)	CR2	Pathogenic	criteria provided, single submitter
1018003	NM_001006658.3(CR2):c.1191del (p.Thr398fs)	CR2	Pathogenic	criteria provided, single submitter
1021348	NM_001006658.3(CR2):c.2518C>T (p.Arg840Ter)	CR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1047654	NM_001006658.3(CR2):c.2176_2177dup (p.Gln726fs)	CR2	Pathogenic	criteria provided, single submitter
1061097	NM_001006658.3(CR2):c.2204C>G (p.Ser735Ter)	CR2	Pathogenic	criteria provided, single submitter
1469632	NM_001006658.3(CR2):c.2864_2865del (p.His955fs)	CR2	Pathogenic	criteria provided, single submitter
1683519	NM_001006658.3(CR2):c.624dup (p.Thr209fs)	CR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1903089	NM_001006658.3(CR2):c.2244C>A (p.Tyr748Ter)	CR2	Pathogenic	criteria provided, single submitter
2041808	NM_001006658.3(CR2):c.1231C>T (p.Gln411Ter)	CR2	Pathogenic	criteria provided, single submitter
2086090	NM_001006658.3(CR2):c.412del (p.Trp138fs)	CR2	Pathogenic	criteria provided, single submitter
2128585	NM_001006658.3(CR2):c.1877_1878del (p.Val626fs)	CR2	Pathogenic	criteria provided, single submitter
2169328	NM_001006658.3(CR2):c.2423del (p.Asp808fs)	CR2	Pathogenic	criteria provided, single submitter
2188566	NM_001006658.3(CR2):c.1174C>T (p.Arg392Ter)	CR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2756144	NM_001006658.3(CR2):c.1458del (p.Phe486fs)	CR2	Pathogenic	criteria provided, single submitter
2781409	NM_001006658.3(CR2):c.40dup (p.Val14fs)	CR2	Pathogenic	criteria provided, single submitter
2880311	NM_001006658.3(CR2):c.3230T>G (p.Leu1077Ter)	CR2	Pathogenic	criteria provided, single submitter
2954886	NM_001006658.3(CR2):c.1518T>A (p.Tyr506Ter)	CR2	Pathogenic	criteria provided, single submitter
2987740	NM_001006658.3(CR2):c.3070_3088del (p.Leu1024fs)	CR2	Pathogenic	criteria provided, single submitter
3022333	NM_001006658.3(CR2):c.2275C>T (p.Gln759Ter)	CR2	Pathogenic	criteria provided, single submitter
35453	NM_001006658.3(CR2):c.2297G>A (p.Trp766Ter)	CR2	Pathogenic	no assertion criteria provided
35454	NM_001006658.3(CR2):c.1225+1G>C	CR2	Pathogenic	criteria provided, multiple submitters, no conflicts
3616630	NM_001006658.3(CR2):c.909C>G (p.Tyr303Ter)	CR2	Pathogenic	criteria provided, single submitter
3622853	NM_001006658.3(CR2):c.739C>T (p.Arg247Ter)	CR2	Pathogenic	criteria provided, single submitter
3629192	NM_001006658.3(CR2):c.2479G>T (p.Gly827Ter)	CR2	Pathogenic	criteria provided, single submitter
3643091	NM_001006658.3(CR2):c.630T>A (p.Cys210Ter)	CR2	Pathogenic	criteria provided, single submitter
3653659	NM_001006658.3(CR2):c.909C>A (p.Tyr303Ter)	CR2	Pathogenic	criteria provided, single submitter
3663085	NM_001006658.3(CR2):c.52del (p.Val18fs)	CR2	Pathogenic	criteria provided, single submitter
3664550	NM_001006658.3(CR2):c.2608dup (p.Ile870fs)	CR2	Pathogenic	criteria provided, single submitter
3696802	NM_001006658.3(CR2):c.2454dup (p.Leu819fs)	CR2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
CR2	Definitive	Autosomal recessive	immunodeficiency, common variable, 7	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CR2	Orphanet:536	Systemic lupus erythematosus
CR2	Orphanet:696894	Common variable immunodeficiency phenotype due to CD21 deficiency
CRB2	Orphanet:443988	Ventriculomegaly-cystic kidney disease
CRB2	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CR2	HGNC:2336	ENSG00000117322	P20023	Complement receptor type 2	gencc,clinvar
C4BPA	HGNC:1325	ENSG00000123838	P04003	C4b-binding protein alpha chain	clinvar
CRB2	HGNC:18688	ENSG00000148204	Q5IJ48	Protein crumbs homolog 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CR2	Complement receptor type 2	Serves as a receptor for various ligands including complement component CD3d, HNRNPU OR IFNA1.
C4BPA	C4b-binding protein alpha chain	Controls the classical pathway of complement activation.
CRB2	Protein crumbs homolog 2	Apical polarity protein that plays a central role during the epithelial-to-mesenchymal transition (EMT) at gastrulation, when newly specified mesodermal cells move inside the embryo.

Protein-family classification

Druggable: 2 · Difficult: 0 · 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
Complement	2	178.7×	8e-05
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CR2	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, SEZ6_CSMD_C4BPB_Regulators
C4BPA	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, C4bp_oligo
CRB2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
secondary oocyte	1
spleen	1
liver	1
lower lobe of lung	1
right lobe of liver	1
ganglionic eminence	1
male germ line stem cell (sensu Vertebrata) in testis	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CR2	150	broad	marker	secondary oocyte, oocyte, spleen
C4BPA	166	tissue_specific	marker	right lobe of liver, liver, lower lobe of lung
CRB2	99	broad	marker	ventricular zone, ganglionic eminence, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CRB2	1,640
CR2	1,484
C4BPA	1,211

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CR2	P20023	9
C4BPA	P04003	9
CRB2	Q5IJ48	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of Complement cascade	2	233.1×	9e-05	CR2, C4BPA
Complement cascade	1	317.2×	0.008	C4BPA
Dengue virus activates/modulates innate and adaptive immune responses	1	167.9×	0.010	C4BPA
Innate Immune System	1	12.8×	0.096	C4BPA
Immune System	1	6.5×	0.148	C4BPA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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 complement activation, classical pathway	2	1605.0×	1e-05	CR2, C4BPA
T cell mediated immunity	2	660.9×	4e-05	CR2, C4BPA
complement activation, classical pathway	2	362.4×	1e-04	CR2, C4BPA
ingression involved in gastrulation with mouth forming second	1	5617.3×	0.001	CRB2
regulation of opsonization	1	2808.7×	0.002	C4BPA
notochord formation	1	1872.4×	0.003	CRB2
response to symbiotic bacterium	1	936.2×	0.004	C4BPA
regulation of gastrulation	1	936.2×	0.004	CRB2
maintenance of epithelial cell apical/basal polarity	1	802.5×	0.004	CRB2
negative regulation of endopeptidase activity	1	561.7×	0.006	CRB2
retinal cone cell development	1	468.1×	0.006	CRB2
circulatory system development	1	468.1×	0.006	CRB2
retina homeostasis	1	374.5×	0.006	CRB2
complement activation, alternative pathway	1	330.4×	0.007	CR2
establishment or maintenance of epithelial cell apical/basal polarity	1	193.7×	0.011	CRB2
mesoderm formation	1	165.2×	0.011	CRB2
B cell proliferation	1	160.5×	0.011	CR2
positive regulation of BMP signaling pathway	1	151.8×	0.011	CRB2
B cell activation	1	151.8×	0.011	CR2
symbiont entry into host cell	1	133.8×	0.011	CR2
establishment of cell polarity	1	127.7×	0.011	CRB2
somitogenesis	1	124.8×	0.011	CRB2
photoreceptor cell maintenance	1	119.5×	0.011	CRB2
type I interferon-mediated signaling pathway	1	114.6×	0.011	CR2
heterophilic cell-cell adhesion	1	112.3×	0.011	CRB2
positive regulation of epithelial to mesenchymal transition	1	106.0×	0.011	CRB2
B cell differentiation	1	73.0×	0.016	CR2
positive regulation of protein catabolic process	1	67.7×	0.016	C4BPA
visual perception	1	26.5×	0.040	CRB2
immune response	1	15.7×	0.064	CR2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CR2	0	0
C4BPA	0	0
CRB2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	CR2, C4BPA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CRB2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CR2	0	—
C4BPA	0	—
CRB2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.