CD19

Summary

CD19 (CD19 molecule, HGNC:1633) is a protein-coding gene on chromosome 16p11.2, encoding B-lymphocyte antigen CD19 (P15391). Functions as a coreceptor for the B-cell antigen receptor complex (BCR) on B-lymphocytes.

This gene encodes a member of the immunoglobulin gene superfamily. Expression of this cell surface protein is restricted to B cell lymphocytes. This protein is a reliable marker for pre-B cells but its expression diminishes during terminal B cell differentiation in antibody secreting plasma cells. The protein has two N-terminal extracellular Ig-like domains separated by a non-Ig-like domain, a hydrophobic transmembrane domain, and a large C-terminal cytoplasmic domain. This protein forms a complex with several membrane proteins including complement receptor type 2 (CD21) and tetraspanin (CD81) and this complex reduces the threshold for antigen-initiated B cell activation. Activation of this B-cell antigen receptor complex activates the phosphatidylinositol 3-kinase signalling pathway and the subsequent release of intracellular stores of calcium ions. This protein is a target of chimeric antigen receptor (CAR) T-cells used in the treatment of lymphoblastic leukemia. Mutations in this gene are associated with the disease common variable immunodeficiency 3 (CVID3) which results in a failure of B-cell differentiation and impaired secretion of immunoglobulins. CVID3 is characterized by hypogammaglobulinemia, an inability to mount an antibody response to antigen, and recurrent bacterial infections. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 930 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency, common variable, 3 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 16
• Clinical variants (ClinVar): 420 total — 10 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 33
• Druggable target: yes
• MANE Select transcript: NM_001770

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1633
Approved symbol	CD19
Name	CD19 molecule
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000177455
Ensembl biotype	protein_coding
OMIM	107265
Entrez	930

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 retained_intron, 2 protein_coding

ENST00000324662, ENST00000538922, ENST00000565089, ENST00000566890, ENST00000567368

RefSeq mRNA: 3 — MANE Select: NM_001770 NM_001178098, NM_001385732, NM_001770

CCDS: CCDS10644, CCDS53998

Canonical transcript exons

ENST00000538922 — 15 exons

Exon	Start	End
ENSE00001227618	28932911	28933114
ENSE00001227623	28932346	28932612
ENSE00001891235	28931971	28932088
ENSE00001909384	28939141	28939342
ENSE00003483139	28935444	28935554
ENSE00003483648	28933234	28933509
ENSE00003491521	28938872	28938978
ENSE00003503251	28937624	28937680
ENSE00003552325	28936153	28936201
ENSE00003576853	28937271	28937375
ENSE00003612733	28937023	28937136
ENSE00003630794	28936512	28936600
ENSE00003654607	28938676	28938768
ENSE00003688168	28937455	28937523
ENSE00003691135	28937769	28937825

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 95.76.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.5405 / max 283.1520, expressed in 79 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153436	2.0771	73
153437	0.4634	56

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
spleen	UBERON:0002106	95.76	gold quality
lymph node	UBERON:0000029	93.90	gold quality
vermiform appendix	UBERON:0001154	93.25	gold quality
granulocyte	CL:0000094	89.47	gold quality
caecum	UBERON:0001153	88.72	gold quality
ileal mucosa	UBERON:0000331	88.14	gold quality
epithelium of nasopharynx	UBERON:0001951	85.81	gold quality
bone marrow cell	CL:0002092	82.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.97	gold quality
blood	UBERON:0000178	80.50	gold quality
small intestine Peyer’s patch	UBERON:0003454	79.52	gold quality
bone marrow	UBERON:0002371	79.29	gold quality
tonsil	UBERON:0002372	79.08	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.39	gold quality
superficial temporal artery	UBERON:0001614	77.31	gold quality
mucosa of transverse colon	UBERON:0004991	76.92	gold quality
small intestine	UBERON:0002108	75.16	gold quality
nasal cavity epithelium	UBERON:0005384	74.18	gold quality
trabecular bone tissue	UBERON:0002483	71.97	silver quality
left testis	UBERON:0004533	70.14	gold quality
right testis	UBERON:0004534	68.80	gold quality
testis	UBERON:0000473	67.88	gold quality
rectum	UBERON:0001052	67.30	gold quality
oocyte	CL:0000023	67.27	gold quality
gall bladder	UBERON:0002110	67.04	gold quality
sperm	CL:0000019	67.03	gold quality
male germ cell	CL:0000015	66.45	gold quality
colonic mucosa	UBERON:0000317	66.28	gold quality
leukocyte	CL:0000738	65.71	gold quality
nasal cavity mucosa	UBERON:0001826	65.10	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	291.12
E-GEOD-75688	yes	113.11
E-CURD-112	yes	36.35
E-ANND-3	yes	24.31
E-MTAB-9067	yes	18.66
E-HCAD-10	yes	14.52
E-MTAB-9801	yes	5.22

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, APEX1, EBF1, EGR1, PAX5, PREB, SP1, TCF3, XBP1

miRNA regulators (miRDB)

18 targeting CD19, 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-8485	100.00	77.57	4731
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-6810-5P	98.29	66.21	975
HSA-MIR-3670	97.88	64.39	763
HSA-MIR-10526-3P	97.86	64.97	1342
HSA-MIR-4642	97.52	67.60	916
HSA-MIR-4689	96.97	65.79	1209
HSA-MIR-4652-5P	96.46	64.22	553
HSA-MIR-6858-5P	96.05	64.59	1020
HSA-MIR-635	96.00	65.54	687
HSA-MIR-6774-5P	95.94	65.18	722
HSA-MIR-4515	95.70	65.73	716

Literature-anchored findings (GeneRIF, showing 40)

• REVIEW:lack OF CD19 expression in malignant plasma cells (myeloma cells) may contribute to proliferative advantage of the malignant cell clones. (PMID:12002767)
• The physiologic role of eight CD19 tyrosines was examined in CD19-knockout mice expressing transgenic human CD19 constructs. (PMID:12387743)
• Coligation of the B cell antigen receptor with the complement (C3)-binding CD21/CD19/CD81 costimulatory complex can enhance the escape of human B cells from Fas-induced death. (PMID:14607925)
• CD19 is continuously and stably expressed on all stages of B lineage differentiation, and it is a reliable cell membrane marker for diagnosing B lineage ALL and an ideal target for antibody-targeting treatment of leukemia. (PMID:15144712)
• each of these signaling proteins (Lyn, Vav, PLCgamma2, Grb2, and the p85 subunit of phosphatidylinositol 3-kinase) contains at least one Src homology 2 (SH2) domain that interacts directly with the phosphorylated CD19 cytoplasmic domain with high affinity (PMID:15187135)
• Overexpression in these cells indicates diseaase progression in B=cell leukemia patients. (PMID:15549146)
• The CD19 -499G>T polymorphism is associated with higher CD19 expression in B cells, and with susceptibility to systemic sclerosis. (PMID:15593213)
• Umbiliccal cord blood-derived CD19-specific T cells after cord blood transplantation can reduce the incidence of CD19+ acute B-cell leukemia relapse. (PMID:16352804)
• CD19 is not always strongly expressed in B-cell neoplasms. Furthermore, the lymphocytic and histiocytic (L&H) cells of lymphocyte predominant Hodgkin’s disease (which express most B-cell-associated markers) commonly lack CD19. (PMID:16430470)
• This suggests that CD19 overexpression may promote anergic B cells to escape tolerance by converging with B Cell Receptor independent pathways, thereby rendering these B cells hyper-responsive to innate signaling. (PMID:16430962)
• Mutation of the CD19 gene causes a type of hypogammaglobulinemia in which the response of mature B cells to antigenic stimulation is defective. (PMID:16672701)
• lipid microdomain disruption and silencing of CD19 directly impacts on CD38’s ability to mediate Ca(2+) fluxes, while leaving its surface expression unchanged (PMID:17327405)
• These findings extend the mutation spectrum of the CD19 deficiency to four, and confirm the homogeneity of the CD19 deficiency as a unique type of CVID. (PMID:17882224)
• Of 9 CVID patients…No mutations of SAP, ICOS, TACI, BAFFR, and CD19 were identified (PMID:18051214)
• relative frequency of CD19 and/or CD56 expression in acute myeloid leukemia (AML) with t(8;21) was significantly higher than those without this translocation and co-expression of these two antigens may serve as the surrogate markers for AML with t(8;21) (PMID:18333845)
• B-lineage commitment can occur before the expression of B220 and CD19 (PMID:18495958)
• Using Flow Cytometry, we describe the first case of peripheral T-cell lymphoma with aberrant coexpression of CD19. (PMID:18671252)
• Data report the first hematopoietic mHag presented by HLA class II molecules to CD4(+) T cells, which is encoded by a single-nucleotide polymorphism in the B cell lineage-specific CD19 gene. (PMID:19001137)
• Activation of B cells by anti-sIgM or anti-CD19 antibodies also leads to cell aggregation that is promoted by CEACAM1, also in a PI3K-dependent manner. (PMID:19454653)
• Data show anti-CD19-CAR-transduced CD8+ and CD4+ T cells produced interferon-gamma and interleukin-2 specifically in response to CD19+ target cells. (PMID:19561539)
• these results suggest that increased hyaluronan accumulation in injured skin induces cytokine production by stimulating B cells through TLR4 in a CD19-dependent manner. (PMID:19574428)
• CD81 up-regulation can increase the risk of hepatitis C virus, particularly in HIV-infected subjects. (PMID:19828092)
• case report of a patient with CD19-positive acute myeloblastic leukemia with trisomy 21 as the sole cytogenetic abnormality [case report] (PMID:19882758)
• Ca(2+) down-regulates SLC and CD19 gene expression upon pre-BCR activation through inhibition of E2A by Ca(2+)/calmodulin. (PMID:20022378)
• Studies indicate taht B lymphocytes proliferated when approximately 100 antigen receptors per cell, 0.03 percent of the total, were coligated with CD19. (PMID:20164433)
• Aberrant expression of CD19 in acute myeloblastic leukemia with t(8;21) involves a poised chromatin structure and PAX5. (PMID:20208555)
• CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. (PMID:20237408)
• CD23 and CD19 are important factors that associated with serum total IgE in the pathogenesis of allergic rhinitis. (PMID:20359104)
• The CD27(+) B-cell population was found to highly express CXCR3 in chronic hepatitis C (CHC), thus suggesting that the CD27(+) B-cell population was recruited from peripheral blood to the inflammatory site of the liver of CHC. (PMID:20377416)
• Heterozygous loss of CD19 causes some changes in the naive B-cell compartment, but overall in vivo B-cell maturation or humoral immunity is not affected. (PMID:20445561)
• Altered CD19/CD22 balance in Egyptian children and adolescents with systemic lupus erythematosus. (PMID:20726320)
• Data suggest that CD19 and CD33 are present on the surface of the leukemic cell lines such that they can be connected by a single sctb molecule. (PMID:21081841)
• A missense mutation of CD19 in the conserved tryptophan 41 in immunoglobulin superfamily domain resulted in antibody deficiency. (PMID:21330302)
• binding sites for CD19 and CD16 have a role in antibody-dependent cellular cytotoxicity against B-lymphoid tumor cells (PMID:21339041)
• Studies showed the qualitative and quantitative expression of four target surface antigens, CD19, CD20, CD22, and CD33, for which MoAbs are currently available for clinical use, in ALL. (PMID:21348573)
• Data show that CD45+CD19- MCL-ICs play a role in the drug resistance of MCL, and this drug resistance was largely due to quiescent properties with enriched ABC transporters. (PMID:21599592)
• Data indicate that among MDS cases, CD15+ and CD19+ cell TLs were positively correlated, and PBL TL was was not associated with hTERT genotype. (PMID:21635204)
• Identified are four patients with agammaglobulinemia and markedly reduced but detectable B cells in the peripheral circulation. These B cells have an unusual phenotype characterized by increased expression of CD19 but no BCR. (PMID:21693761)
• immunological significance of CD19 for the IL-10 production by CD5(+) B cells (PMID:21786452)
• Results obtained through a large cohort of European caucasian patients with systemic sclerosis do not support the contribution of CD19, CD20, CD22, CD24 variants to the genetic susceptibility. (PMID:21961844)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cd19	ENSMUSG00000030724
rattus_norvegicus	Cd19	ENSRNOG00000018311

Protein

Protein identifiers

B-lymphocyte antigen CD19 — P15391 (reviewed: P15391)

Alternative names: B-lymphocyte surface antigen B4, Differentiation antigen CD19, T-cell surface antigen Leu-12

All UniProt accessions (1): P15391

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a coreceptor for the B-cell antigen receptor complex (BCR) on B-lymphocytes. Decreases the threshold for activation of downstream signaling pathways and for triggering B-cell responses to antigens. Activates signaling pathways that lead to the activation of phosphatidylinositol 3-kinase and the mobilization of intracellular Ca(2+) stores. Is not required for early steps during B cell differentiation in the blood marrow. Required for normal differentiation of B-1 cells. Required for normal B cell differentiation and proliferation in response to antigen challenges. Required for normal levels of serum immunoglobulins, and for production of high-affinity antibodies in response to antigen challenge.

Subunit / interactions. Interacts with CR2/CD21. Part of a complex composed of CD19, CR2/CD21, CD81 and IFITM1/CD225 in the membrane of mature B-cells. Interacts directly with CD81 (via the second extracellular domain); this interaction is initiated early during biosynthesis in the ER/pre-Golgi compartments and is essential for trafficking and compartmentalization of CD19 receptor on the cell surface of activated B cells. Interacts with VAV. Interacts with GRB2 and SOS when phosphorylated on Tyr-348 and/or Tyr-378. Interacts with PLCG2 when phosphorylated on Tyr-409. Interacts with LYN. Interacts (when tyrosine phosphorylated) with the regulatory p85 subunit of phosphatidylinositol 3-kinase (PIK3R1 or PIK3R2). Interacts with GRB2.

Subcellular location. Cell membrane. Membrane raft.

Tissue specificity. Detected on marginal zone and germinal center B cells in lymph nodes. Detected on blood B cells (at protein level).

Post-translational modifications. Phosphorylated on tyrosine following B-cell activation. Phosphorylated on tyrosine residues by LYN. Tyrosine residues are phosphorylated sequentially after activation of the B cell receptor. Phosphorylation of Tyr-531 is extremely rapid, followed by phosphorylation at Tyr-409. In contrast, phosphorylation of Tyr-500 appears more slowly and is more transient, returning rapidly to basal levels.

Disease relevance. Immunodeficiency, common variable, 3 (CVID3) [MIM:613493] 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.

Isoforms (2)

UniProt ID	Names	Canonical?
P15391-1	1	yes
P15391-2	2

RefSeq proteins (3): NP_001171569, NP_001372661, NP_001761* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR042341	CD19	Family

UniProt features (65 total): strand 18, mutagenesis site 9, modified residue 7, glycosylation site 5, compositionally biased region 4, disulfide bond 3, sequence conflict 3, helix 3, region of interest 3, topological domain 2, sequence variant 2, domain 2, signal peptide 1, chain 1, splice variant 1, transmembrane region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6AL5	X-RAY DIFFRACTION	3
7URV	ELECTRON MICROSCOPY	3.05
7URX	ELECTRON MICROSCOPY	3.4
7JIC	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15391-F1	62.99	0.24

Antibody-complex structures (SAbDab): 3 — 6AL5, 7URV, 7URX

Functional residue map

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

Post-translational modifications (7): 227, 348, 378, 409, 439, 500, 531

Disulfide bonds (3): 38–261, 97–200, 134–173

Glycosylation sites (5): 86, 125, 138, 181, 265

Mutagenesis-validated functional residues (9):

Position	Phenotype
309–556	abolishes the ability to activate signaling pathways that mediate mobilization of cytoplasmic ca(2+). abolishes the abil
348	no effect on the ability to complement impaired b cell development and functions; when associated with f-378.
378	no effect on the ability to complement impaired b cell development and functions; when associated with f-348.
409	no effect on the ability to complement impaired b cell development and functions; when associated with f-439.
421	no effect on the ability to complement impaired b cell development and functions; when associated with f-461.
439	no effect on the ability to complement impaired b cell development and functions; when associated with f-409.
461	no effect on the ability to complement impaired b cell development and functions; when associated with f-421.
500	strongly reduced tyrosine phosphorylation; when associated with f-531. abolishes activation of signaling pathways that m
531	strongly reduced tyrosine phosphorylation; when associated with f-500. abolishes activation of signaling pathways that m

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-977606	Regulation of Complement cascade
R-HSA-983695	Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-166658	Complement cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-199418	Negative regulation of the PI3K/AKT network
R-HSA-2219528	PI3K/AKT Signaling in Cancer
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-9006925	Intracellular signaling by second messengers
R-HSA-983705	Signaling by the B Cell Receptor (BCR)

MSigDB gene sets: 337 (showing top): PID_BCR_5PATHWAY, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_REGULATION_OF_B_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_B_CELL_ACTIVATION, MODULE_64, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, GOBP_B_CELL_PROLIFERATION, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT

GO Biological Process (13): B-1 B cell differentiation (GO:0001923), B cell proliferation involved in immune response (GO:0002322), immunoglobulin mediated immune response (GO:0016064), B cell proliferation (GO:0042100), antigen receptor-mediated signaling pathway (GO:0050851), B cell receptor signaling pathway (GO:0050853), regulation of B cell receptor signaling pathway (GO:0050855), regulation of B cell activation (GO:0050864), positive regulation of release of sequestered calcium ion into cytosol (GO:0051281), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), adaptive immune response (GO:0002250), immune system process (GO:0002376), B cell mediated immunity (GO:0019724)

GO Molecular Function (0):

GO Cellular Component (6): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), protein-containing complex (GO:0032991), membrane raft (GO:0045121), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Adaptive Immune System	2
Immune System	2
Intracellular signaling by second messengers	1
PI3K/AKT Signaling in Cancer	1
Negative regulation of the PI3K/AKT network	1
Complement cascade	1
Signaling by the B Cell Receptor (BCR)	1
Innate Immune System	1
PIP3 activates AKT signaling	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Disease	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
immune response	2
B cell activation	2
mature B cell differentiation	1
B cell activation involved in immune response	1
B cell proliferation	1
B cell mediated immunity	1
lymphocyte proliferation	1
immune response-activating cell surface receptor signaling pathway	1
antigen receptor-mediated signaling pathway	1
B cell receptor signaling pathway	1
regulation of antigen receptor-mediated signaling pathway	1
regulation of lymphocyte activation	1
release of sequestered calcium ion into cytosol	1
regulation of release of sequestered calcium ion into cytosol	1
positive regulation of calcium ion transmembrane transport	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
biological_process	1
lymphocyte mediated immunity	1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
cellular_component	1
membrane microdomain	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3498 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD19	CR2	P20023	999
CD19	CD81	P18582	998
CD19	FCGR3B	O75015	998
CD19	FCGR3A	P08637	998
CD19	IFITM1	P13164	994
CD19	LYN	P07948	987
CD19	CEP70	Q8NHQ1	979
CD19	CD22	P20273	977
CD19	NCAM1	P13591	972
CD19	CD79A	P11912	971
CD19	MME	P08473	954
CD19	CD38	P28907	941
CD19	CD5	P06127	933
CD19	CD27	P26842	932
CD19	CD2	P06729	932

IntAct

13 interactions, top by confidence:

A	B	Type	Score
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
IGHM	CD19	psi-mi:“MI:2364”(proximity)	0.480
IGHM	CD19	psi-mi:“MI:0914”(association)	0.480
ARID3A	IGHM	psi-mi:“MI:0403”(colocalization)	0.460
CD19	PIK3R3	psi-mi:“MI:0915”(physical association)	0.400
CD19	POLR2M	psi-mi:“MI:0914”(association)	0.350
CD19	MYZAP	psi-mi:“MI:0914”(association)	0.350
BTK	IGHM	psi-mi:“MI:0914”(association)	0.350
PIK3R1	CD19	psi-mi:“MI:0914”(association)	0.350
IGHD	CD19	psi-mi:“MI:2364”(proximity)	0.270
CD82	CD19	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (41): POLR2M (Affinity Capture-MS), FAM188A (Affinity Capture-MS), B3GNT3 (Affinity Capture-MS), CD82 (Co-localization), POLR2M (Affinity Capture-MS), FAM188A (Affinity Capture-MS), B3GNT3 (Affinity Capture-MS), IGSF8 (Affinity Capture-MS), CD19 (Affinity Capture-Western), CD19 (Affinity Capture-Western), CD19 (Affinity Capture-Western), CD19 (Reconstituted Complex), PIK3R1 (Reconstituted Complex), CD19 (Reconstituted Complex), CD19 (Reconstituted Complex)

ESM2 similar proteins: A2A7Y5, A6NKC9, B1ASB6, F1MGG3, M3WHG5, O54824, O88834, P15391, P24394, P25917, P25918, P27987, P60669, Q13796, Q14005, Q32PJ7, Q3LRP3, Q49AM3, Q4R2Z8, Q5FVQ5, Q5JXC2, Q6VYH9, Q6ZMY3, Q7M4L6, Q7Z591, Q7Z6P3, Q80VR2, Q80VW7, Q863Z5, Q8BG26, Q8BI17, Q8BLR5, Q8BZW2, Q8C886, Q8CB87, Q8IY92, Q8NAV2, Q8NDX1, Q8NHY3, Q8R2H3

Diamond homologs: P15391, P25917, P25918, Q3LRP3

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
CD19	“up-regulates activity”	MAPK1
blinatumomab	“down-regulates activity”	CD19	binding
CR2	“up-regulates activity”	CD19	binding
LYN	up-regulates	CD19	phosphorylation
CD19	up-regulates	B_cell_maturation
LYN	“up-regulates activity”	CD19	phosphorylation
CD19	“up-regulates activity”	LYN	binding
CD19	“up-regulates activity”	VAV1	binding
CD19	“up-regulates activity”	PIK3R1	binding
ABL1	“up-regulates activity”	CD19	phosphorylation
CD19	“up-regulates activity”	PI3K	binding

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	6
Uncertain significance	182
Likely benign	185
Benign	13

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1401146	NM_001770.6(CD19):c.128C>A (p.Ser43Ter)	Pathogenic
18054	NM_001770.6(CD19):c.971dup (p.Arg325fs)	Pathogenic
18055	NM_001770.6(CD19):c.1386_1387del (p.Asn463fs)	Pathogenic
1927283	NM_001770.6(CD19):c.278dup (p.Phe94fs)	Pathogenic
254194	NM_001770.6(CD19):c.947-1G>T	Pathogenic
254195	NM_001770.6(CD19):c.156G>C (p.Trp52Cys)	Pathogenic
254196	NM_001770.6(CD19):c.1464del (p.Ser489fs)	Pathogenic
254197	NM_001770.5(CD19):c.1653_*9delins23	Pathogenic
831810	NC_000016.10:g.(?28932001)(28963863_?)del	Pathogenic
987364	NM_001770.6(CD19):c.960del (p.Arg321fs)	Pathogenic
2107970	NM_001770.6(CD19):c.1199-3_1202del	Likely pathogenic
3689631	NM_001770.6(CD19):c.1429+2T>A	Likely pathogenic
421012	NM_001770.6(CD19):c.1372+1G>A	Likely pathogenic
811565	NM_001770.6(CD19):c.1198+2T>G	Likely pathogenic
827692	NM_001770.6(CD19):c.274G>T (p.Gly92Trp)	Likely pathogenic
827693	NM_001770.6(CD19):c.321G>A (p.Trp107Ter)	Likely pathogenic

SpliceAI

2085 predictions. Top by Δscore:

Variant	Effect	Δscore
16:28932419:G:GT	donor_gain	1.0000
16:28937130:G:GT	donor_gain	1.0000
16:28937133:G:GG	donor_gain	1.0000
16:28937155:G:T	donor_gain	1.0000
16:28937261:A:AG	acceptor_gain	1.0000
16:28937262:A:G	acceptor_gain	1.0000
16:28937266:CCCAG:C	acceptor_loss	1.0000
16:28937267:CCAGG:C	acceptor_loss	1.0000
16:28937268:CAGGC:C	acceptor_loss	1.0000
16:28937269:A:AG	acceptor_gain	1.0000
16:28937269:AGG:A	acceptor_loss	1.0000
16:28937270:G:A	acceptor_loss	1.0000
16:28937270:G:GA	acceptor_gain	1.0000
16:28937270:GGC:G	acceptor_gain	1.0000
16:28937373:AGGG:A	donor_loss	1.0000
16:28937374:GG:G	donor_gain	1.0000
16:28937375:GG:G	donor_gain	1.0000
16:28937375:GGTAA:G	donor_loss	1.0000
16:28937376:GTA:G	donor_loss	1.0000
16:28937377:T:A	donor_loss	1.0000
16:28937454:GAT:G	acceptor_gain	1.0000
16:28938765:G:GT	donor_gain	1.0000
16:28938859:T:TA	acceptor_gain	1.0000
16:28938860:G:A	acceptor_gain	1.0000
16:28938870:A:AG	acceptor_gain	1.0000
16:28938871:G:GG	acceptor_gain	1.0000
16:28932049:G:GT	donor_gain	0.9900
16:28932083:TGG:T	donor_gain	0.9900
16:28932084:GGAA:G	donor_gain	0.9900
16:28932085:GAAG:G	donor_gain	0.9900

AlphaMissense

3602 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:28933316:G:C	W214C	0.991
16:28933316:G:T	W214C	0.991
16:28933314:T:A	W214R	0.990
16:28933314:T:C	W214R	0.990
16:28932537:T:C	F94L	0.988
16:28932539:C:A	F94L	0.988
16:28932539:C:G	F94L	0.988
16:28932919:T:C	F122L	0.987
16:28932921:C:A	F122L	0.987
16:28932921:C:G	F122L	0.987
16:28932927:G:C	W124C	0.983
16:28932927:G:T	W124C	0.983
16:28932920:T:G	F122C	0.982
16:28936513:T:C	F333L	0.982
16:28936515:C:A	F333L	0.982
16:28936515:C:G	F333L	0.982
16:28932413:G:C	W52C	0.978
16:28932413:G:T	W52C	0.978
16:28932411:T:A	W52R	0.976
16:28932411:T:C	W52R	0.976
16:28932546:T:C	C97R	0.974
16:28932540:T:G	Y95D	0.973
16:28933455:T:A	C261S	0.973
16:28933456:G:C	C261S	0.973
16:28932920:T:C	F122S	0.972
16:28932595:T:A	V113D	0.971
16:28933032:G:C	W159C	0.971
16:28933032:G:T	W159C	0.971
16:28933450:A:G	Y259C	0.971
16:28932546:T:A	C97S	0.969

dbSNP variants (sampled 300 via entrez): RS1000862005 (16:28933793 A>T), RS1001307869 (16:28936197 A>T), RS1001844110 (16:28936030 C>G,T), RS1002314950 (16:28934359 T>A), RS1002428033 (16:28934824 T>C,G), RS1002776627 (16:28933934 A>C), RS1002979504 (16:28937766 C>G), RS1003725757 (16:28939392 G>A), RS1003734209 (16:28932684 A>C,G), RS1004231303 (16:28936969 G>A,C,T), RS1004317085 (16:28931723 T>C), RS1004355280 (16:28930338 G>T), RS1004431718 (16:28931452 T>C), RS1005647727 (16:28935137 G>A,T), RS1006241164 (16:28933591 C>G,T)

Disease associations

OMIM: gene MIM:107265 | disease phenotypes: MIM:613493, MIM:240500

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency, common variable, 3	Definitive	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
immunodeficiency, common variable, 3	Definitive	AR

Mondo (3): immunodeficiency, common variable, 3 (MONDO:0013283), immunodeficiency, common variable, 2 (MONDO:0009413), common variable immunodeficiency (MONDO:0015517)

Orphanet (1): OBSOLETE: Common variable immunodeficiency (Orphanet:1572)

HPO phenotypes

33 total (30 of 33 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:0002014	Diarrhea
HP:0002110	Bronchiectasis
HP:0002205	Recurrent respiratory infections
HP:0002240	Hepatomegaly
HP:0002664	Neoplasm
HP:0002665	Lymphoma
HP:0002716	Lymphadenopathy
HP:0002718	Recurrent bacterial infections
HP:0002720	Decreased circulating IgA concentration
HP:0002729	Follicular hyperplasia
HP:0002837	Recurrent bronchitis
HP:0002850	Decreased circulating total IgM
HP:0002960	Autoimmunity
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0004315	Decreased circulating IgG concentration
HP:0005387	Combined immunodeficiency
HP:0006532	Recurrent pneumonia
HP:0010975	Abnormal B cell count
HP:0011108	Recurrent sinusitis
HP:0011463	Childhood onset
HP:0011839	Abnormal total T cell count
HP:0011840	Abnormal T cell physiology
HP:0030388	Decreased class-switched memory B cell proportion

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000879_2	Crohn’s disease	2.000000e-11
GCST004131_83	Inflammatory bowel disease	2.000000e-12
GCST004132_69	Crohn’s disease	3.000000e-10
GCST005316_520	Intelligence (MTAG)	3.000000e-10
GCST007293_116	Body fat distribution (arm fat ratio)	2.000000e-08
GCST007293_16	Body fat distribution (arm fat ratio)	4.000000e-09
GCST007293_43	Body fat distribution (arm fat ratio)	2.000000e-12
GCST007294_71	Body fat distribution (trunk fat ratio)	2.000000e-12
GCST007294_97	Body fat distribution (trunk fat ratio)	1.000000e-11
GCST007295_20	Body fat distribution (leg fat ratio)	3.000000e-06
GCST007295_44	Body fat distribution (leg fat ratio)	1.000000e-21
GCST007295_79	Body fat distribution (leg fat ratio)	2.000000e-24
GCST008129_84	Body mass index	1.000000e-35
GCST009325_21	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	8.000000e-10
GCST010703_152	Brain morphology (MOSTest)	3.000000e-09
GCST90020029_564	Waist circumference adjusted for body mass index	2.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004341	body fat distribution
EFO:0004340	body mass index
EFO:0004346	neuroimaging measurement
EFO:0007789	BMI-adjusted waist circumference

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 (1): CHEMBL3390821 (SINGLE PROTEIN)

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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
inebilizumab	Binding	10.3	pKd
blinatumomab	Binding	9.0	pKd

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
entinostat	increases expression, affects cotreatment	2
Catechin	affects cotreatment, increases expression	2
Diethylhexyl Phthalate	decreases expression	2
Methotrexate	decreases expression, affects cotreatment	2
Valproic Acid	affects expression, increases methylation	2
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
2-palmitoylglycerol	increases expression	1
ethinyl estradiol-desogestrel combination	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Fingolimod Hydrochloride	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Gold	increases expression	1
Hydroxychloroquine	affects cotreatment, decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Methyl Methanesulfonate	decreases expression	1
Sulfasalazine	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1

Cellosaurus cell lines

22 cell lines: 17 cancer cell line, 2 telomerase immortalized cell line, 2 spontaneously immortalized cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A5RU	CD#68T-13 iPSC	Induced pluripotent stem cell	Male
CVCL_B8CV	Abcam HCT 116 CD19 KO	Cancer cell line	Male
CVCL_B8TK	Abcam MCF-7 CD19 KO	Cancer cell line	Female
CVCL_B9F3	Abcam A-549 CD19 KO	Cancer cell line	Male
CVCL_C6VW	MSOD	Telomerase immortalized cell line	Female
CVCL_C6VX	MSOD-B	Telomerase immortalized cell line	Female
CVCL_D2TG	CHO/CD19	Spontaneously immortalized cell line	Female
CVCL_D2TH	LN229/CD19	Cancer cell line	Female
CVCL_D2TI	LN229/CD19ec	Cancer cell line	Female
CVCL_D5K5	Nalm6-Fluc-Puro/CD19-KO	Cancer cell line	Male

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)