MS4A1

Summary

MS4A1 (membrane spanning 4-domains A1, HGNC:7315) is a protein-coding gene on chromosome 11q12.2, encoding B-lymphocyte antigen CD20 (P11836). B-lymphocyte-specific membrane protein that plays a role in the regulation of cellular calcium influx necessary for the development, differentiation, and activation of B-lymphocytes. In precision oncology, MS4A1 Mutation is associated with resistance to R-CHOP Regimen in Diffuse Large B-cell Lymphoma (CIViC Level B).

This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns among hematopoietic cells and nonlymphoid tissues. This gene encodes a B-lymphocyte surface molecule which plays a role in the development and differentiation of B-cells into plasma cells. This family member is localized to 11q12, among a cluster of family members. Alternative splicing of this gene results in two transcript variants which encode the same protein.

Source: NCBI Gene 931 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency, common variable, 5 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 225 total
• Phenotypes (HPO): 9
• Druggable target: yes
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_152866

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7315
Approved symbol	MS4A1
Name	membrane spanning 4-domains A1
Location	11q12.2
Locus type	gene with protein product
Status	Approved
Aliases	B1, Bp35, FMC7
Ensembl gene	ENSG00000156738
Ensembl biotype	protein_coding
OMIM	112210
Entrez	931

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 11 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000345732, ENST00000389939, ENST00000527101, ENST00000528313, ENST00000530482, ENST00000532073, ENST00000532418, ENST00000532491, ENST00000533306, ENST00000534503, ENST00000534668, ENST00000674194, ENST00000904593, ENST00000904594, ENST00000966396

RefSeq mRNA: 3 — MANE Select: NM_152866 NM_021950, NM_152866, NM_152867

CCDS: CCDS31570

Canonical transcript exons

ENST00000345732 — 8 exons

Exon	Start	End
ENSE00001107910	60465921	60466157
ENSE00001107918	60468250	60470752
ENSE00001507320	60464288	60464344
ENSE00002151083	60461072	60461160
ENSE00002167805	60455847	60455945
ENSE00002182645	60462185	60462533
ENSE00003537343	60466959	60467060
ENSE00003625964	60463002	60463121

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 98.77.

FANTOM5 (CAGE): breadth broad, TPM avg 28.6553 / max 3822.1619, expressed in 185 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114474	26.2205	178
114473	1.6730	68
206297	0.6710	49
114476	0.0367	19
114475	0.0304	22
114472	0.0237	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelium of nasopharynx	UBERON:0001951	98.77	gold quality
spleen	UBERON:0002106	98.73	gold quality
lymph node	UBERON:0000029	98.29	gold quality
ileal mucosa	UBERON:0000331	97.83	gold quality
vermiform appendix	UBERON:0001154	97.37	gold quality
granulocyte	CL:0000094	95.86	gold quality
caecum	UBERON:0001153	95.02	gold quality
blood	UBERON:0000178	92.45	gold quality
tonsil	UBERON:0002372	89.69	gold quality
bone marrow	UBERON:0002371	89.35	gold quality
superficial temporal artery	UBERON:0001614	88.80	gold quality
trabecular bone tissue	UBERON:0002483	88.07	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.48	gold quality
bone marrow cell	CL:0002092	86.46	gold quality
small intestine Peyer’s patch	UBERON:0003454	84.40	gold quality
rectum	UBERON:0001052	84.03	gold quality
gall bladder	UBERON:0002110	81.37	gold quality
thymus	UBERON:0002370	79.55	gold quality
mucosa of sigmoid colon	UBERON:0004993	79.26	gold quality
small intestine	UBERON:0002108	79.10	gold quality
buccal mucosa cell	CL:0002336	78.79	gold quality
leukocyte	CL:0000738	78.45	gold quality
colonic mucosa	UBERON:0000317	78.32	gold quality
mucosa of transverse colon	UBERON:0004991	78.21	gold quality
colonic epithelium	UBERON:0000397	78.05	gold quality
parietal pleura	UBERON:0002400	77.50	gold quality
mononuclear cell	CL:0000842	76.73	gold quality
monocyte	CL:0000576	76.19	gold quality
cardia of stomach	UBERON:0001162	75.11	gold quality

Single-cell (SCXA)

Detected in 39 experiment(s), a significant marker in 37.

Experiment	Marker?	Max mean expression
E-GEOD-75688	yes	3595.07
E-GEOD-150728	yes	3265.35
E-CURD-77	yes	2962.19
E-MTAB-9801	yes	2600.17
E-GEOD-139324	yes	2532.17
E-GEOD-110499	yes	2292.12
E-CURD-112	yes	2003.07
E-CURD-55	yes	1975.29
E-CURD-122	yes	1776.35
E-MTAB-8911	yes	1672.74
E-MTAB-8207	yes	1617.43
E-MTAB-8410	yes	1435.75
E-HCAD-1	yes	1307.97
E-GEOD-149689	yes	1304.95
E-HCAD-32	yes	1253.70

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BCL6, IRF4, SP1, SPI1

miRNA regulators (miRDB)

121 targeting MS4A1, 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-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-153-5P	99.89	73.86	6317

Literature-anchored findings (GeneRIF, showing 40)

• review of structure, function, tissue and cell distribution (PMID:12144126)
• CD20 functionally associates with the B cell receptor (BCR) on the surface of stimulated B lymphocytes, then rapidly dissociates before BCR internalization. (PMID:12218101)
• Differences in complement recruitment correlated with the redistribution of CD20 in the cell membrane following mAb ligation (PMID:12393541)
• presence of this antigen, but not CD3 antigen in T-cell prolymphocytic leukemia (PMID:12447967)
• FMC7 antigen is identified as a CD20 epitope; sensitivity to cholesterol reveals conformational state of CD20 that is regulated by cholesterol (PMID:12835728)
• raft-associated CD20 constitutes a component of a SOC entry pathway activated by the B cell receptor (PMID:12920111)
• CD20 calcium channel is localized to microvilli and constitutively associated with membrane rafts (PMID:14976189)
• a marker of follicular B-cell non-Hodgkin’s lymphoma (PMID:15480506)
• Estimating the expression of CD20+ lymphocytes in the antrum mucosa in children, infected with Helicobacter pylori and after bacterial eradication. (PMID:15638430)
• Neither upregulation of CD20 antigen nor a change of the proportion of CD20 positive cells was observed after a dose of 5 microg/kg GM-CSFin B cell chronic leukemia. (PMID:15927668)
• CD20 may have a role in steroid-resistant renal allograft rejection and reduced graft survival (PMID:16095505)
• expression in bacterial cells; isolation and biophysical and structural studies (PMID:16285718)
• PegIFN does not appear to upregulate CD20 expression in peripheral lymph node tumor cells (PMID:16923555)
• analysis of CD5-positive diffuse large B-cell lymphoma with the unusual phenotype of cytoplasmic CD20 (+), surface CD20 (-) [case report] (PMID:16923582)
• CD20, a trans-membrane B-cell-specific antigen, is a potential target for treatment of certain malignant and nonmalignant plasma cell disorders including refractory idiopathic thrombocytopenic purpura. (PMID:17000895)
• Rituximab may be effective in patients with multiple myeloma expressing this antigen. (PMID:17268523)
• human tonsil contains long-lived plasma cells, the majority of which express CD20 (PMID:17299094)
• binding of Gb(3)/CD77 by its cognate ligand transmits information within the lipid bilayer of model lymphoma cells to impact the behaviour of selective proteins, most notably CD20, via a mechanism influenced by the level of cholesterol within the membrane (PMID:17336267)
• Possibly detected in B lymphocytes in renal allograft biopsy specimens and might be useful as a prognostic marker. (PMID:17362749)
• Monitoring of serum HCV RNA levels and transaminases may be helpful to understand the cause of liver dysfunction in patients receiving chemotherapy (PMID:17712791)
• CD20-targeted and convertase-armed measles virus can synergize with fludarabine (PMID:18006839)
• current study showed that the level of CD20 was differentially expressed among fluorescent in-situ hybridization subtypes of chronic lymphocytic leukaemia (CLL); patients with trisomy 12 CLL showed strong leukemic cell CD20 expression (PMID:18324964)
• Chimeric 2H7 (C2H7) can mediate complement dependent cytotoxicity and antibody-dependent cellular cytotoxicity effects on CD20 positive human Burkitt lymphoma cells. (PMID:18346788)
• CD20 induces cytosolic calcium flux through its ability to associate with and “hijack” the signaling potential of the BCR (PMID:18426802)
• Statistically significant difference in disease free survival has been found between groups with and without CD20 expression in patients with Hodgkins lymphoma (PMID:18652276)
• The expression of CD20 is not an independent prognostic factor for failure-free survival and overall survival of naive classical Hodgkin’s Lymphoma patients. (PMID:19000453)
• urinary levels of CD20 detected by RT-PCR had a high sensitivity for CD20+ staining in the corresponding renal tissue, but with a low specificity. Patients with clusters of CD20+ cells >50/HPF had higher serum creatinine after 2 years of follow up. (PMID:19111631)
• CD20 expression is frequent in classical Hodgkin’s Lymphoma and our results are in consensus with reported literature on this subject. (PMID:19136769)
• Results identify a subpopulation of CD133(+) cells expressing the B-cell marker CD20, which display myogenic properties. (PMID:19153665)
• the initial interpretation of a malignant effusion should not have had to be reconsidered only due to the CD20 negativity. (PMID:19207312)
• Data dhow that CD20 mutations involving the rituximab epitope were detected in only 1/264 (0.4%) and 1/15 (6%) of the biopsies taken at diagnosis and relapse, respectively. (PMID:19211644)
• Some epigenetic mechanisms may be partly related to the down-regulation of CD20 expression after rituximab treatment. (PMID:19246561)
• CD20 mutations were found in 11 of 50 patients in non-Hodgkin’s lymphoma. (PMID:19276251)
• Report dual functional molecular imaging probe targeting CD20 with PET and optical imaging. (PMID:19513512)
• Report combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate. (PMID:19513562)
• Host immune responses to EOC vary widely according to histological subtype and the extent of residual disease. TIA-1, FoxP3 and CD20 emerge as new positive prognostic factors in high-grade serous EOC from optimally debulked patients (PMID:19641607)
• CD20 deficiency in humans results in impaired T cell-independent antibody responses. (PMID:20038800)
• CD20 immunoexpresion in early rheumatoid arthritis synovium. (PMID:20191119)
• The structure of CD20, its membrane distribution, internalization, and role in calcium signaling in B cells are described. Its functions make it a target for monoclonal antibody therapy. Review. (PMID:20350657)
• type I CD20 antibody cytotoxicity critically depends on Fc receptor ITAM signaling (PMID:20354182)

Cross-species orthologs

25 orthologs

Organism	Symbol	Gene ID
danio_rerio	ms4a17a.6	ENSDARG00000007018
danio_rerio	ms4a17a.4	ENSDARG00000014024
danio_rerio	si:dkey-77f5.10	ENSDARG00000020548
danio_rerio	ms4a17c.2	ENSDARG00000028659
danio_rerio	ms4a17a.7	ENSDARG00000043796
danio_rerio	ms4a17a.1	ENSDARG00000043798
danio_rerio	ms4a17a.8	ENSDARG00000043802
danio_rerio	ms4a17a.12	ENSDARG00000053563
danio_rerio	ms4a17a.16	ENSDARG00000054898
danio_rerio	si:dkey-7j14.6	ENSDARG00000090552
danio_rerio	ms4a17a.3	ENSDARG00000091970
danio_rerio	ms4a17a.5	ENSDARG00000092204
danio_rerio	si:dkey-174k12.3	ENSDARG00000092593
danio_rerio	si:dkey-238j22.1	ENSDARG00000093512
danio_rerio	si:ch73-56d11.5	ENSDARG00000093546
danio_rerio	ms4a17c.1	ENSDARG00000094643
danio_rerio	ms4a17a.11	ENSDARG00000094809
danio_rerio	ms4a17a.9	ENSDARG00000094854
danio_rerio	ms4a17a.10	ENSDARG00000095695
danio_rerio	si:ch73-56d11.3	ENSDARG00000097527
danio_rerio	tmem176l.3a	ENSDARG00000098387
danio_rerio	ms4a17a.2	ENSDARG00000105674
danio_rerio	ms4a17a.17	ENSDARG00000116378
mus_musculus	Ms4a1	ENSMUSG00000024673
rattus_norvegicus	Ms4a1	ENSRNOG00000020945

Paralogs (16): MS4A12 (ENSG00000071203), MS4A6A (ENSG00000110077), MS4A4A (ENSG00000110079), MS4A3 (ENSG00000149516), MS4A2 (ENSG00000149534), MS4A6E (ENSG00000166926), MS4A7 (ENSG00000166927), MS4A14 (ENSG00000166928), MS4A5 (ENSG00000166930), MS4A8 (ENSG00000166959), MS4A15 (ENSG00000166961), MS4A10 (ENSG00000172689), TMEM212 (ENSG00000186329), MS4A13 (ENSG00000204979), MS4A18 (ENSG00000214782), MS4A4E (ENSG00000214787)

Protein

Protein identifiers

B-lymphocyte antigen CD20 — P11836 (reviewed: P11836)

Alternative names: B-lymphocyte surface antigen B1, Bp35, Leukocyte surface antigen Leu-16, Membrane-spanning 4-domains subfamily A member 1

All UniProt accessions (3): P11836, E9PKH8, E9PPL6

UniProt curated annotations — full annotation on UniProt →

Function. B-lymphocyte-specific membrane protein that plays a role in the regulation of cellular calcium influx necessary for the development, differentiation, and activation of B-lymphocytes. Functions as a store-operated calcium (SOC) channel component promoting calcium influx after activation by the B-cell receptor/BCR.

Subunit / interactions. Forms homotetramers. Interacts with the heavy and light chains of cell surface IgM, the antigen-binding components of the BCR.

Subcellular location. Cell membrane.

Tissue specificity. Expressed on B-cells.

Post-translational modifications. Phosphorylated on serines and threonines in resting B-cells. Protein kinase C/PKC can use CD20 as substrate.

Disease relevance. Immunodeficiency, common variable, 5 (CVID5) [MIM:613495] 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.

Similarity. Belongs to the MS4A family.

Isoforms (2)

UniProt ID	Names	Canonical?
P11836-1	1	yes
P11836-2	2

RefSeq proteins (3): NP_068769, NP_690605, NP_690606 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007237	CD20-like_TM	Domain
IPR030417	MS4A	Family

Pfam: PF04103

UniProt features (40 total): helix 8, topological domain 5, mutagenesis site 5, region of interest 4, transmembrane region 4, modified residue 3, compositionally biased region 2, lipid moiety-binding region 2, sequence conflict 2, chain 1, disulfide bond 1, splice variant 1, strand 1, turn 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
3PP4	X-RAY DIFFRACTION	1.6
8VGN	ELECTRON MICROSCOPY	2.5
2OSL	X-RAY DIFFRACTION	2.6
8VGO	ELECTRON MICROSCOPY	2.6
3BKY	X-RAY DIFFRACTION	2.61
6VJA	ELECTRON MICROSCOPY	3.3
6Y90	ELECTRON MICROSCOPY	3.69
6Y9A	ELECTRON MICROSCOPY	4.2
6Y97	ELECTRON MICROSCOPY	4.33
6Y92	ELECTRON MICROSCOPY	4.73

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P11836-F1	70.34	0.26

Antibody-complex structures (SAbDab): 10 — 2OSL, 3BKY, 3PP4, 6VJA, 6Y90, 6Y92, 6Y97, 6Y9A, 8VGN, 8VGO

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 (5): 36, 225, 239, 111, 220

Disulfide bonds (1): 167–183

Mutagenesis-validated functional residues (5):

Position	Phenotype
159	abrogates recognition by some antibodies; when associated with d-163 and d-166. slight decrease of rituximab binding; wh
163	decreased binding of some antibodies. no effect on rituximab binding.
166	decreased binding of some antibodies. no effect on rituximab binding.
170	abrogates recognition by therapeutic antibodies, including rituximab; when associated with s-172.
172	marked reduction in rituximab binding. abrogates recognition by antibodies, including rituximab; when associated with s-

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 332 (showing top): GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, WALLACE_PROSTATE_CANCER_RACE_UP, MCLACHLAN_DENTAL_CARIES_UP, GOBP_B_CELL_ACTIVATION, NKX25_02, MODULE_64, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, GOBP_B_CELL_PROLIFERATION, MORI_IMMATURE_B_LYMPHOCYTE_UP, CHX10_01, GGGTGGRR_PAX4_03, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOLDRATH_ANTIGEN_RESPONSE

GO Biological Process (11): store-operated calcium entry (GO:0002115), humoral immune response (GO:0006959), cell surface receptor signaling pathway (GO:0007166), response to bacterium (GO:0009617), B cell differentiation (GO:0030183), B cell proliferation (GO:0042100), B cell activation (GO:0042113), B cell receptor signaling pathway (GO:0050853), protein tetramerization (GO:0051262), calcium ion import into cytosol (GO:1902656), positive regulation of calcium ion import across plasma membrane (GO:1905665)

GO Molecular Function (5): epidermal growth factor receptor binding (GO:0005154), immunoglobulin binding (GO:0019865), MHC class II protein complex binding (GO:0023026), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (8): obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), plasma membrane raft (GO:0044853), extracellular exosome (GO:0070062), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
calcium ion transport	2
B cell activation	2
plasma membrane	2
immune response	1
signal transduction	1
response to other organism	1
lymphocyte differentiation	1
lymphocyte proliferation	1
lymphocyte activation	1
antigen receptor-mediated signaling pathway	1
protein complex oligomerization	1
positive regulation of calcium ion import	1
calcium ion import across plasma membrane	1
positive regulation of calcium ion transmembrane transport	1
regulation of calcium ion import across plasma membrane	1
growth factor receptor binding	1
protein-containing complex binding	1
MHC protein complex binding	1
protein binding	1
binding	1
nuclear lumen	1
membrane	1
cell periphery	1
cell surface	1
side of membrane	1
membrane raft	1
plasma membrane region	1
extracellular vesicle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

111 interactions, top by confidence:

A	B	Type	Score
YWHAQ	WDR62	psi-mi:“MI:0914”(association)	0.830
MS4A1	KASH5	psi-mi:“MI:0915”(physical association)	0.560
KASH5	MS4A1	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	AQP6	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	SLC10A6	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	REEP4	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	GPR42	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	TMEM72	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	FCRL3	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	TMX2	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	SLC10A1	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	REEP2	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	HSD17B11	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	MTIF3	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	ACKR2	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	MFSD14B	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
	MS4A1	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	RNF5	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (55): CCDC155 (Two-hybrid), MS4A1 (Protein-peptide), MS4A1 (Two-hybrid), MS4A1 (Synthetic Lethality), MS4A1 (Two-hybrid), MS4A1 (Affinity Capture-MS), MS4A1 (Two-hybrid), MS4A1 (Two-hybrid), MS4A1 (Two-hybrid), MS4A1 (Two-hybrid), MS4A1 (Two-hybrid), MS4A1 (Two-hybrid), MS4A1 (Two-hybrid), MS4A1 (Two-hybrid), MS4A1 (Two-hybrid)

ESM2 similar proteins: A4IIU3, A6NML5, D3YWQ9, O75204, P0DP42, P11836, P20490, P56749, Q01362, Q0IIL2, Q2KJ11, Q2YDM3, Q32KQ5, Q3T110, Q3YBM2, Q497B3, Q4G068, Q504G0, Q5EB63, Q5FWC3, Q5HYL7, Q5M962, Q5R8D6, Q5R9K1, Q5RCD5, Q5RFC1, Q6GV28, Q7T392, Q7TQI0, Q7YQI4, Q8BGP5, Q8BHH8, Q8C6V3, Q8K177, Q8NCR9, Q8VHW1, Q8WXS4, Q920C4, Q925D4, Q940P5

Diamond homologs: A6QPF4, P11836, P13386, P19437, P20490, Q01362, Q3C1V0, Q3C2E2, Q3UPL6, Q8N5U1, Q920C4, Q96JA4, Q96JQ5, Q99N05, Q99N07, Q99N09, Q99N10, Q9BY19, Q9H2W1, Q9H3V2, Q9NXJ0, Q99N08, Q9GZW8, Q99N03, Q5REZ6, Q96PG2, Q96HJ5, Q96PG1, Q2YDM3

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
CSNK2A1	unknown	MS4A1	phosphorylation
CSNK2A2	unknown	MS4A1	phosphorylation
“ibritumomab tiuxetan”	“down-regulates activity”	MS4A1	binding
obinutuzumab	“down-regulates activity”	MS4A1	binding
ofatumumab	“down-regulates activity”	MS4A1	binding
rituximab	“down-regulates activity”	MS4A1	binding
“tositumomab and iodine i 131 tositumomab”	“down-regulates activity”	MS4A1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 45 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	6	198.6×	1e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	175.2×	2e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	175.2×	2e-11
Activation of BH3-only proteins	6	129.5×	1e-10
RHO GTPases activate PKNs	6	82.8×	2e-09
Intrinsic Pathway for Apoptosis	6	76.4×	2e-09
SARS-CoV-1-host interactions	6	45.8×	5e-08
Apoptosis	6	43.8×	6e-08

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	49.5×	1e-05
intracellular protein localization	6	17.0×	2e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	153
Likely benign	59
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

778 predictions. Top by Δscore:

Variant	Effect	Δscore
11:60455942:TCAGG:T	donor_loss	1.0000
11:60455944:AGGT:A	donor_loss	1.0000
11:60455945:GGTA:G	donor_loss	1.0000
11:60455946:G:C	donor_loss	1.0000
11:60462532:GG:G	donor_gain	1.0000
11:60462533:GG:G	donor_gain	1.0000
11:60463001:GGCT:G	acceptor_gain	1.0000
11:60463119:ATGG:A	donor_loss	1.0000
11:60463120:TGG:T	donor_loss	1.0000
11:60463121:GGT:G	donor_loss	1.0000
11:60463122:GTGA:G	donor_loss	1.0000
11:60463123:T:A	donor_loss	1.0000
11:60463124:G:GG	donor_loss	1.0000
11:60463125:AG:A	donor_loss	1.0000
11:60464286:A:AG	acceptor_gain	1.0000
11:60464287:G:GG	acceptor_gain	1.0000
11:60464335:G:GT	donor_gain	1.0000
11:60464349:G:GG	donor_gain	1.0000
11:60467056:AATCT:A	donor_gain	1.0000
11:60467057:ATCT:A	donor_gain	1.0000
11:60467058:TCT:T	donor_gain	1.0000
11:60467059:CT:C	donor_gain	1.0000
11:60467061:G:C	donor_loss	1.0000
11:60467061:G:GG	donor_gain	1.0000
11:60467062:T:A	donor_loss	1.0000
11:60468242:T:A	acceptor_gain	1.0000
11:60468245:TTTA:T	acceptor_loss	1.0000
11:60468247:TAG:T	acceptor_loss	1.0000
11:60468248:A:AG	acceptor_gain	1.0000
11:60468248:A:AT	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000042904 (11:60467412 G>A), RS1000329142 (11:60461115 C>T), RS1000446602 (11:60460783 C>T), RS1000596835 (11:60455250 T>A), RS1000836010 (11:60467868 C>T), RS1001292394 (11:60466235 C>A,T), RS1001356082 (11:60466344 CTATT>C), RS1001524622 (11:60459588 T>A), RS1001619956 (11:60466940 T>A), RS1001666702 (11:60460424 G>A), RS1001672169 (11:60467265 T>C), RS1002089138 (11:60454400 C>T), RS1002148882 (11:60454585 G>A,C), RS1002550084 (11:60459446 C>T), RS1002666729 (11:60465676 C>G)

Disease associations

OMIM: gene MIM:112210 | disease phenotypes: MIM:613495

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency, common variable, 5	Moderate	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, 5	Limited	AR

Mondo (2): immunodeficiency, common variable, 5 (MONDO:0013285), common variable immunodeficiency (MONDO:0015517)

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

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0002205	Recurrent respiratory infections
HP:0002718	Recurrent bacterial infections
HP:0003493	Antinuclear antibody positivity
HP:0005387	Combined immunodeficiency
HP:0010975	Abnormal B cell count
HP:0011463	Childhood onset
HP:0011839	Abnormal total T cell count
HP:0032134	Chronic decreased circulating total IgG

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005230_22	Recurrent major depressive disorder	6.000000e-06

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): CHEMBL2058 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
MS4A1 Mutation	R-CHOP Regimen	Diffuse Large B-cell Lymphoma	Resistance	CIViC B	EID10367

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 (6 total), top 6:

Ligand	Action	Affinity	Parameter
ofatumumab	Binding	9.92	pKd
ocrelizumab	Binding	9.08	pKd
rituximab	Binding	8.51	pKd
veltuzumab	Binding	8.44	pKd
glofitamab	Binding	8.32	pEC50
BsAb (CD89-CD20)	Binding	8.03	pKd

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Curcumin	decreases expression, increases expression	2
Nickel	increases expression	2
triphenyl phosphate	affects expression	1
sodium arsenite	affects expression	1
butylbenzyl phthalate	decreases expression	1
Capecitabine	decreases expression	1
Norethindrone Acetate	affects cotreatment, decreases expression	1
Asbestos	affects response to substance	1
Vehicle Emissions	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Diuron	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Formaldehyde	decreases expression	1
Hydroxychloroquine	affects cotreatment, decreases expression	1
Methotrexate	decreases expression, affects cotreatment	1
Methyl Methanesulfonate	decreases expression	1
Sulfasalazine	decreases expression, affects cotreatment	1
Zinc	decreases expression	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	decreases expression	1

Cellosaurus cell lines

9 cell lines: 6 cancer cell line, 3 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8V4	CHO/CD20	Spontaneously immortalized cell line	Female
CVCL_A8V5	LN229/CD20	Cancer cell line	Female
CVCL_A8V6	BALL-1/CD20-KO	Cancer cell line	Male
CVCL_B7YC	Abcam Raji MS4A1 KO	Cancer cell line	Male
CVCL_C6XH	MG87/CD20	Spontaneously immortalized cell line	Male
CVCL_C6XI	NS0-hCD20	Cancer cell line	Female
CVCL_E6BL	EL4-hCD20-LZ	Cancer cell line	Sex unspecified
CVCL_E6P8	Genomeditech CHO-K1 H_CD20	Spontaneously immortalized cell line	Female
CVCL_VD92	BJAB GFP-CD20	Cancer 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)