BLNK

Summary

BLNK (B cell linker, HGNC:14211) is a protein-coding gene on chromosome 10q24.1, encoding B-cell linker protein (Q8WV28). Functions as a central linker protein, downstream of the B-cell receptor (BCR), bridging the SYK kinase to a multitude of signaling pathways and regulating biological outcomes of B-cell function and development.

This gene encodes a cytoplasmic linker or adaptor protein that plays a critical role in B cell development. This protein bridges B cell receptor-associated kinase activation with downstream signaling pathways, thereby affecting various biological functions. The phosphorylation of five tyrosine residues is necessary for this protein to nucleate distinct signaling effectors following B cell receptor activation. Mutations in this gene cause hypoglobulinemia and absent B cells, a disease in which the pro- to pre-B-cell transition is developmentally blocked. Deficiency in this protein has also been shown in some cases of pre-B acute lymphoblastic leukemia. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 29760 — RefSeq curated summary.

At a glance

• Gene–disease (curated): agammaglobulinemia 4, autosomal recessive (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 405 total — 9 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 40
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_013314

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14211
Approved symbol	BLNK
Name	B cell linker
Location	10q24.1
Locus type	gene with protein product
Status	Approved
Aliases	SLP65, Ly57, SLP-65, BLNK-s, BASH, bca
Ensembl gene	ENSG00000095585
Ensembl biotype	protein_coding
OMIM	604515
Entrez	29760

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 12 protein_coding, 11 nonsense_mediated_decay, 5 retained_intron

ENST00000224337, ENST00000371176, ENST00000413476, ENST00000427367, ENST00000467799, ENST00000468252, ENST00000472763, ENST00000485193, ENST00000495266, ENST00000696248, ENST00000696253, ENST00000696255, ENST00000696257, ENST00000696513, ENST00000696514, ENST00000696515, ENST00000696516, ENST00000696517, ENST00000696518, ENST00000696519, ENST00000696521, ENST00000696522, ENST00000696523, ENST00000696524, ENST00000696525, ENST00000896451, ENST00000896452, ENST00000896453

RefSeq mRNA: 5 — MANE Select: NM_013314 NM_001114094, NM_001258440, NM_001258441, NM_001258442, NM_013314

CCDS: CCDS44464, CCDS58091, CCDS73171, CCDS7446, CCDS91311

Canonical transcript exons

ENST00000224337 — 17 exons

Exon	Start	End
ENSE00000000178	96271352	96271569
ENSE00000000179	96189171	96192092
ENSE00002430102	96196908	96197063
ENSE00002510484	96200075	96200158
ENSE00002532353	96227410	96227566
ENSE00002839777	96246984	96247049
ENSE00002910075	96242735	96242784
ENSE00002975285	96230794	96230834
ENSE00003463764	96209838	96209907
ENSE00003508261	96215321	96215389
ENSE00003521610	96207872	96207899
ENSE00003529264	96204057	96204088
ENSE00003546418	96223826	96223989
ENSE00003581577	96207011	96207053
ENSE00003628225	96200982	96201058
ENSE00003679654	96216653	96216734
ENSE00003687145	96204532	96204616

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 97.01.

FANTOM5 (CAGE): breadth broad, TPM avg 8.8011 / max 1459.0018, expressed in 601 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110843	4.3200	516
110844	3.9283	522
110842	0.3793	144
110841	0.0882	44
110845	0.0805	35
110846	0.0049	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tongue squamous epithelium	UBERON:0006919	97.01	gold quality
oral cavity	UBERON:0000167	96.04	gold quality
corpus epididymis	UBERON:0004359	95.77	gold quality
spleen	UBERON:0002106	95.74	gold quality
jejunal mucosa	UBERON:0000399	95.60	gold quality
esophagus squamous epithelium	UBERON:0006920	95.44	gold quality
lower esophagus mucosa	UBERON:0035834	95.03	gold quality
epithelium of esophagus	UBERON:0001976	94.86	gold quality
duodenum	UBERON:0002114	94.24	gold quality
epithelium of nasopharynx	UBERON:0001951	94.10	gold quality
nasopharynx	UBERON:0001728	94.08	gold quality
squamous epithelium	UBERON:0006914	94.07	gold quality
esophagus mucosa	UBERON:0002469	93.43	gold quality
vermiform appendix	UBERON:0001154	92.95	gold quality
pharyngeal mucosa	UBERON:0000355	92.83	gold quality
cervix squamous epithelium	UBERON:0006922	92.79	gold quality
lymph node	UBERON:0000029	92.42	gold quality
right lobe of liver	UBERON:0001114	92.24	gold quality
gingiva	UBERON:0001828	91.90	gold quality
ileal mucosa	UBERON:0000331	91.20	gold quality
cervix epithelium	UBERON:0004801	91.15	gold quality
tonsil	UBERON:0002372	90.72	gold quality
pancreatic ductal cell	CL:0002079	90.56	gold quality
gingival epithelium	UBERON:0001949	90.56	gold quality
rectum	UBERON:0001052	90.36	gold quality
liver	UBERON:0002107	90.25	gold quality
cauda epididymis	UBERON:0004360	89.87	gold quality
mucosa of sigmoid colon	UBERON:0004993	89.75	gold quality
metanephros cortex	UBERON:0010533	89.75	gold quality
caecum	UBERON:0001153	89.60	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-CURD-6	yes	961.98
E-GEOD-76312	yes	487.15
E-CURD-122	yes	92.26
E-CURD-112	yes	45.46
E-ANND-3	yes	22.36
E-HCAD-10	yes	20.08
E-MTAB-9067	yes	18.01
E-MTAB-6701	yes	14.93
E-MTAB-8498	yes	13.48
E-MTAB-9801	yes	7.42
E-MTAB-6678	yes	6.50
E-CURD-88	yes	3.89

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
LAPTM5	Activation

Upstream regulators (CollecTRI, top): PAX5, SPI1, SPIB

miRNA regulators (miRDB)

26 targeting BLNK, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-12132	99.47	68.90	1341
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-488-5P	99.28	68.12	821
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-11399	98.71	65.69	869
HSA-MIR-1243	97.07	65.44	719
HSA-MIR-365A-5P	94.91	63.72	471
HSA-MIR-365B-5P	94.91	63.79	470
HSA-MIR-5681B	94.82	69.30	514

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• 16 of the 34 childhood pre-B acute lymphoblastic leukaemia samples that were tested showed a complete loss or drastic reduction of SLP-65 expression (PMID:12761551)
• Identifies BLNK as a potential target for the protein-tyrosine phosphatase SHP-1. (PMID:15588985)
• The BLNK protein is present in the majority of mediastinal B cell lymphomas. (PMID:15744341)
• In B cells SLP-65 exists in a 180 kDa complex as well as in monomeric form. (PMID:16356554)
• V(H) gene rearrangement represents a frequent feature in B-lymphoid malignancy, which can be attributed to SLP65 deficiency in many cases. (PMID:16636677)
• Syk is required to link phosphorylated SLP-65 to Ca(2+) mobilization. (PMID:17681949)
• Plasmacytoid dendritic cells express a signalosome consisting of Lyn, Syk, Btk, Slp65 (Blnk) and PLCgamma2. Triggering CD303 leads to tyrosine phosphorylation of Syk, Slp65, PLCgamma2 & cytoskeletal proteins. (PMID:18022864)
• BLNK prevents aneuploidy by inhibiting cytokinesis. (PMID:19018766)
• BLNK recruits active H-Ras to the BCR complex, which is essential for sustained surface expression of BCR in the form of the cap and for the signal leading to functional ERK activation (PMID:19218240)
• Data show that SLP-65 phosphorylation acts upstream for signal initiation and also downstream during selective processing of the B cell receptor signal. (PMID:19372136)
• Live cell imaging and co-immunoprecipitation experiments confirmed that both SLP65 and CIN85 are both required for the onset and progression phases of B-cell antigen receptor signal transduction. (PMID:21822214)
• up-regulation of BLNK is associated with RUNX1 mutations in cytogenetically normal acute myeloid leukemia. (PMID:22689681)
• early Ca(2+) fluxing provides feed-forward signal amplification by promoting anchoring of the PLCgamma2 C2 domain to phospho-SLP65. (PMID:24166973)
• vesicular signaling scaffolds are required for B cell activation indicates that vesicles may deliver preassembled signaling cargo to sites of BCR activation. (PMID:25140054)
• Prognostic value of B-cell linker protein in colorectal cancer. (PMID:31980295)
• Further delineation of primary B cell immunodeficiency caused by novel variants of the BLNK gene in two Chinese patients. (PMID:32194234)
• Involvement of Blnk and Foxo1 in tumor suppression in BCRABL1transformed proB cells. (PMID:33416167)
• Silencing BLNK protects against interleukin-1beta-induced chondrocyte injury through the NF-kappaB signaling pathway. (PMID:34521030)
• C/EBPbeta induces B-cell acute lymphoblastic leukemia and cooperates with BLNK mutations. (PMID:34653294)
• ErbB2/Her2-dependent downregulation of a cell death-promoting protein BLNK in breast cancer cells is required for 3D breast tumor growth. (PMID:35933456)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	blnk	ENSDARG00000042722
danio_rerio	si:dkeyp-117b11.1	ENSDARG00000090607
mus_musculus	Blnk	ENSMUSG00000061132
rattus_norvegicus	Blnk	ENSRNOG00000013967

Paralogs (3): LCP2 (ENSG00000043462), CLNK (ENSG00000109684), SH2D6 (ENSG00000152292)

Protein

Protein identifiers

B-cell linker protein — Q8WV28 (reviewed: Q8WV28)

Alternative names: B-cell adapter containing a SH2 domain protein, B-cell adapter containing a Src homology 2 domain protein, Cytoplasmic adapter protein, Src homology 2 domain-containing leukocyte protein of 65 kDa

All UniProt accessions (15): Q8WV28, A0A8Q3SIR3, A0A8Q3SIW1, A0A8Q3SJD7, A0A8Q3WLC3, A0A8Q3WLC4, A0A8Q3WLN9, A0A8U0WPF8, K7EKR2, Q2MD42, Q2MD46, Q2MD47, Q2MD51, Q2MD54, Q2MD59

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a central linker protein, downstream of the B-cell receptor (BCR), bridging the SYK kinase to a multitude of signaling pathways and regulating biological outcomes of B-cell function and development. Plays a role in the activation of ERK/EPHB2, MAP kinase p38 and JNK. Modulates AP1 activation. Important for the activation of NF-kappa-B and NFAT. Plays an important role in BCR-mediated PLCG1 and PLCG2 activation and Ca(2+) mobilization and is required for trafficking of the BCR to late endosomes. However, does not seem to be required for pre-BCR-mediated activation of MAP kinase and phosphatidyl-inositol 3 (PI3) kinase signaling. May be required for the RAC1-JNK pathway. Plays a critical role in orchestrating the pro-B cell to pre-B cell transition. May play an important role in BCR-induced B-cell apoptosis.

Subunit / interactions. Associates with PLCG1, VAV1 and NCK1 in a B-cell antigen receptor-dependent fashion. Interacts with VAV3, PLCG2 and GRB2. Interacts through its SH2 domain with CD79A. Interacts (via SH2 domain) with SYK; phosphorylated and activated by SYK. Interacts (via SH2 domain) with SCIMP; this interaction is dependent on phosphorylation of SCIMP ‘Tyr-131’.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in B-cell lineage and fibroblast cell lines (at protein level). Highest levels of expression in the spleen, with lower levels in the liver, kidney, pancreas, small intestines and colon.

Post-translational modifications. Following BCR activation, phosphorylated on tyrosine residues by SYK and LYN. When phosphorylated, serves as a scaffold to assemble downstream targets of antigen activation, including PLCG1, VAV1, GRB2 and NCK1. Phosphorylation of Tyr-84, Tyr-178 and Tyr-189 facilitates PLCG1 binding. Phosphorylation of Tyr-96 facilitates BTK binding. Phosphorylation of Tyr-72 facilitates VAV1 and NCK1 binding. Phosphorylation is required for both Ca(2+) and MAPK signaling pathways.

Disease relevance. Agammaglobulinemia 4, autosomal recessive (AGM4) [MIM:613502] A primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8WV28-1	1	yes
Q8WV28-2	2
Q8WV28-3	3

RefSeq proteins (5): NP_001107566, NP_001245369, NP_001245370, NP_001245371, NP_037446* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR051751	Immunoreceptor_sig_adapters	Family

Pfam: PF00017

UniProt features (21 total): compositionally biased region 6, modified residue 5, mutagenesis site 4, splice variant 2, chain 1, domain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6YLU	X-RAY DIFFRACTION	1.88

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WV28-F1	64.46	0.23

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): 84, 96, 178, 189, 72

Mutagenesis-validated functional residues (4):

Position	Phenotype
72	significant phosphorylation reduction; when associated with f-84; f-96 and f-178.
84	significant phosphorylation reduction; when associated with f-72; f-96 and f-178.
96	significant phosphorylation reduction; when associated with f-72; f-84 and f-178.
178	significant phosphorylation reduction; when associated with f-72; f-84 and f-96.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-912631	Regulation of signaling by CBL
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-983695	Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1280218	Adaptive Immune System
R-HSA-1643685	Disease
R-HSA-168256	Immune System
R-HSA-449147	Signaling by Interleukins
R-HSA-512988	Interleukin-3, Interleukin-5 and GM-CSF signaling
R-HSA-5663205	Infectious disease
R-HSA-9679506	SARS-CoV Infections
R-HSA-9824446	Viral Infection Pathways
R-HSA-983705	Signaling by the B Cell Receptor (BCR)

MSigDB gene sets: 400 (showing top): PID_BCR_5PATHWAY, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, VERHAAK_AML_WITH_NPM1_MUTATED_DN, ZHAN_MULTIPLE_MYELOMA_PR_DN, MCLACHLAN_DENTAL_CARIES_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_B_CELL_ACTIVATION, BROWNE_HCMV_INFECTION_8HR_UP, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, CAIRO_HEPATOBLASTOMA_CLASSES_DN, BORLAK_LIVER_CANCER_EGF_UP, GOBP_REGULATION_OF_IMMUNE_RESPONSE

GO Biological Process (8): inflammatory response (GO:0006954), humoral immune response (GO:0006959), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), positive regulation of gene expression (GO:0010628), B cell differentiation (GO:0030183), intracellular signal transduction (GO:0035556), B cell receptor signaling pathway (GO:0050853), B cell activation (GO:0042113)

GO Molecular Function (10): transmembrane receptor protein tyrosine kinase adaptor activity (GO:0005068), lipid binding (GO:0008289), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), signaling adaptor activity (GO:0035591), SH2 domain binding (GO:0042169), phospholipase binding (GO:0043274), molecular condensate scaffold activity (GO:0140693), protein tyrosine kinase binding (GO:1990782), protein binding (GO:0005515)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Immune System	2
Interleukin-3, Interleukin-5 and GM-CSF signaling	1
SARS-CoV Infections	1
Signaling by the B Cell Receptor (BCR)	1
Cytokine Signaling in Immune system	1
Signaling by Interleukins	1
Disease	1
Viral Infection Pathways	1
Infectious disease	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular anatomical structure	2
binding	2
protein-macromolecule adaptor activity	2
defense response	1
immune response	1
enzyme-linked receptor protein signaling pathway	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
lymphocyte differentiation	1
B cell activation	1
signal transduction	1
antigen receptor-mediated signaling pathway	1
lymphocyte activation	1
cell surface receptor protein tyrosine kinase signaling pathway	1
signaling receptor complex adaptor activity	1
receptor tyrosine kinase binding	1
protein binding	1
kinase binding	1
protein domain specific binding	1
enzyme binding	1
protein kinase binding	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1372 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BLNK	PLCG2	P16885	998
BLNK	SYK	P43405	998
BLNK	BTK	Q06187	998
BLNK	CD79A	P11912	991
BLNK	VAV1	P15498	991
BLNK	LYN	P07948	986
BLNK	GRB2	P29354	972
BLNK	SH3KBP1	Q96B97	930
BLNK	CD79B	P40259	925
BLNK	CD19	P15391	910
BLNK	LCP2	Q13094	905
BLNK	ZAP70	P43403	900
BLNK	CD5	P06127	848
BLNK	LAT	O43561	841
BLNK	IGLL1	P15814	815

IntAct

31 interactions, top by confidence:

A	B	Type	Score
GRB2	BLNK	psi-mi:“MI:0915”(physical association)	0.740
GRB2	BLNK	psi-mi:“MI:0407”(direct interaction)	0.740
BLNK	GRB2	psi-mi:“MI:0407”(direct interaction)	0.740
BTK	BLNK	psi-mi:“MI:0407”(direct interaction)	0.670
BLNK	BTK	psi-mi:“MI:0915”(physical association)	0.670
BLNK	Grap2	psi-mi:“MI:0915”(physical association)	0.610
BLNK	Grap2	psi-mi:“MI:0407”(direct interaction)	0.610
	BLNK	psi-mi:“MI:0915”(physical association)	0.560
SCIMP	CSK	psi-mi:“MI:0914”(association)	0.500
SCIMP	LYN	psi-mi:“MI:0914”(association)	0.500
CD2AP	BLNK	psi-mi:“MI:0915”(physical association)	0.500
BLNK		psi-mi:“MI:0914”(association)	0.460
BLNK	SH3KBP1	psi-mi:“MI:0407”(direct interaction)	0.440
BLNK	ERBB2	psi-mi:“MI:0407”(direct interaction)	0.440
BLNK	AR	psi-mi:“MI:0407”(direct interaction)	0.440
BLNK	GAB1	psi-mi:“MI:0407”(direct interaction)	0.440
BLNK	KIT	psi-mi:“MI:0407”(direct interaction)	0.440
Sh3kbp1	BLNK	psi-mi:“MI:0915”(physical association)	0.400
BLNK	SYK	psi-mi:“MI:0915”(physical association)	0.400
Grb2	BLNK	psi-mi:“MI:0915”(physical association)	0.400
BLNK	EBNA2	psi-mi:“MI:0915”(physical association)	0.370
SCIMP	GRB2	psi-mi:“MI:0914”(association)	0.350
BLNK	PLCG2	psi-mi:“MI:0914”(association)	0.350
BLNK	CAPZA1	psi-mi:“MI:0914”(association)	0.350
NCK1	BLNK	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (72): BLNK (Co-localization), BLNK (Affinity Capture-RNA), NCK1 (Affinity Capture-Western), VAV1 (Affinity Capture-Western), GRB2 (Affinity Capture-Western), MAP4K1 (Reconstituted Complex), MAP4K1 (Affinity Capture-Western), BLNK (Two-hybrid), SH3KBP1 (Affinity Capture-Western), BLNK (Affinity Capture-Western), GRB2 (Reconstituted Complex), CD79A (Reconstituted Complex), BLNK (Affinity Capture-Western), BLNK (Reconstituted Complex), BLNK (Reconstituted Complex)

ESM2 similar proteins: A1X283, A2AAY5, A5D7F8, A5GFW5, A6ND36, D3ZIE4, D3ZUI5, E2RP94, M0R4F8, O15117, O35601, O54967, O75128, O89032, Q04584, Q06649, Q07912, Q13094, Q13625, Q15942, Q17R10, Q17R13, Q1LYG0, Q32LQ1, Q3TC93, Q3UH68, Q498M5, Q4KM52, Q5DTU0, Q5JV73, Q5NBX1, Q5TCZ1, Q5U2X5, Q62523, Q6IQ23, Q6TXD4, Q80TI1, Q8BI17, Q8BZI0, Q8CG79

Diamond homologs: P24604, P42680, P97504, Q4KM52, Q60787, Q7Z4S9, Q7Z7G1, Q8WV28, Q9D413, Q9QUN3, Q9QZE2, Q9YGC1, P08487, P10686, P19174, Q13094, Q62077, A6QLK6, P23727, P26450, P27986, P35235, P41499, Q06124, Q5R685, Q63787, Q90687, P16885, O00459, O08908, O46404, P23726, P29349, P53356, Q24708, Q63788, Q63789, Q64143, Q92569, Q9CX99

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
SH2B1	“down-regulates activity”	BLNK	dephosphorylation
SYK	up-regulates	BLNK	phosphorylation
PTPRG	“up-regulates activity”	BLNK	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 19 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
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	7	178.4×	7e-13
FCERI mediated Ca+2 mobilization	5	127.5×	3e-08
Signaling by the B Cell Receptor (BCR)	5	123.6×	3e-08
FCGR3A-mediated phagocytosis	5	66.9×	4e-07
Potential therapeutics for SARS	6	48.9×	9e-08
Constitutive Signaling by Aberrant PI3K in Cancer	5	45.3×	2e-06
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	34.6×	5e-06
PIP3 activates AKT signaling	5	23.9×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
B cell receptor signaling pathway	5	133.8×	1e-07
positive regulation of MAPK cascade	6	32.2×	1e-06
intracellular signal transduction	7	17.8×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	8
Uncertain significance	143
Likely benign	178
Benign	46

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1072783	NM_013314.4(BLNK):c.1195C>T (p.Arg399Ter)	Pathogenic
1075117	NM_013314.4(BLNK):c.1031del (p.Lys344fs)	Pathogenic
2090455	NM_013314.4(BLNK):c.26del (p.Val9fs)	Pathogenic
3661859	NM_013314.4(BLNK):c.252C>A (p.Tyr84Ter)	Pathogenic
3729465	NC_000010.11:g.96201059del	Pathogenic
4845848	NM_013314.4(BLNK):c.676+1G>A	Pathogenic
538835	NC_000010.11:g.96242785del	Pathogenic
5507	NM_013314.4(BLNK):c.47+3A>T	Pathogenic
831064	NC_000010.11:g.(?96271332)(96271418_?)del	Pathogenic
1348172	NM_013314.4(BLNK):c.113+2T>G	Likely pathogenic
2630855	NM_013314.4(BLNK):c.264del (p.Glu89fs)	Likely pathogenic
2860444	NM_013314.4(BLNK):c.747-2A>G	Likely pathogenic
3065608	NM_013314.4(BLNK):c.145C>T (p.Arg49Ter)	Likely pathogenic
3347419	NM_013314.4(BLNK):c.426G>A (p.Trp142Ter)	Likely pathogenic
3768783	NM_013314.4(BLNK):c.902+2T>C	Likely pathogenic
4075317	NM_013314.4(BLNK):c.289G>T (p.Glu97Ter)	Likely pathogenic
976234	NM_013314.4(BLNK):c.746+1G>A	Likely pathogenic

SpliceAI

2601 predictions. Top by Δscore:

Variant	Effect	Δscore
10:96200155:CTTC:C	acceptor_gain	1.0000
10:96200157:TCCTG:T	acceptor_loss	1.0000
10:96200159:C:CA	acceptor_loss	1.0000
10:96200159:C:CC	acceptor_gain	1.0000
10:96200160:T:A	acceptor_loss	1.0000
10:96204526:TCTTA:T	donor_loss	1.0000
10:96204527:CTTAC:C	donor_loss	1.0000
10:96204528:TTACT:T	donor_loss	1.0000
10:96204529:TA:T	donor_loss	1.0000
10:96204530:A:AC	donor_gain	1.0000
10:96204530:ACT:A	donor_loss	1.0000
10:96204531:C:CT	donor_gain	1.0000
10:96204531:CT:C	donor_gain	1.0000
10:96204531:CTT:C	donor_gain	1.0000
10:96204533:T:TA	donor_gain	1.0000
10:96204617:C:CC	acceptor_gain	1.0000
10:96204624:A:T	acceptor_gain	1.0000
10:96207007:TTA:T	donor_loss	1.0000
10:96207008:TA:T	donor_loss	1.0000
10:96207053:TC:T	acceptor_loss	1.0000
10:96207054:C:CC	acceptor_gain	1.0000
10:96207054:CT:C	acceptor_loss	1.0000
10:96207055:T:C	acceptor_loss	1.0000
10:96207056:A:AC	acceptor_gain	1.0000
10:96207056:A:C	acceptor_gain	1.0000
10:96207058:G:C	acceptor_gain	1.0000
10:96207866:A:C	donor_gain	1.0000
10:96207868:TTACT:T	donor_loss	1.0000
10:96207869:TACT:T	donor_loss	1.0000
10:96207870:A:AC	donor_gain	1.0000

AlphaMissense

2974 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:96192037:A:G	L436P	1.000
10:96196963:C:G	R399P	1.000
10:96197005:A:G	L385P	1.000
10:96197044:C:G	R372P	1.000
10:96197050:A:G	L370P	1.000
10:96191998:A:G	L449P	0.999
10:96191998:A:T	L449Q	0.999
10:96192037:A:T	L436H	0.999
10:96192043:A:G	L434S	0.999
10:96192059:G:C	H429D	0.999
10:96192079:A:T	V422D	0.999
10:96192087:A:C	F419L	0.999
10:96192087:A:T	F419L	0.999
10:96192089:A:G	F419L	0.999
10:96196930:C:A	G410V	0.999
10:96196930:C:T	G410D	0.999
10:96196931:C:G	G410R	0.999
10:96196933:A:G	L409S	0.999
10:96196936:G:T	A408D	0.999
10:96196937:C:G	A408P	0.999
10:96196940:A:C	Y407D	0.999
10:96196964:G:C	R399G	0.999
10:96196966:A:T	V398E	0.999
10:96196974:A:C	N395K	0.999
10:96196974:A:T	N395K	0.999
10:96196979:A:C	Y394D	0.999
10:96197005:A:T	L385Q	0.999
10:96197037:G:C	S374R	0.999
10:96197037:G:T	S374R	0.999
10:96197039:T:G	S374R	0.999

dbSNP variants (sampled 300 via entrez): RS1000004813 (10:96269463 G>A), RS1000067540 (10:96260081 G>A), RS1000112047 (10:96218562 T>A,C), RS1000179225 (10:96266433 T>C), RS1000207837 (10:96266746 G>C,T), RS1000242119 (10:96224955 C>T), RS1000331014 (10:96273178 A>G), RS1000403046 (10:96273558 T>C), RS1000487115 (10:96236916 G>A,C), RS1000526349 (10:96218908 T>C), RS1000702250 (10:96199908 C>T), RS1000724464 (10:96243564 C>T), RS1000767266 (10:96249852 C>T), RS1000884772 (10:96207373 T>C), RS1000887554 (10:96213667 G>A)

Disease associations

OMIM: gene MIM:604515 | disease phenotypes: MIM:613502

GenCC curated gene-disease

Disease	Classification	Inheritance
agammaglobulinemia 4, autosomal recessive	Strong	Autosomal recessive
autosomal agammaglobulinemia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
agammaglobulinemia 4, autosomal recessive	Definitive	AR

Mondo (2): agammaglobulinemia 4, autosomal recessive (MONDO:0013289), autosomal agammaglobulinemia (MONDO:0011096)

Orphanet (0):

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000246	Sinusitis
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000377	Abnormal pinna morphology
HP:0000389	Chronic otitis media
HP:0000403	Recurrent otitis media
HP:0000509	Conjunctivitis
HP:0000988	Skin rash
HP:0001287	Meningitis
HP:0001369	Arthritis
HP:0001508	Failure to thrive
HP:0001581	Recurrent skin infections
HP:0001875	Decreased total neutrophil count
HP:0001944	Dehydration
HP:0001945	Fever
HP:0002014	Diarrhea
HP:0002024	Malabsorption
HP:0002110	Bronchiectasis
HP:0002205	Recurrent respiratory infections
HP:0002243	Protein-losing enteropathy
HP:0002718	Recurrent bacterial infections
HP:0002719	Recurrent infections
HP:0002720	Decreased circulating IgA concentration
HP:0002721	Immunodeficiency
HP:0002754	Osteomyelitis
HP:0002843	Abnormal T cell morphology
HP:0002850	Decreased circulating total IgM
HP:0003593	Infantile onset

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002397_545	Mean spheric corpuscular volume	7.000000e-11

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538056	Agammaglobulinemia, non-Bruton type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

48 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects expression, affects cotreatment, decreases expression, increases expression	7
Aflatoxin B1	affects expression, decreases methylation, increases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
Resveratrol	decreases expression, affects cotreatment	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	affects expression, decreases methylation	2
Lipopolysaccharides	decreases expression, decreases reaction, affects cotreatment	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	2
sotorasib	affects cotreatment, increases expression	1
Asian ginseng	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
afimoxifene	decreases expression, decreases reaction	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, decreases reaction	1
2-palmitoylglycerol	increases expression	1
nutlin 3	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
jinfukang	affects cotreatment, increases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Air Pollutants	decreases expression	1
Arsenic	increases abundance, decreases expression	1
Vehicle Emissions	decreases expression	1
Camptothecin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Coumestrol	affects cotreatment, decreases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dietary Carbohydrates	increases expression	1
Diethylhexyl Phthalate	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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