CD244

Summary

CD244 (CD244 molecule, HGNC:18171) is a protein-coding gene on chromosome 1q23.3, encoding Natural killer cell receptor 2B4 (Q9BZW8). Heterophilic receptor of the signaling lymphocytic activation molecule (SLAM) family; its ligand is CD48.

This gene encodes a cell surface receptor expressed on natural killer (NK) cells (and some T cells) that mediate non-major histocompatibility complex (MHC) restricted killing. The interaction between NK-cell and target cells via this receptor is thought to modulate NK-cell cytolytic activity. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 51744 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 60 total
• Phenotypes (HPO): 16
• MANE Select transcript: NM_016382

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18171
Approved symbol	CD244
Name	CD244 molecule
Location	1q23.3
Locus type	gene with protein product
Status	Approved
Aliases	2B4, NAIL, NKR2B4, Nmrk, SLAMF4
Ensembl gene	ENSG00000122223
Ensembl biotype	protein_coding
OMIM	605554
Entrez	51744

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000322302, ENST00000368033, ENST00000368034, ENST00000481677, ENST00000492063, ENST00000884349

RefSeq mRNA: 3 — MANE Select: NM_016382 NM_001166663, NM_001166664, NM_016382

CCDS: CCDS1210, CCDS53398, CCDS53399

Canonical transcript exons

ENST00000368034 — 9 exons

Exon	Start	End
ENSE00000425477	160838939	160839049
ENSE00000829191	160836195	160836254
ENSE00001224337	160841210	160841485
ENSE00001224356	160841584	160841901
ENSE00001693637	160830160	160831427
ENSE00001750789	160862617	160862887
ENSE00003475320	160832519	160832575
ENSE00003489392	160838451	160838518
ENSE00003619787	160834051	160834116

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 96.43.

FANTOM5 (CAGE): breadth broad, TPM avg 2.8609 / max 162.8423, expressed in 231 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15543	0.9709	147
15547	0.8416	149
15545	0.4885	133
15544	0.3203	116
15546	0.1990	82
15541	0.0165	10
15539	0.0098	1
15540	0.0091	6
15542	0.0053	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.43	gold quality
monocyte	CL:0000576	94.84	gold quality
leukocyte	CL:0000738	94.64	gold quality
mononuclear cell	CL:0000842	94.59	gold quality
blood	UBERON:0000178	86.50	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.89	silver quality
spleen	UBERON:0002106	81.72	gold quality
bone marrow	UBERON:0002371	75.35	gold quality
bone marrow cell	CL:0002092	75.23	gold quality
lymph node	UBERON:0000029	70.13	gold quality
vermiform appendix	UBERON:0001154	68.71	gold quality
right lobe of liver	UBERON:0001114	67.41	gold quality
amniotic fluid	UBERON:0000173	67.21	gold quality
rectum	UBERON:0001052	65.95	gold quality
upper lobe of left lung	UBERON:0008952	65.81	gold quality
caecum	UBERON:0001153	64.95	gold quality
omental fat pad	UBERON:0010414	64.43	gold quality
peritoneum	UBERON:0002358	64.36	gold quality
right coronary artery	UBERON:0001625	64.31	gold quality
male germ cell	CL:0000015	64.22	gold quality
sperm	CL:0000019	64.11	gold quality
upper lobe of lung	UBERON:0008948	64.00	gold quality
adipose tissue of abdominal region	UBERON:0007808	63.49	gold quality
gall bladder	UBERON:0002110	63.44	gold quality
colonic epithelium	UBERON:0000397	63.32	gold quality
palpebral conjunctiva	UBERON:0001812	63.19	silver quality
liver	UBERON:0002107	63.04	gold quality
germinal epithelium of ovary	UBERON:0001304	62.92	silver quality
smooth muscle tissue	UBERON:0001135	62.03	gold quality
duodenum	UBERON:0002114	61.57	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.21

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1

miRNA regulators (miRDB)

38 targeting CD244, 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-3185	99.99	68.12	1959
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-1251-3P	99.64	67.21	1408
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-4777-5P	99.33	67.53	1148
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-1911-3P	99.15	66.17	528
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-7153-3P	99.00	65.35	608
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-26B-3P	98.71	67.49	1102
HSA-MIR-193A-3P	98.59	66.36	769
HSA-MIR-193B-3P	98.59	66.62	748
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-2681-3P	98.18	65.28	577

Literature-anchored findings (GeneRIF, showing 40)

• Up-regulation of the activatory receptor 2B4 by CD8+ alpha beta T cells in vivo correlates with the acquisition of effector cell properties such as granzyme B and perforin expression, IFN-gamma production, and down-regulation of chemokine receptor CCR7. (PMID:11714776)
• 2B4-mediated activation of natural killer cells involves the complex interactions of LAT, Ras, Raf, ERK and p38 kinase in the regulation of lytic function and cytokine production. (PMID:11714782)
• X-linked lymphoproliferative disease causes impaired 2b4 function in NK cells. (PMID:11774610)
• expressed on CD3+/CD56+ large granular lymphocytes proliferating in response to a tumor-expressed activating ligand (CD48) and killing autologous leukemia cells by a novel mechanism in a patient with acute myeloid leukemia. (PMID:11986947)
• Natural killer cell inhibitory receptors block actin cytoskeleton-dependent recruitment of 2B4 (CD244) to lipid rafts. (PMID:12515815)
• engagement of 2B4 on NK cells triggered a tyrosine phosphorylation signal (PMID:15169881)
• expression significantly up-regulated on CD4 and CD8 T cells during infectious mononucleosis, and significantly more lymphocytes expressing CD8 and CD244/CD8 in patients with severe sore throat. (PMID:15195244)
• The function of 2B4 as an adhesion molecule is underscored and a relevant role is suggested in the initial binding, scanning of target cells, and formation of cytotoxic natural killer cell immune synapse. (PMID:15356108)
• the SAP/2B4 pathway plays a key role in CTL lytic activity against EBV-positive targets by promoting the polarization of the lytic machinery (PMID:15677558)
• analysis of the molecular basis for the different signals generated by 2B4 (PMID:15713798)
• Functional analysis indicates that Lys-68 and Glu-70 in the extracellular domain of human 2B4 play a key role in the activation of human natural killer (NK) cells through 2B4/CD48 interaction. (PMID:16002700)
• Review of recent studies suggests an important role for interactions between 2B4 and CD48 in the course of T cell activation and proliferation (PMID:16081768)
• CD244-3BP2 association regulates cytolytic function but not IFN-gamma release (PMID:16177062)
• blocking the engagement of 2B4, NTB-A and CRACC has no effect on the proliferation or development of the cytotoxic potential of NK cells but triggering by their physiological ligands on MHC class I-negative target cells induces potent NK cell cytotoxicity (PMID:16410313)
• 2B4 (CD244) can stimulate NK cell cytotoxicity and cytokine production by interacting with NK cell expressed CD48 and adds CD48 to the growing number of activating NK cell receptors (PMID:16585556)
• REVIEW: different functions of the murine and human 2B4 (CD244) receptor on NK cells (PMID:16621032)
• CD48 is a CD2 and CD244 (2B4)-binding protein (PMID:16803907)
• The lower surface expression of 2B4 after ligand-induced down-modulation results in reduced 2B4-mediated NK cell activation and cytotoxicity. (PMID:17111350)
• The triggering of 2B4 (CD244) alone is sufficient to induce natural killer (NK) cell cytotoxicity in IL-2-activated NK cells with high SLAM-associated protein expression. (PMID:17171759)
• stimulation of natural killer cells through surface 2B4 (CD244) down-regulates its own expression due to a reduction in the promoter activity at the Ets element (PMID:17300754)
• the mechanism of signal transduction by CD244 is to regulate FYN kinase recruitment and/or activity and the outcome of CD48/CD244 interactions is determined by which other receptors are engaged. (PMID:17599905)
• HTLV-1-infected CD4+ T cells did not express ligands for NK cell activating receptors, NCR and NKG2D, although they did express ligands for NK cell coactivating receptors, NTB-A and 2B4. (PMID:17609265)
• 2B4, NTB-A and CRACC have roles in the regulation of Natural Killer cell function [review] (PMID:17981603)
• 3BP2 acts downstream of SAP, increases CD244 phosphorylation and links the receptor with PI3K, Vav, PLC gamma, and PKC downstream events in order to achieve maximum natural killer cell killing function. (PMID:18479751)
• Studies under identical and controlled conditions reveal that both human and mouse 2B4 can activate or inhibit natural killer (NK) cells. (PMID:18523281)
• Single nucleotide polymorphism in CD244 gene is associated with rheumatoid arthritis. (PMID:18794858)
• Down-regulation of 2B4 isoforms may be an important factor in controlling NK cell activation during immune responses. (PMID:19499526)
• CD244 inhibition and activation depends on CD2 and phospholipase C-gamma1 (PMID:19586919)
• the 2B4 receptor has a potent costimulatory effect in NK cells (PMID:19638467)
• CD244 is not associated with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in a Korean population. (PMID:19790054)
• Data show that pair-wise ligations of 2B4 with DNAM-1 and/or NKG2D lead to increased effector functions of primary CD4(+)CD28(-) T cells to suboptimal levels of anti-CD3 stimulation. (PMID:19904767)
• Major histocompatibility class (MHC) I proteins expressed on natural killer (NK) cells inhibit NKR2B4 receptor self-killing not only by serving as an inhibitory ligand for inhibitory NK receptors but also through the association with 2B4. (PMID:20164429)
• altered expression of splice variants of CS1 and 2B4 that mediate differential signalling in PBMC from patients with SLE. (PMID:20345977)
• Single nucleotide polymorphisms of CD244 gene predispose to renal and neuro-psychiatric manifestations with systemic lupus erythematosus. (PMID:20437071)
• analysis of the importance of homotypic NK-to-NK cell cross-talk through 2B4/CD48 and CD2/CD58 pairs and further present their differential and overlapping roles in human NK cells (PMID:20813844)
• CD244 and PD-1 are highly coexpressed on virus-specific CD8+ T-cells in chronic HBV infection and blocking CD244 or its ligand CD48 may restore T-cell function independent of the PD-1 pathway. (PMID:21064032)
• Data show that an increase in 2B4-expressing NK cells and a decrease in NKp46(+) NK cells occurred following intramuscular influenza vaccination. (PMID:21214542)
• Engagement of the activating natural killer (NK) cell receptor 2B4 rapidly mediates an increase in the force necessary to separate NK cells from tumor cells. (PMID:21270395)
• These results suggest a potential physical association between 2B4 and the ITAM receptor complexes that is required for 2B4-initiated signaling and cell-mediated killing. (PMID:21439641)
• The results obtained through a cohort of European Caucasian Systemic sclerosis patients do not support the implication of CD244 gene in the pathogenesis of SSc but the gene were identified as Rheumatoid arthritis susceptibility gene. (PMID:21586211)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:cabz01074946.1	ENSDARG00000090396
mus_musculus	Cd244a	ENSMUSG00000004709
rattus_norvegicus	Cd244	ENSRNOG00000064255
rattus_norvegicus	Cd244l1	ENSRNOG00000068754

Paralogs (9): SLAMF7 (ENSG00000026751), CD84 (ENSG00000066294), CD2 (ENSG00000116824), SLAMF1 (ENSG00000117090), CD48 (ENSG00000117091), LY9 (ENSG00000122224), SLAMF8 (ENSG00000158714), SLAMF9 (ENSG00000162723), SLAMF6 (ENSG00000162739)

Protein

Protein identifiers

Natural killer cell receptor 2B4 — Q9BZW8 (reviewed: Q9BZW8)

Alternative names: NK cell activation-inducing ligand, NK cell type I receptor protein 2B4, SLAM family member 4, Signaling lymphocytic activation molecule 4

All UniProt accessions (1): Q9BZW8

UniProt curated annotations — full annotation on UniProt →

Function. Heterophilic receptor of the signaling lymphocytic activation molecule (SLAM) family; its ligand is CD48. SLAM receptors triggered by homo- or heterotypic cell-cell interactions are modulating the activation and differentiation of a wide variety of immune cells and thus are involved in the regulation and interconnection of both innate and adaptive immune response. Activities are controlled by presence or absence of small cytoplasmic adapter proteins, SH2D1A/SAP and/or SH2D1B/EAT-2. Acts as activating natural killer (NK) cell receptor. Activating function implicates association with SH2D1A and FYN. Downstreaming signaling involves predominantly VAV1, and, to a lesser degree, INPP5D/SHIP1 and CBL. Signal attenuation in the absence of SH2D1A is proposed to be dependent on INPP5D and to a lesser extent PTPN6/SHP-1 and PTPN11/SHP-2. Stimulates NK cell cytotoxicity, production of IFN-gamma and granule exocytosis. Optimal expansion and activation of NK cells seems to be dependent on the engagement of CD244 with CD48 expressed on neighboring NK cells. Acts as costimulator in NK activation by enhancing signals by other NK receptors such as NCR3 and NCR1. At early stages of NK cell differentiation may function as an inhibitory receptor possibly ensuring the self-tolerance of developing NK cells. Involved in the regulation of CD8(+) T-cell proliferation; expression on activated T-cells and binding to CD48 provides costimulatory-like function for neighboring T-cells. Inhibits inflammatory responses in dendritic cells (DCs).

Subunit / interactions. Interacts with CD48. Interacts (via phosphorylated ITSM 1-4) with SH2D1A (via SH2 domain); SH2D1A probably mediates association with FYN. Interacts (via phosphorylated ITSM 3) with PTPN11/SHP-2, INPP5D/SHIP1, PTPN6/SHP-1 and CSK; binding of SH2D1A/SAP prevents association with PTPN11, PTPN6 and CSK; conflictingly a similar association has been described for phosphorylated ITSM 1 also including GRB2 and PLCG1. Interacts weakly (via phosphorylated ITSM 2) with PTPN11/SHP-2 and CSK. Interacts with SH2D1B. Interacts with PIK3R1; PI3K recruits SH2D1A. Interacts with MHC class I proteins; the interaction is proposed to prevent self-killing of NK cells.

Subcellular location. Membrane. Cell membrane. Membrane raft.

Tissue specificity. Expressed in spleen, PBL, followed by lung, liver, testis and small intestine. Expressed in all natural killer (NK) cells, monocytes and basophils, TCR-gamma/delta+ T-cells, monocytes, basophils, and on a subset of CD8(+) T-cells.

Post-translational modifications. N-linked glycosylation is essential for the binding to its ligand CD48. Also O-glycosylated, in contrast, O-linked sialylation has a negative impact on ligand binding. Phosphorylated by FYN and CSK on tyrosine residues following activation. Coligation with inhibitory receptors such as KIR2DL1 inhibits phosphorylation upon contact of NK cells with sensitive target cells.

Domain organisation. The ITSMs (immunoreceptor tyrosine-based switch motifs) with the consensus sequence T-X-Y-X-X-[VI] present in SLAM family receptors have overlapping specificity for activating and inhibitory SH2 domain-containing binding partners. Especially they mediate the interaction with the SH2 domain of SH2D1A and SH2D1B. A ’three-pronged’ mechanism is proposed involving threonine (position -2), phosphorylated tyrosine (position 0) and valine/isoleucine (position +3).

Miscellaneous. Binds to CD48 with a stronger affinity than isoform 1, and interactions induces greater cytotoxicity and intracellular calcium release.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9BZW8-1	1, H2B4-B	yes
Q9BZW8-2	2, H2B4-A
Q9BZW8-3	3, H2B4
Q9BZW8-4	4, H2B4b

RefSeq proteins (3): NP_001160135, NP_001160136, NP_057466* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007110	Ig-like_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015631	CD2/SLAM_rcpt	Family
IPR024303	NK_rcpt_2B4_Ig_dom	Domain
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF11465

UniProt features (34 total): glycosylation site 8, short sequence motif 4, modified residue 4, splice variant 4, topological domain 2, sequence variant 2, mutagenesis site 2, domain 2, signal peptide 1, chain 1, disulfide bond 1, transmembrane region 1, sequence conflict 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZW8-F1	71.23	0.24

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 (4): 271, 297, 317, 342

Disulfide bonds (1): 157–199

Glycosylation sites (8): 71, 77, 89, 164, 181, 192, 200, 213

Mutagenesis-validated functional residues (2):

Position	Phenotype
68	disrupts interaction with cd48; when associated with a-70.
70	disrupts interaction with cd48; when associated with a-68.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-202733	Cell surface interactions at the vascular wall
R-HSA-109582	Hemostasis

MSigDB gene sets: 262 (showing top): GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_8_PRODUCTION, GOBP_INOSITOL_PHOSPHATE_METABOLIC_PROCESS, GOBP_POLYOL_METABOLIC_PROCESS, GOCC_CELL_SURFACE, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_ALCOHOL_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CARBOHYDRATE_METABOLIC_PROCESS, GOLDRATH_ANTIGEN_RESPONSE, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, JAZAG_TGFB1_SIGNALING_DN, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN

GO Biological Process (11): adaptive immune response (GO:0002250), natural killer cell activation involved in immune response (GO:0002323), immune response (GO:0006955), signal transduction (GO:0007165), natural killer cell activation (GO:0030101), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-8 production (GO:0032757), positive regulation of inositol phosphate biosynthetic process (GO:0060732), positive regulation of granzyme B production (GO:0071663), immune system process (GO:0002376), innate immune response (GO:0045087)

GO Molecular Function (3): signaling receptor activity (GO:0038023), MHC class I protein binding (GO:0042288), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane raft (GO:0045121), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
immune response	2
positive regulation of cytokine production	2
lymphocyte activation involved in immune response	1
natural killer cell activation	1
innate immune response	1
immune system process	1
response to stimulus	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
lymphocyte activation	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-8 production	1
regulation of interleukin-8 production	1
positive regulation of phosphorus metabolic process	1
regulation of inositol phosphate biosynthetic process	1
inositol phosphate biosynthetic process	1
positive regulation of carbohydrate metabolic process	1
positive regulation of alcohol biosynthetic process	1
positive regulation of production of molecular mediator of immune response	1
granzyme B production	1
regulation of granzyme B production	1
biological_process	1
defense response to symbiont	1
molecular transducer activity	1
MHC protein binding	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
membrane microdomain	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2358 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD244	CD48	P09326	997
CD244	SH2D1A	O60880	942
CD244	SLAMF6	Q96DU3	902
CD244	EZH2	Q15910	874
CD244	SH2D1B	O14796	864
CD244	KLRD1	Q13241	821
CD244	NCR1	O76036	800
CD244	CD226	Q15762	789
CD244	CD160	O95971	774
CD244	CD2	P06729	738
CD244	KIR2DL1	P43626	704
CD244	KLRK1	P26718	701
CD244	LAG3	P18627	700
CD244	HAVCR2	Q8TDQ0	700
CD244	CD8A	P01732	661

IntAct

44 interactions, top by confidence:

A	B	Type	Score
SH2D1A	CD244	psi-mi:“MI:0407”(direct interaction)	0.870
CD244	SH2D1A	psi-mi:“MI:0915”(physical association)	0.870
SH2D1A	CD244	psi-mi:“MI:0915”(physical association)	0.870
CD244	CD48	psi-mi:“MI:0915”(physical association)	0.790
CD48	CD244	psi-mi:“MI:0915”(physical association)	0.790
CD244	CD48	psi-mi:“MI:0407”(direct interaction)	0.790
SH2D1B	CD244	psi-mi:“MI:0407”(direct interaction)	0.690
CD244	SH2D1B	psi-mi:“MI:0914”(association)	0.690
SH2D1B	CD244	psi-mi:“MI:0915”(physical association)	0.690
INPP5D	CD244	psi-mi:“MI:0407”(direct interaction)	0.670
CD244	PTPN6	psi-mi:“MI:0915”(physical association)	0.560
SH2D1A	CD244	psi-mi:“MI:0915”(physical association)	0.560
CD244	SH2D1A	psi-mi:“MI:0914”(association)	0.560
CD244	MTX2	psi-mi:“MI:0914”(association)	0.530
PLCG1	CD244	psi-mi:“MI:0407”(direct interaction)	0.520
PTPN11	CD244	psi-mi:“MI:0407”(direct interaction)	0.520

BioGRID (71): IMMT (Affinity Capture-MS), CAND2 (Affinity Capture-MS), HEATR1 (Affinity Capture-MS), HEATR6 (Affinity Capture-MS), PDXDC1 (Affinity Capture-MS), PI4KA (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), MTOR (Affinity Capture-MS), POMT2 (Affinity Capture-MS), POMT1 (Affinity Capture-MS), PIK3R1 (Affinity Capture-MS), UFSP2 (Affinity Capture-MS), LTN1 (Affinity Capture-MS), RNF213 (Affinity Capture-MS)

ESM2 similar proteins: A6NJW9, O02757, P01730, P01731, P01732, P05541, P07725, P09793, P0DSE1, P10300, P10747, P10966, P15530, P16003, P16004, P16410, P30433, P30434, P31041, P31042, P31043, P31783, P33705, P33706, P40259, P41688, P42069, P42072, P50283, P79184, P79336, Q08338, Q08340, Q28071, Q2YFS1, Q2YFS2, Q2YFS3, Q3LRV9, Q495A1, Q5JXA9

Diamond homologs: P09326, P10252, P18181, Q9BZW8, Q07763, Q9JLM2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 17 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
Adaptive Immune System	5	10.7×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
T cell receptor signaling pathway	6	56.9×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	39
Likely benign	10
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1497 predictions. Top by Δscore:

Variant	Effect	Δscore
1:160831423:CCAAT:C	acceptor_gain	1.0000
1:160831424:CAAT:C	acceptor_gain	1.0000
1:160831424:CAATC:C	acceptor_gain	1.0000
1:160831425:AATCT:A	acceptor_loss	1.0000
1:160831426:ATC:A	acceptor_loss	1.0000
1:160831427:TCTGC:T	acceptor_loss	1.0000
1:160831428:C:A	acceptor_loss	1.0000
1:160831428:C:CC	acceptor_gain	1.0000
1:160831429:T:A	acceptor_loss	1.0000
1:160834117:C:CC	acceptor_gain	1.0000
1:160838449:A:AC	donor_gain	1.0000
1:160838450:C:CC	donor_gain	1.0000
1:160839048:TT:T	acceptor_gain	1.0000
1:160831237:AT:A	donor_gain	0.9900
1:160831425:AAT:A	acceptor_gain	0.9900
1:160831426:AT:A	acceptor_gain	0.9900
1:160838148:C:CT	donor_gain	0.9900
1:160838517:CT:C	acceptor_gain	0.9900
1:160838519:C:CC	acceptor_gain	0.9900
1:160839047:ATT:A	acceptor_gain	0.9900
1:160839050:C:CC	acceptor_gain	0.9900
1:160832518:CCA:C	donor_gain	0.9800
1:160832576:C:CC	acceptor_gain	0.9800
1:160838163:G:A	donor_gain	0.9800
1:160838931:CCACT:C	donor_loss	0.9800
1:160838932:CACTC:C	donor_loss	0.9800
1:160838933:ACTCA:A	donor_loss	0.9800
1:160838934:CTCA:C	donor_loss	0.9800
1:160838935:TCA:T	donor_loss	0.9800
1:160838936:CA:C	donor_loss	0.9800

AlphaMissense

2403 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:160841284:C:G	C199S	0.992
1:160841285:A:T	C199S	0.992
1:160841804:C:A	W53C	0.989
1:160841804:C:G	W53C	0.989
1:160841284:C:T	C199Y	0.988
1:160841847:A:G	L39S	0.987
1:160841285:A:G	C199R	0.986
1:160841410:C:G	C157S	0.984
1:160841411:A:T	C157S	0.984
1:160841283:G:C	C199W	0.983
1:160841409:G:C	C157W	0.983
1:160841411:A:G	C157R	0.982
1:160841373:C:A	W169C	0.981
1:160841373:C:G	W169C	0.981
1:160841600:G:C	F121L	0.979
1:160841600:G:T	F121L	0.979
1:160841602:A:G	F121L	0.979
1:160841375:A:G	W169R	0.978
1:160841375:A:T	W169R	0.978
1:160841650:A:C	Y105D	0.978
1:160841806:A:G	W53R	0.978
1:160841806:A:T	W53R	0.978
1:160841410:C:T	C157Y	0.977
1:160841284:C:A	C199F	0.976
1:160841291:A:C	Y197D	0.972
1:160841688:A:G	L92P	0.966
1:160841649:T:G	Y105S	0.965
1:160841278:A:T	V201D	0.961
1:160841285:A:C	C199G	0.959
1:160841805:C:G	W53S	0.957

dbSNP variants (sampled 300 via entrez): RS1000133732 (1:160840228 C>A), RS1000166097 (1:160834406 A>G), RS1000265254 (1:160839953 A>C), RS1000319537 (1:160839679 T>G), RS1000413909 (1:160849703 A>G), RS1000426165 (1:160846115 G>T), RS1000516614 (1:160834619 G>A), RS1000612208 (1:160838756 G>A), RS1000706683 (1:160855587 C>T), RS1000880994 (1:160850935 G>A), RS1000891836 (1:160845887 T>A,C), RS1000911297 (1:160833228 T>G), RS1001166860 (1:160849805 G>A), RS1001188424 (1:160850668 G>A,T), RS1001219178 (1:160849573 A>G)

Disease associations

OMIM: gene MIM:605554 | disease phenotypes: MIM:180300

GenCC curated gene-disease

Mondo (2): prostate cancer (MONDO:0008315), rheumatoid arthritis (MONDO:0008383)

Orphanet (2): Familial prostate cancer (Orphanet:1331), NON RARE IN EUROPE: Rheumatoid arthritis (Orphanet:284130)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0001370	Rheumatoid arthritis
HP:0001386	Joint swelling
HP:0001387	Joint stiffness
HP:0001824	Weight loss
HP:0001945	Fever
HP:0002633	Vasculitis
HP:0002829	Arthralgia
HP:0002923	Rheumatoid factor positive
HP:0003565	Elevated erythrocyte sedimentation rate
HP:0005764	Polyarticular arthritis
HP:0006150	Swan neck-like deformities of the fingers
HP:0006252	Interphalangeal joint erosions
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0012276	Digital flexor tenosynovitis
HP:0012378	Fatigue
HP:0033034	Anti-citrullinated protein antibody positivity

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000879_21	Crohn’s disease	6.000000e-07
GCST001725_36	Inflammatory bowel disease	7.000000e-09
GCST90002389_88	Lymphocyte percentage of white cells	3.000000e-11
GCST90002399_13	Neutrophil percentage of white cells	3.000000e-10
GCST90002407_8	White blood cell count	6.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001172	Arthritis, Rheumatoid	C05.550.114.154; C05.799.114; C17.300.775.099; C20.111.199
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	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
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	affects expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Catechin	affects cotreatment, decreases expression	1
Cisplatin	increases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Nickel	decreases expression	1
Ozone	affects expression, increases abundance	1
Polychlorinated Biphenyls	affects expression	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
Asbestos, Serpentine	decreases expression	1
Antirheumatic Agents	decreases expression	1
Palmitic Acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer