CD247

Summary

CD247 (CD247 molecule, HGNC:1677) is a protein-coding gene on chromosome 1q24.2, encoding T-cell surface glycoprotein CD3 zeta chain (P20963). Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.

The protein encoded by this gene is T-cell receptor zeta, which together with T-cell receptor alpha/beta and gamma/delta heterodimers, and with CD3-gamma, -delta and -epsilon, forms the T-cell receptor-CD3 complex. The zeta chain plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. Low expression of the antigen results in impaired immune response. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

Source: NCBI Gene 919 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 25 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 30
• Clinical variants (ClinVar): 206 total — 8 pathogenic
• Phenotypes (HPO): 79
• MANE Select transcript: NM_198053

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1677
Approved symbol	CD247
Name	CD247 molecule
Location	1q24.2
Locus type	gene with protein product
Status	Approved
Aliases	CD3H, CD3Q, TCRZ, CD3-ZETA, CD3ZETA
Ensembl gene	ENSG00000198821
Ensembl biotype	protein_coding
OMIM	186780
Entrez	919

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 22 protein_coding, 9 protein_coding_CDS_not_defined, 8 retained_intron, 4 nonsense_mediated_decay

ENST00000362089, ENST00000392122, ENST00000470379, ENST00000476733, ENST00000479979, ENST00000483825, ENST00000485089, ENST00000700105, ENST00000700106, ENST00000700107, ENST00000700108, ENST00000700109, ENST00000700110, ENST00000700111, ENST00000700112, ENST00000700113, ENST00000700134, ENST00000700135, ENST00000700136, ENST00000700137, ENST00000700138, ENST00000700139, ENST00000700140, ENST00000700141, ENST00000700142, ENST00000700143, ENST00000700155, ENST00000700156, ENST00000700157, ENST00000700158, ENST00000700159, ENST00000700160, ENST00000700161, ENST00000700163, ENST00000700164, ENST00000700165, ENST00000700166, ENST00000700167, ENST00000700168, ENST00000700169, ENST00000888363, ENST00000888364, ENST00000888365

RefSeq mRNA: 4 — MANE Select: NM_198053 NM_000734, NM_001378515, NM_001378516, NM_198053

CCDS: CCDS1260, CCDS1261

Canonical transcript exons

ENST00000362089 — 8 exons

Exon	Start	End
ENSE00001878735	167430640	167431746
ENSE00003461649	167438570	167438650
ENSE00003479880	167434020	167434076
ENSE00003490529	167433024	167433059
ENSE00003498505	167435399	167435434
ENSE00003567850	167440664	167440767
ENSE00003600043	167439344	167439400
ENSE00003978996	167518408	167518529

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 99.39.

FANTOM5 (CAGE): breadth broad, TPM avg 10.3906 / max 864.2595, expressed in 200 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15776	10.3906	200

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.39	gold quality
thymus	UBERON:0002370	97.45	gold quality
blood	UBERON:0000178	95.07	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.92	gold quality
lymph node	UBERON:0000029	91.61	gold quality
spleen	UBERON:0002106	91.34	gold quality
vermiform appendix	UBERON:0001154	89.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.53	gold quality
bone marrow	UBERON:0002371	85.09	gold quality
bone marrow cell	CL:0002092	83.90	gold quality
ileal mucosa	UBERON:0000331	82.74	silver quality
caecum	UBERON:0001153	81.45	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.69	gold quality
mucosa of transverse colon	UBERON:0004991	79.44	gold quality
upper lobe of left lung	UBERON:0008952	79.13	gold quality
jejunal mucosa	UBERON:0000399	78.94	gold quality
small intestine	UBERON:0002108	78.46	gold quality
leukocyte	CL:0000738	77.62	gold quality
right lung	UBERON:0002167	76.92	gold quality
gall bladder	UBERON:0002110	76.75	gold quality
colonic epithelium	UBERON:0000397	76.73	gold quality
upper lobe of lung	UBERON:0008948	76.48	gold quality
right lobe of liver	UBERON:0001114	76.28	gold quality
mononuclear cell	CL:0000842	75.57	gold quality
duodenum	UBERON:0002114	74.85	gold quality
monocyte	CL:0000576	74.83	gold quality
superficial temporal artery	UBERON:0001614	74.67	silver quality
rectum	UBERON:0001052	74.42	gold quality
epithelium of nasopharynx	UBERON:0001951	74.35	silver quality
amniotic fluid	UBERON:0000173	73.97	gold quality

Single-cell (SCXA)

Detected in 26 experiment(s), a significant marker in 24.

Experiment	Marker?	Max mean expression
E-MTAB-6653	yes	1207.00
E-CURD-97	yes	1205.47
E-GEOD-149689	yes	1150.64
E-CURD-112	yes	915.75
E-MTAB-11268	yes	575.65
E-HCAD-4	yes	164.78
E-HCAD-1	yes	160.21
E-MTAB-6701	yes	113.34
E-CURD-122	yes	70.29
E-MTAB-9467	yes	58.50
E-MTAB-8142	yes	48.99
E-MTAB-10553	yes	48.86
E-MTAB-10287	yes	40.23
E-CURD-88	yes	36.43
E-HCAD-10	yes	34.12

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREM, ELF1

miRNA regulators (miRDB)

43 targeting CD247, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-486-5P	99.51	70.39	707
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-5693	99.24	66.67	1106
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-622	98.99	66.48	1050
HSA-MIR-491-3P	98.88	68.86	1224
HSA-MIR-936	98.87	70.51	1124
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-214-3P	98.71	68.12	2128

Literature-anchored findings (GeneRIF, showing 40)

• T cells grafted with a recombinant CD3zeta/CD28 signaling receptor secrete high amounts of IL-2 upon antigen binding without exogenous B7/CD28 costimulation, demonstrating that complete T cell activation can be delivered by one chimeric receptor molecule. (PMID:11714771)
• experimental, computational and evolutionary approaches predicts the presence of a tetrameric form for CD3-zeta (PMID:11851345)
• Our data indicate that TCR-signaling pathways are differentially affected by physiological levels of oxidative stress (PMID:11916964)
• reduced expression in tumor-infiltrating lymphocytes strongly correlated with progressive disease in gastric carcinoma (PMID:11920499)
• Regulation of T cell receptor CD3zeta chain expression by L-arginine. (PMID:11950832)
• Defective expression and altered tyrosine phosphorylation of TCR zeta was found in a large proportion of SLE patients, suggesting that it may play an important role in T cell dysfunction in SLE. (PMID:12100036)
• ZAP-70, a tyrosine kinase known to be crucial for T cell activation, as a key player in TCR down-modulation and zeta degradation. (PMID:12165490)
• results demonstrate that antioxidants restore the expression of TCR zeta chain and reverse the TCR/CD3-mediated signaling abnormalities associated with heat stress (PMID:12202152)
• Absence or reduction of TCR zeta-chain expression in inflammatory skin lymphocytic infiltrates not consistent with pivotal role of TCR zeta-chain in process of immune escape of tumour cells. (PMID:12420108)
• The transcriptional defect of TCR zeta-chain in patients with systemic lupus erythematosus is the result of defective expression of the functional 98-kDa form of Elf-1. (PMID:12421992)
• there is a high prevalence of TCR zeta chain deficiency in SLE patients that is independent of disease activity, and persists over time indicating an important role for TCR zeta chain deficiency in SLE pathogenesis. (PMID:12587826)
• TCRzeta is phosphorylated by protein tyrosine kinase Lck (PMID:12755691)
• reconstitution of deficient TCR zeta chain can reverse the TCR/CD3-mediated signaling abnormalities as well as the defective IL-2 production in T cells of patients with SLE. (PMID:12847689)
• The TCR zeta-chain participates as a key component in the CD43 signaling pathway in T lymphocytes and other leukocytes such as natural killer cells. (PMID:12902492)
• The lower stability of zeta mRNA containing the wild-type 3’-untranslated region, which is predominant in systemic lupus erythematosus (SLE) T cells, may be responsible for reduced expression of the TCR/CD3 complex, including zeta protein, in SLE T cells. (PMID:12928398)
• CD38 initiates and propagates several activating signaling pathways including those with Lck and CD3-zeta (PMID:14523017)
• T-cell receptor/CD3-zeta antigen expression is normally suppressed in pregnancy but loss of this suppression occurs in preeclamptic patients (PMID:14526327)
• alternatively spliced TCRzeta has a role in linking T cell receptor signaling to a G-protein-related signaling pathway (PMID:14550268)
• first reported demonstration that protein tyrosine phosphatase H1(PTPH1) is capable of interacting with and dephosphorylating T cell receptor zeta subunit (PMID:14672952)
• decreased expression of the CD3zeta transcript and protein in T cells from the synovial membranes of patients with osteoarthritis relative to that of the CD3epsilon transcript is suggestive of chronic T-cell stimulation (PMID:14715568)
• The cytoplasmic domain of the immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling subunit of the recombinant T cell receptor zeta chain is predominantly dimeric in solution but can also form higher oligomers. (PMID:14967045)
• CD3 zeta expression in peripherial blood lymphocytes was significantly correlated with depth of invasion but not nodal involvement in gastric cancer. (PMID:15274412)
• decreased zeta chain expression in T cells in MPE may be related to the abundance of monocyte/macrophages in malignant pleural effusions (PMID:15323357)
• Low expression of the TCR zeta chain is associated with tumor-infiltrating lymphocytes in renal cancer (PMID:15641485)
• nucleotides 672-1233 bp of TCR zeta 3’ UTR play a critical role in its stability and also have elements required for the translational regulation of TCR zeta chain expression in human T cells (PMID:15743765)
• the lower stability of zeta mRNA/exon 7(-) might be responsible for the reduced expression of the TCR/CD3 complex, including zeta protein, in SLE T cells (PMID:15749888)
• Expression of the constitutively tyrosine-phosphorylated T cell receptor zeta subunit (p21) in the absence of p23 promotes development of potentially autoreactive T cells in male antigen (HY) TCR-transgenic mice. (PMID:15879101)
• The decreased expression of CD3zeta is not caused by a decreased CD3zeta mRNA, an increased CD3zeta degradation or T cell apoptosis. (PMID:15922712)
• Type II PtdIns 4-kinase beta interacts with TCR-CD3 zeta chain. The C-terminal ITAM is critical for enzyme docking on the zeta chain. The association is tyrosyl phosphorylation dependent. Mutation of Y-151 & Y-142 disrupts interaction of the 2 proteins. (PMID:16337488)
• T cells expressing decreased zeta exhibit differential transcription patterns in systemic lupus erythematosus. (PMID:16393980)
• low CD3zeta expression would render T lymphocytes unable to control the growth of tumor cells (PMID:16616055)
• T lymphocytes from patients with active pulmonary tuberculosis (PTB) had significantly decreased expression of CD3zeta & absence of the p65/p50 heterodimer of NF- kappa B; findings provide a novel mechanism for the T cell dysfunction in patients with PTB (PMID:17054067)
• NMR structure of the zetazeta transmembrane dimer; mutagenesis experiments demonstrate that three polar positions are critical for zetazeta dimerization and assembly with TCR (PMID:17055436)
• simulations and experiments reveal that infrared line shapes are sensitive probes of membrane protein structural and environmental heterogeneity (PMID:17134238)
• These results revealed that the absent CD3zeta chain in cancer T lymphocytes was not replaced by FcRgamma either in fresh T cells or T-cell lines, in contrast to lupus T cells. (PMID:17134755)
• Immune recognition receptor TCR zeta cytoplasmic domain binds to acidic and mixed phospholipid vesicles with a binding strength that correlates with the protein net charge and the presence of clustered basic amino acid residues. (PMID:17176095)
• TCRzeta(dim) T cells accumulate in inflamed tissues in vivo and have intrinsic migratory activity in vitro. (PMID:17255353)
• These data demonstrate the unique properties of CD99 co-stimulation that distinguish this molecule from CD28 and other raft-resident co-stimulatory factors. (PMID:17464179)
• Since zeta-chain plays a key role in the transduction of the signal that follows antigen recognition by the TCR, its downregulation could be responsible for the deficient cellular immune response observed in hemodialysis patients (PMID:17951997)
• Sera from women with cervical intraepithelial neoplasia I, II, and III suppressed 58.9%, 75.3%, and 80.5% of CD3-zeta expression of Jurkat cells. (PMID:17997796)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cd247	ENSMUSG00000005763
rattus_norvegicus	Cd247	ENSRNOG00000003298

Protein

Protein identifiers

T-cell surface glycoprotein CD3 zeta chain — P20963 (reviewed: P20963)

Alternative names: T-cell receptor T3 zeta chain

All UniProt accessions (16): A0A8V8TPB2, A0A8V8TPD5, A0A8V8TPD9, A0A8V8TPP4, A0A8V8TPQ0, A0A8V8TPR5, A0A8V8TPS3, A0A8V8TPT5, A0A8V8TPX3, A0A8V8TQM0, A0A8V8TQN4, A0A8V8TQP3, A0A8V8TQY8, A0A8V8TR07, A9Y844, P20963

UniProt curated annotations — full annotation on UniProt →

Function. Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. When antigen presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD247/CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of downstream signaling pathways. CD247/CD3Z ITAMs phosphorylation creates multiple docking sites for the protein kinase ZAP70 leading to ZAP70 phosphorylation and its conversion into a catalytically active enzyme. Plays an important role in intrathymic T-cell differentiation. Additionally, participates in the activity-dependent synapse formation of retinal ganglion cells (RGCs) in both the retina and dorsal lateral geniculate nucleus (dLGN).

Subunit / interactions. The TCR-CD3 complex is composed of a CD3D-CD3E and a CD3G-CD3E heterodimers that preferentially associate with TCRalpha and TCRbeta, respectively, to form TCRalpha-CD3E-CD3G and TCRbeta/CD3G-CD3E trimers. In turn, the hexamer interacts with CD247/CD3Z homodimer to form the TCR-CD3 complex. Alternatively, TCRalpha and TCRbeta can be replaced by TCRgamma and TCRdelta. Interacts with SLA. Interacts with TRAT1. Interacts with DOCK2. Interacts with SLA2. Interacts with SHB. Interacts with ZAP70. Interacts (tyrosine phosphorylated) with SHC1 (via SH2 domain). Interacts with PTPRC. Interacts with CRK; this interaction regulates CD247/CD3Z phosphorylation. Interacts (on T cell side) with CD81, ICAM1 and CD9 at immunological synapses between antigen-presenting cells and T cells. Interacts with CD160. Interacts with LY6E. The signaling subunit of immunoglobulin gamma (IgG) Fc receptor complex. As a homodimer or a heterodimer with FCER1G, associates with the ligand binding subunit FCGR3A (via transmembrane domain); this interaction is a prerequisite for Fc receptor complex expression on the cell surface. Interacts with CD5. (Microbial infection) Interacts with HIV-1 Nef; this interaction up-regulates the expression of the Fas ligand (FASLG) at the cell surface. (Microbial infection) Interacts with HIV-2 Nef protein; this interaction induces down-regulation of cell surface TCR-CD3 complexes.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in normal lymphoid tissue and in peripheral blood mononuclear cells (PBMCs).

Post-translational modifications. Phosphorylated on Tyr residues after T-cell receptor triggering by LCK in association with CD4/CD8.

Disease relevance. Immunodeficiency 25 (IMD25) [MIM:610163] An immunological deficiency characterized by T-cells impaired immune response to alloantigens, tetanus toxoid and mitogens. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The ITAM domains mediate interaction with SHB.

Similarity. Belongs to the CD3Z/FCER1G family.

Isoforms (3)

UniProt ID	Names	Canonical?
P20963-1	1, CD-3-zeta	yes
P20963-2	2, CD-3-eta
P20963-3	3

RefSeq proteins (4): NP_000725, NP_001365444, NP_001365445, NP_932170* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003110	Phos_immunorcpt_sig_ITAM	Repeat
IPR021663	CD3_zeta/IgE_Fc_rcpt_gamma	Family
IPR024128	T-cell_CD3_zeta	Family

Pfam: PF02189, PF11628

UniProt features (27 total): modified residue 8, helix 4, domain 3, topological domain 2, region of interest 2, signal peptide 1, chain 1, compositionally biased region 1, splice variant 1, mutagenesis site 1, sequence conflict 1, turn 1, transmembrane region 1

Structure

Experimental structures (PDB)

38 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2OQ1	X-RAY DIFFRACTION	1.9
3IK5	X-RAY DIFFRACTION	2.05
8ES8	ELECTRON MICROSCOPY	2.65
4XZ1	X-RAY DIFFRACTION	2.8
1YGR	X-RAY DIFFRACTION	2.9
7FJE	ELECTRON MICROSCOPY	3
9CI8	ELECTRON MICROSCOPY	3.01
8ES7	ELECTRON MICROSCOPY	3.04
7PHR	ELECTRON MICROSCOPY	3.08
9JY1	ELECTRON MICROSCOPY	3.08
7FJF	ELECTRON MICROSCOPY	3.1
8TW6	ELECTRON MICROSCOPY	3.1
9IRU	ELECTRON MICROSCOPY	3.14
9IRS	ELECTRON MICROSCOPY	3.18
7FJD	ELECTRON MICROSCOPY	3.2
9JY2	ELECTRON MICROSCOPY	3.24
8ES9	ELECTRON MICROSCOPY	3.25
9CQ4	ELECTRON MICROSCOPY	3.27
9JY4	ELECTRON MICROSCOPY	3.29
8TW4	ELECTRON MICROSCOPY	3.3
9BBC	ELECTRON MICROSCOPY	3.3
9JXZ	ELECTRON MICROSCOPY	3.31
9JY3	ELECTRON MICROSCOPY	3.35
9CIA	ELECTRON MICROSCOPY	3.39
8JC0	ELECTRON MICROSCOPY	3.4
8ZA6	ELECTRON MICROSCOPY	3.43
9C3E	ELECTRON MICROSCOPY	3.5
9JY0	ELECTRON MICROSCOPY	3.69
3IOZ	X-RAY DIFFRACTION	3.7
6JXR	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20963-F1	62.36	0.08

Antibody-complex structures (SAbDab): 5 — 9CIA, 9CQ4, 9JY0, 9JY1, 9JY2

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 (8): 58, 64, 72, 83, 111, 123, 142, 153

Mutagenesis-validated functional residues (1):

Position	Phenotype
36	decreases cell surface expression of igg fc receptor complex.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-164944	Nef and signal transduction
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-202424	Downstream TCR signaling
R-HSA-202427	Phosphorylation of CD3 and TCR zeta chains
R-HSA-202430	Translocation of ZAP-70 to Immunological synapse
R-HSA-202433	Generation of second messenger molecules
R-HSA-2029481	FCGR activation
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-2029485	Role of phospholipids in phagocytosis
R-HSA-389948	Co-inhibition by PD-1
R-HSA-9664323	FCGR3A-mediated IL10 synthesis
R-HSA-9664422	FCGR3A-mediated phagocytosis

MSigDB gene sets: 526 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, REACTOME_INNATE_IMMUNE_SYSTEM, MYOGENIN_Q6, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, BIOCARTA_TCRA_PATHWAY, MODULE_45, MODULE_64, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION_TO_CELL_SURFACE, REACTOME_THE_ROLE_OF_NEF_IN_HIV_1_REPLICATION_AND_DISEASE_PATHOGENESIS, CAGCTG_AP4_Q5, GNF2_ZAP70, SREBP1_02, NFKB_C

GO Biological Process (10): adaptive immune response (GO:0002250), cell surface receptor signaling pathway (GO:0007166), Fc-gamma receptor signaling pathway (GO:0038094), gamma-delta T cell activation (GO:0046629), alpha-beta T cell activation (GO:0046631), T cell receptor signaling pathway (GO:0050852), protein complex oligomerization (GO:0051259), protein-containing complex assembly (GO:0065003), positive regulation of protein localization to cell surface (GO:2000010), immune system process (GO:0002376)

GO Molecular Function (7): transmembrane signaling receptor activity (GO:0004888), protein-macromolecule adaptor activity (GO:0030674), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982), protein tyrosine kinase binding (GO:1990782), protein binding (GO:0005515)

GO Cellular Component (9): cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), Fc-gamma receptor III complex (GO:0033001), T cell receptor complex (GO:0042101), alpha-beta T cell receptor complex (GO:0042105), gamma-delta T cell receptor complex (GO:0042106), membrane (GO:0016020), plasma membrane protein complex (GO:0098797)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
TCR signaling	4
Fcgamma receptor (FCGR) dependent phagocytosis	3
The role of Nef in HIV-1 replication and disease pathogenesis	1
Adaptive Immune System	1
Regulation of T cell activation by CD28 family	1
Anti-inflammatory response favouring Leishmania parasite infection	1
Leishmania phagocytosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
T cell activation	2
protein binding	2
protein dimerization activity	2
cellular anatomical structure	2
T cell receptor complex	2
immune response	1
signal transduction	1
Fc receptor signaling pathway	1
antigen receptor-mediated signaling pathway	1
protein-containing complex assembly	1
cellular component assembly	1
protein-containing complex organization	1
protein localization to cell surface	1
positive regulation of protein localization	1
regulation of protein localization to cell surface	1
biological_process	1
signaling receptor activity	1
molecular adaptor activity	1
identical protein binding	1
protein kinase binding	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
Fc receptor complex	1
plasma membrane signaling receptor complex	1
plasma membrane	1
membrane protein complex	1

Protein interactions and networks

STRING

2286 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD247	ZAP70	P43403	998
CD247	CD3D	P04234	998
CD247	CD3G	P09693	998
CD247	NCR1	O76036	995
CD247	FCGR3A	P08637	995
CD247	FCGR3B	O75015	994
CD247	CD3E	P07766	991
CD247	NCR3	O14931	990
CD247	TNFRSF9	Q07011	988
CD247	CD28	P10747	975
CD247	SYK	P43405	967
CD247	LCK	P06239	945
CD247	NCR2	O95944	935
CD247	CD8A	P01732	932
CD247	HCST	Q9UBK5	918

IntAct

73 interactions, top by confidence:

A	B	Type	Score
ZAP70	CD247	psi-mi:“MI:0915”(physical association)	0.920
ZAP70	CD247	psi-mi:“MI:0914”(association)	0.920
PTPN22	LCK	psi-mi:“MI:0914”(association)	0.780
CD247	CD247	psi-mi:“MI:0407”(direct interaction)	0.720
CD247	CD247	psi-mi:“MI:0915”(physical association)	0.720
ARRB1	CD247	psi-mi:“MI:0407”(direct interaction)	0.640

BioGRID (58): CD247 (Affinity Capture-Western), CD3E (Co-localization), DOCK2 (Co-localization), LCK (Affinity Capture-Western), ZAP70 (Affinity Capture-Western), RNF41 (Affinity Capture-Western), CD247 (Affinity Capture-Western), CD247 (Affinity Capture-Western), CD247 (Affinity Capture-Western), CD247 (Reconstituted Complex), ZAP70 (Affinity Capture-Western), CD247 (Affinity Capture-Western), ZAP70 (Affinity Capture-Western), FYN (Affinity Capture-Western), PIK3R1 (Affinity Capture-Western)

ESM2 similar proteins: A4F4L0, O00453, O14669, O43914, O54885, P04234, P04235, P07766, P0CAN6, P18438, P19377, P20963, P24161, P29328, P29329, P59646, Q13113, Q28072, Q28073, Q2KIP5, Q3TYX2, Q5R1Q1, Q5RA41, Q63113, Q64159, Q6AYD4, Q6ITQ4, Q6X9T7, Q764N2, Q8K1T1, Q8MII8, Q8N386, Q8NET5, Q8R182, Q8WNQ8, Q923S2, Q925F2, Q95J79, Q95LI5, Q95LI8

Diamond homologs: P20411, P20491, P20963, P24161, P29329, P30273, Q07249, Q8SPW1, Q9BDR7, Q9TUF8, Q9XSJ9, Q9XSZ6

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PTPN22	down-regulates	CD247	dephosphorylation
PTPN22	“down-regulates activity”	CD247	dephosphorylation
CD247	“form complex”	CD3	binding
LCK	up-regulates	CD247	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 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	8.8×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	0
Uncertain significance	68
Likely benign	98
Benign	27

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
12749	NM_198053.3(CD247):c.208C>T (p.Gln70Ter)	Pathogenic
12750	NM_198053.3(CD247):c.208_209inv (p.Gln70Trp)	Pathogenic
12751	NM_198053.3(CD247):c.209A>T (p.Gln70Leu)	Pathogenic
12752	NM_198053.3(CD247):c.208_210delinsTAT (p.Gln70Tyr)	Pathogenic
1367517	NM_198053.3(CD247):c.235C>T (p.Arg79Ter)	Pathogenic
162005	NM_198053.3(CD247):c.2T>C (p.Met1Thr)	Pathogenic
2427629	NC_000001.10:g.(?167487625)(167487702_?)del	Pathogenic
534695	NM_198053.3(CD247):c.51dup (p.Ile18fs)	Pathogenic

SpliceAI

2310 predictions. Top by Δscore:

Variant	Effect	Δscore
1:167431578:T:TA	donor_gain	1.0000
1:167431618:T:TA	donor_gain	1.0000
1:167433074:G:GC	acceptor_gain	1.0000
1:167434015:CTCA:C	donor_loss	1.0000
1:167434016:TCACC:T	donor_loss	1.0000
1:167434017:CACC:C	donor_loss	1.0000
1:167434018:A:C	donor_loss	1.0000
1:167434019:C:G	donor_loss	1.0000
1:167438569:CCGG:C	donor_gain	1.0000
1:167438576:T:A	donor_gain	1.0000
1:167438649:TCCTA:T	acceptor_loss	1.0000
1:167438651:C:A	acceptor_loss	1.0000
1:167439338:ACTT:A	donor_loss	1.0000
1:167439340:TTA:T	donor_loss	1.0000
1:167439341:T:TG	donor_loss	1.0000
1:167439342:A:AC	donor_gain	1.0000
1:167439342:A:C	donor_loss	1.0000
1:167439343:C:CG	donor_gain	1.0000
1:167439343:CG:C	donor_gain	1.0000
1:167439343:CGT:C	donor_gain	1.0000
1:167439396:CTGAA:C	acceptor_gain	1.0000
1:167439397:TGAA:T	acceptor_gain	1.0000
1:167439399:AA:A	acceptor_gain	1.0000
1:167439399:AAC:A	acceptor_loss	1.0000
1:167439401:C:CC	acceptor_gain	1.0000
1:167439401:C:CG	acceptor_loss	1.0000
1:167440660:CCA:C	donor_loss	1.0000
1:167440661:CA:C	donor_loss	1.0000
1:167440662:A:AT	donor_loss	1.0000
1:167440766:CT:C	acceptor_gain	1.0000

AlphaMissense

1072 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:167440699:C:G	G43R	0.988
1:167440698:C:T	G43D	0.986
1:167440695:A:T	V44D	0.983
1:167440683:G:T	A48D	0.979
1:167440732:A:G	C32R	0.979
1:167440717:C:G	G37R	0.978
1:167440717:C:T	G37R	0.978
1:167440716:C:T	G37E	0.977
1:167434046:A:G	Y123H	0.976
1:167440720:C:G	D36H	0.976
1:167440710:A:T	L39H	0.974
1:167440718:A:C	D36E	0.973
1:167440718:A:T	D36E	0.973
1:167440719:T:A	D36V	0.971
1:167434046:A:C	Y123D	0.969
1:167438623:A:G	Y83H	0.969
1:167440710:A:C	L39R	0.969
1:167440719:T:G	D36A	0.967
1:167431709:A:T	L156H	0.965
1:167440731:C:T	C32Y	0.965
1:167440720:C:T	D36N	0.961
1:167440730:G:C	C32W	0.961
1:167431730:G:A	T149I	0.958
1:167438622:T:C	Y83C	0.956
1:167440710:A:G	L39P	0.951
1:167440731:C:G	C32S	0.951
1:167440732:A:T	C32S	0.951
1:167431742:A:T	L145H	0.949
1:167431725:C:G	D151H	0.948
1:167440719:T:C	D36G	0.947

dbSNP variants (sampled 300 via entrez): RS1000028617 (1:167475816 G>A), RS1000047227 (1:167481058 G>T), RS1000067501 (1:167455427 C>T), RS1000077401 (1:167455144 A>G,T), RS1000080726 (1:167476112 G>A), RS1000087524 (1:167436535 T>C), RS1000131255 (1:167476411 T>C), RS1000219365 (1:167430613 G>A,T), RS1000288732 (1:167517817 C>A,T), RS1000303688 (1:167503299 T>C), RS1000331774 (1:167481891 G>A), RS1000338210 (1:167461080 C>T), RS1000360129 (1:167508916 T>C), RS1000377062 (1:167472928 A>G), RS1000528436 (1:167431600 C>T)

Disease associations

OMIM: gene MIM:186780 | disease phenotypes: MIM:610163

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 25	Strong	Autosomal recessive
T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunodeficiency 25	Definitive	AR

Mondo (3): immunodeficiency 25 (MONDO:0012426), severe combined immunodeficiency (MONDO:0015974), T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta (MONDO:0015703)

Orphanet (1): Severe combined immunodeficiency (Orphanet:183660)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000388	Otitis media
HP:0000501	Glaucoma
HP:0000518	Cataract
HP:0000554	Uveitis
HP:0000572	Visual loss
HP:0000585	Band keratopathy
HP:0001019	Erythroderma
HP:0001094	Iridocyclitis
HP:0001155	Abnormality of the hand
HP:0001369	Arthritis
HP:0001370	Rheumatoid arthritis
HP:0001371	Flexion contracture
HP:0001382	Joint hypermobility
HP:0001384	Abnormal hip joint morphology
HP:0001386	Joint swelling
HP:0001387	Joint stiffness
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001530	Mild postnatal growth retardation
HP:0001785	Ankle swelling
HP:0001824	Weight loss
HP:0001832	Abnormal metatarsal morphology
HP:0001880	Increased total eosinophil count
HP:0001888	Decreased total lymphocyte count
HP:0001890	Autoimmune hemolytic anemia
HP:0001903	Anemia
HP:0001945	Fever
HP:0002014	Diarrhea
HP:0002039	Anorexia

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST000612_16	Celiac disease	4.000000e-07
GCST000650_4	Systemic sclerosis	3.000000e-09
GCST000987_12	Celiac disease or Rheumatoid arthritis	2.000000e-11
GCST001146_3	Systemic sclerosis	1.000000e-06
GCST001160_1	Systemic sclerosis	3.000000e-06
GCST003987_22	Asthma	1.000000e-08
GCST005038_12	Allergic disease (asthma, hay fever or eczema)	4.000000e-14
GCST005336_2	Systemic sclerosis	6.000000e-06
GCST006911_4	Asthma (moderate or severe)	5.000000e-09
GCST007563_17	Allergic disease (asthma, hay fever or eczema)	5.000000e-10
GCST007564_4	Asthma or allergic disease (pleiotropy)	5.000000e-11
GCST007798_10	Asthma	5.000000e-21
GCST007798_11	Asthma	2.000000e-19
GCST007799_38	Asthma (adult onset)	8.000000e-11
GCST007800_76	Asthma (childhood onset)	3.000000e-22
GCST007932_82	Medication use (thyroid preparations)	7.000000e-10
GCST007941_54	Medication use (adrenergics, inhalants)	4.000000e-14
GCST007942_12	Medication use (glucocorticoids)	8.000000e-11
GCST008758_26	Pre-treatment viral load in HIV-1 infection	6.000000e-17
GCST008916_65	Asthma	9.000000e-10
GCST009131_2	Systemic sclerosis	1.000000e-11
GCST009719_14	Allergic rhinitis	3.000000e-10
GCST009720_87	Asthma	2.000000e-17
GCST009798_40	Asthma	8.000000e-11
GCST010042_102	Asthma	2.000000e-21
GCST010043_87	Asthma	3.000000e-22
GCST010571_81	Autoimmune thyroid disease	3.000000e-10
GCST90002381_7	Eosinophil count	7.000000e-15
GCST90002382_15	Eosinophil percentage of white cells	6.000000e-19
GCST90014325_5	Asthma	3.000000e-11

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:1002011	adult onset asthma
EFO:0009933	Thyroid preparation use measurement
EFO:0009941	Inhalant adrenergic use measurement
EFO:0009942	Glucocorticoid use measurement
EFO:0010125	viral load
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750
C565712	Immunodeficiency due to Defect in CD3-Zeta (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases methylation, increases expression	2
Acetaminophen	increases expression	2
Methotrexate	decreases expression	2
Paris saponin VII	decreases phosphorylation, affects cotreatment	1
triphenyl phosphate	affects expression	1
butyraldehyde	increases expression	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases phosphorylation, affects cotreatment	1
CGP 52608	increases reaction, affects binding	1
WP1066	affects cotreatment, decreases phosphorylation	1
licochalcone B	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Antineoplastic Agents, Immunological	increases expression	1
Fulvestrant	increases methylation	1
Arsenic	affects expression	1
Benzene	decreases expression, increases expression	1
Calcifediol	affects binding, affects cotreatment, increases expression, increases reaction, decreases reaction	1
Calcitriol	increases expression, increases reaction, increases abundance, decreases reaction, affects binding (+1 more)	1
Ketoconazole	increases abundance, affects binding, affects cotreatment, decreases reaction, increases expression (+1 more)	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Nickel	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	decreases expression	1

Cellosaurus cell lines

3 cell lines: 1 cancer cell line, 1 transformed cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7V9	Abcam Jurkat CD247 KO	Cancer cell line	Male
CVCL_E4AD	Genomeditech HEK-293 H_CD3	Transformed cell line	Female
CVCL_E4IL	Genomeditech CHO-K1 H_CD3	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00794508	PHASE2	COMPLETED	MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
NCT01182675	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02177760	PHASE2	WITHDRAWN	Sirolimus Prophylaxis for aGVHD in TME SCID
NCT03619551	PHASE2	ACTIVE_NOT_RECRUITING	Conditioning SCID Infants Diagnosed Early
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT00028236	PHASE1	COMPLETED	Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)
NCT00152100	PHASE1	COMPLETED	Transplantation of Hematopoietic Cells in Children With Severe Combined Immunodeficiency Syndrome
NCT02860559	PHASE1	UNKNOWN	Safety and Early Efficacy Study of TBX-1400 in Patients With Severe Combined Immunodeficiency
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT00228852	PHASE1/PHASE2	COMPLETED	IMM 0212: Busulfan With Fludarabine and Antithymocyte Globulin as Preparative Therapy for Hematopoietic Stem Cell Transplant for the Treatment of Severe Congenital T-Cell Immunodeficiency
NCT00579137	PHASE1/PHASE2	TERMINATED	Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders
NCT01129544	PHASE1/PHASE2	COMPLETED	Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT02127892	PHASE1/PHASE2	TERMINATED	SCID Bu/Flu/ATG Study With T Cell Depletion
NCT02963064	PHASE1/PHASE2	TERMINATED	JSP191 Antibody Targeting Conditioning in SCID Patients
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT03538899	PHASE1/PHASE2	RECRUITING	Autologous Gene Therapy for Artemis-Deficient SCID
NCT03597594	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)
NCT00001255	Not specified	COMPLETED	Gene Transfer Therapy for Severe Combined Immunodeficieny Disease (SCID) Due to Adenosine Deaminase (ADA) Deficiency: A Natural History Study
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00006335	Not specified	COMPLETED	Influences on Female Adolescents’ Decisions Regarding Testing for Carrier Status of XSCID
NCT00055172	Not specified	RECRUITING	Genetic Basis of Immunodeficiency
NCT00695279	Not specified	COMPLETED	Long Term Follow Up Of Patients Who Have Received Gene Therapy Or Gene Marked Products
NCT00845416	Not specified	COMPLETED	Newborn Screening for Severe Combined Immunodeficiency (SCID) in a High-Risk Population
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT01953016	Not specified	COMPLETED	Participation in a Research Registry for Immune Disorders
NCT02231983	Not specified	UNKNOWN	Clinical Characteristics and Genetic Profiles of Severe Combined Immunodeficiency in China
NCT02590328	Not specified	COMPLETED	Neonatal Screening of Severe Combined Immunodeficiencies
NCT04049084	Not specified	ENROLLING_BY_INVITATION	An Observational LTFU Study for Patients Previously Treated With Autologous ex Vivo Gene Therapy for ADA-SCID
NCT04172181	Not specified	UNKNOWN	Multi-center Clinical Study of Cord Blood Stem Cell Transplantation for SCID
NCT04246840	Not specified	COMPLETED	Study Through Imaging of Visceral Lymphoid Organs in Patients With SCID Who Have Recieved Bone Marrow Allograft
NCT04331483	Not specified	WITHDRAWN	A Study to Assess a Physical Activity Program in Children, Adolescents and Young Adults Requiring Hematopoietic Stem Cell Allografts