CD3G

Summary

CD3G (CD3 gamma subunit of T-cell receptor complex, HGNC:1675) is a protein-coding gene on chromosome 11q23.3, encoding T-cell surface glycoprotein CD3 gamma chain (P09693). 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 the CD3-gamma polypeptide, which together with CD3-epsilon, -delta and -zeta, and the T-cell receptor alpha/beta and gamma/delta heterodimers, forms the T-cell receptor-CD3 complex. This complex plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. The genes encoding the epsilon, gamma and delta polypeptides are located in the same cluster on chromosome 11. Defects in this gene are associated with T cell immunodeficiency.

Source: NCBI Gene 917 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined immunodeficiency due to CD3gamma deficiency (Definitive, ClinGen)
• Clinical variants (ClinVar): 175 total — 8 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 19
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000073

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1675
Approved symbol	CD3G
Name	CD3 gamma subunit of T-cell receptor complex
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	CD3-GAMMA, CD3GAMMA
Ensembl gene	ENSG00000160654
Ensembl biotype	protein_coding
OMIM	186740
Entrez	917

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000292144, ENST00000392883, ENST00000527777, ENST00000528540, ENST00000532903, ENST00000532917, ENST00000533462, ENST00000901817, ENST00000955602

RefSeq mRNA: 1 — MANE Select: NM_000073 NM_000073

CCDS: CCDS8395

Canonical transcript exons

ENST00000532917 — 7 exons

Exon	Start	End
ENSE00002145480	118353119	118355161
ENSE00003536254	118350552	118350683
ENSE00003597472	118351628	118351671
ENSE00003666226	118349743	118349970
ENSE00003682691	118352404	118352487
ENSE00003964676	118349027	118349050
ENSE00003964677	118344344	118344478

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 90.24.

FANTOM5 (CAGE): breadth broad, TPM avg 15.7272 / max 1020.5807, expressed in 258 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116990	9.1273	200
116991	6.4710	175
116989	0.0553	33
206461	0.0312	19
206462	0.0300	21
116988	0.0123	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	90.24	silver quality
lymph node	UBERON:0000029	90.14	gold quality
thymus	UBERON:0002370	89.58	gold quality
granulocyte	CL:0000094	89.51	gold quality
blood	UBERON:0000178	86.26	gold quality
vermiform appendix	UBERON:0001154	82.51	gold quality
colonic epithelium	UBERON:0000397	81.58	gold quality
superficial temporal artery	UBERON:0001614	81.14	gold quality
caecum	UBERON:0001153	77.80	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.97	silver quality
bone marrow cell	CL:0002092	76.16	gold quality
spleen	UBERON:0002106	75.41	gold quality
rectum	UBERON:0001052	74.01	gold quality
gall bladder	UBERON:0002110	73.45	gold quality
tonsil	UBERON:0002372	72.22	gold quality
diaphragm	UBERON:0001103	71.88	gold quality
bone marrow	UBERON:0002371	69.85	gold quality
small intestine Peyer’s patch	UBERON:0003454	69.65	gold quality
jejunal mucosa	UBERON:0000399	69.53	gold quality
olfactory bulb	UBERON:0002264	68.76	gold quality
type B pancreatic cell	CL:0000169	68.69	gold quality
cervix squamous epithelium	UBERON:0006922	68.65	gold quality
small intestine	UBERON:0002108	68.51	gold quality
palpebral conjunctiva	UBERON:0001812	68.20	gold quality
duodenum	UBERON:0002114	67.12	gold quality
mucosa of transverse colon	UBERON:0004991	66.89	gold quality
smooth muscle tissue	UBERON:0001135	64.83	gold quality
epithelium of nasopharynx	UBERON:0001951	63.21	silver quality
nasal cavity epithelium	UBERON:0005384	62.29	gold quality
upper lobe of left lung	UBERON:0008952	61.90	gold quality

Single-cell (SCXA)

Detected in 25 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-GEOD-75688	yes	2031.50
E-GEOD-70580	yes	1020.97
E-MTAB-6678	yes	859.67
E-MTAB-9221	yes	848.87
E-GEOD-149689	yes	553.91
E-CURD-46	yes	298.55
E-CURD-112	yes	293.09
E-MTAB-6701	yes	95.26
E-HCAD-4	yes	90.84
E-CURD-122	yes	76.69
E-MTAB-9467	yes	74.58
E-HCAD-1	yes	73.23
E-CURD-88	yes	33.92
E-HCAD-10	yes	28.19
E-MTAB-8410	yes	26.62

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFATC1, NFATC2, NFKB1

miRNA regulators (miRDB)

53 targeting CD3G, 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-3613-3P	100.00	76.36	7965
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-153-5P	99.89	73.86	6317
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-6817-3P	99.79	68.35	2126
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4777-5P	99.33	67.53	1148
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-422A	99.18	65.83	550
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-6895-3P	98.79	65.69	996
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-6818-3P	98.56	68.23	1307
HSA-MIR-378A-3P	98.43	66.10	548
HSA-MIR-378C	98.43	66.10	548
HSA-MIR-378D	98.43	66.10	548
HSA-MIR-378E	98.43	65.99	551
HSA-MIR-378I	98.43	66.10	548
HSA-MIR-378B	98.43	65.36	573
HSA-MIR-378F	98.43	65.66	554
HSA-MIR-378H	98.43	66.16	545
HSA-MIR-653-3P	98.31	67.71	1542
HSA-MIR-326	98.25	66.44	1565

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• human CD3gamma has specific NFAT binding motifs that differentially bind NFATc1, NFATc2, and NF-kappa B p50 (PMID:12374807)
• CD3 epsilon undergoes a conformational change after dimerization with CD3 gamma or CD3 delta (PMID:12410792)
• CD3 gamma contributes to, but is not absolutely required for, the regulation of T cell receptor trafficking in resting and antigen-stimulated mature T lymphocytes. (PMID:12794121)
• there is one molecule each of CD3delta and CD3gamma in the surface TCR/CD3 complex (PMID:15459203)
• significant rigidity was observed in use of the (D/E)xxxL(L/I) motif in CD3gamma, due to an absolute requirement for the position of this signal in the context of the TCR complex and for a highly conserved lysine residue, K128, not present in CD3delta (PMID:15778375)
• The CD3 gamma gene promoter is lymphoid specific, initiates transcription from multiple start sites and contains two core promoters capable of recruiting the general transcription machinery through specificity protein binding motifs. (PMID:15879122)
• CD3delta and CD3gamma play a different role in humans and mice in pre-TCR and TCR function during alphabeta T-cell development (PMID:16888097)
• Several amino acids are essential for an optimal association between CD3gamma and CD3 and the assembly of a cell-surface expressed TCR-CD3deltagammazeta2 complex. (PMID:16916653)
• analysis of TCRalpha-CD3deltaepsilon and TCRbeta-CD3gammaepsilon dimers and the role of the membrane-proximal tetracysteine motif (PMID:17023417)
• Protein level controlled by OTHER KINASES PROTEINS (PMID:1709425)
• The CD3 gamma immune recognition receptor 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)
• HTLV-I infection initiates a process leading to a complete loss of CD3 membrane expression by an epigenetic mechanism which continues along time, despite an early silencing of the viral genome. (PMID:17822534)
• In CD3gamma-deficient patients there can be substitution of CD3gamma by the CD3delta chain and which can then support gammadelta T cell development. (PMID:17923503)
• (Pre)malignant transformation in refractory celiac disease type II correlates with defective synthesis or defective association of the TCR chains, resulting in loss of surface TCR-CD3 expression (PMID:18815285)
• Stage-dependent molecular changes in Notch signaling that are critical for normal human T-cell development. (PMID:19056690)
• human eosinophils express a functional gammadeltaTCR/CD3 with similar, but not identical, characteristics to gammadeltaTCR from gammadeltaT cells (PMID:19536290)
• Data show CD3 epsilon pairs with CD3 gamma or with CD3 delta, forming CD3 epsilon gamma and CD3 epsilon delta heterodimers, which provide insight into our understanding of the molecular assembly of the CD3 molecular complex. (PMID:19724882)
• In this review, some of the genetic and epigenetic factors that determine the correct assembly and structure of the TCR/CD3 complex are summarized–REVIEW (PMID:19860678)
• When compared with other human T cell subsets, T cell receptor/CD3-activated Vgamma9Vdelta2-expressing T cells display an unusually delayed and sustained intracellular calcium mobilization, dramatically quickened and shortened on costimulation by NKG2D. (PMID:20511557)
• CD3gamma and CD3delta evolved from a common precursor gene to optimize major histocompatibility antigen (MHC)-triggered alphabeta T cell receptor activation. (PMID:20660709)
• Data show that the expression pattern of the four CD3 chains was epsilon>zeta>delta>gamma in peripheral blood mononuclear cells from MM, while a gamma>epsilon>zeta>delta expression pattern was found in healthy controls. (PMID:21669053)
• Study characterized the expression pattern of CD3-gamma, -delta, -epsilon and -zeta chain genes from placenta, which contributes to further understanding of the features of T-cell immune status in placenta. (PMID:21669059)
• A combination of trastuzumab antibody and phosphoantigen-stimulated gammadelta T-lymphocytes increases the efficacy of trastuzumab alone against HER-2-positive breast carcinoma cell lines in vivo and mammary carcinoma xenografts in mice. (PMID:21670311)
• Data show that TCRzeta phosphorylation signal pathways were affected in CD3gamma(-/-) primary and HVS-transformed T cells. (PMID:21764047)
• A transgenic T cell receptor gammadelta-low expressing subset of T cells accumulates in mouse epidermis after IL-23 injections. (PMID:21984702)
• Altered expression of the TCR signaling related genes CD3 and FcepsilonRIgamma in patients with aplastic anemia. (PMID:22401598)
• Data show that the expressions of CD3, CD4 were significantly associated with overall survival(OS) of non-small cell lung cancer (NSCLC) patients. (PMID:22482414)
• roles of CD3G polymorphisms in predisposition for HCC (PMID:22731821)
• The surface TCR expression of primary alphabeta and gammadelta T cells from healthy donors carrying a single null or leaky mutation in CD3G (gamma+/-) or CD3D (delta+/-, delta+/leaky) with that of normal controls, were compared. (PMID:23336327)
• In conclusion, TCR-gamma expression seems to be rare and is confined to cytotoxic primary cutaneous T-cell lymphomas (PMID:23348211)
• deficiency results in autoimmunity (PMID:23590417)
• Data indicate that the high CD68/CD3 ratio identifies a bad prognosis group among muscle-invasive urothelial carcinoma (UC). cases. (PMID:24794251)
• The results suggest that CD3G should be studied as a candidate gene for autoimmunity and that CD3gamma deficiency should be considered among other primary immunodeficiencies with predominantly autoimmune manifestations. (PMID:24910257)
• Case Report: T-cell lymphoblastic leukemia/lymphoma with t(7;14)(p15;q32) [TCRgamma-TCL1A translocation] confirmed by FISH. (PMID:24966976)
• Low cord blood Foxp3/CD3gamma mRNA ratios are highly predictive for early allergy development. (PMID:25113399)
• HER2/CD3 BsAb efficiently inhibited the growth of breast cancer tissue by activating and inducing the proliferation of tumor tissue infiltrating lymphocytes. (PMID:25760691)
• The study identifies an important role of the CD3gamma dileucine motif in T-cell development most probably mediated by its fine-tuning of pre-TCR and TCR expression, down-regulation and signaling. (PMID:25920998)
• CD3 showed a positive correlation with tryptase and microvascular density, while multiple regression analysis efficaciously predicted microvascular density depending on CD3 and tryptase as predictors, supporting a complex interplay between these cells in sustaining tumor angiogenesis in Diffuse large B cell lymphoma patients. (PMID:25957593)
• The docking site for CD3 subunits on the T Cell receptor beta chain has been identified by solution NMR. (PMID:26109064)
• These data demonstrate that the T-cell repertoire of patients with CD3G mutations is characterized by a molecular signature that may contribute to the increased rate of autoimmunity associated with this condition. (PMID:29653965)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cd3g	ENSMUSG00000002033
rattus_norvegicus	Cd3g	ENSRNOG00000015945

Paralogs (2): CD3D (ENSG00000167286), CD3E (ENSG00000198851)

Protein

Protein identifiers

T-cell surface glycoprotein CD3 gamma chain — P09693 (reviewed: P09693)

Alternative names: T-cell receptor T3 gamma chain

All UniProt accessions (5): P09693, A0A3B3IUD8, A8MUH3, B0YIY5, J3KNA5

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. In addition to this role of signal transduction in T-cell activation, CD3G plays an essential role in the dynamic regulation of TCR expression at the cell surface. Indeed, constitutive TCR cycling is dependent on the di-leucine-based (diL) receptor-sorting motif present in CD3G.

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.

Subcellular location. Cell membrane.

Post-translational modifications. Phosphorylated on Tyr residues after T-cell receptor triggering by LCK in association with CD4/CD8. Phosphorylated also by PKC; leading to the TCR complex down-regulation. Phosphorylated on Tyr residues after T-cell receptor triggering by LCK in association with CD4/CD8.

Disease relevance. Immunodeficiency 17 (IMD17) [MIM:615607] An autosomal recessive primary immunodeficiency characterized by highly variable clinical severity. Some patients have onset of severe recurrent infections in early infancy that may be lethal, whereas others may be only mildly affected or essentially asymptomatic into young adulthood. More severely affected patients may have evidence of autoimmune disease or enteropathy. The immunologic pattern is similar among patients, showing partial T-cell lymphopenia, decreased amounts of the CD3 complex, and impaired proliferative responses to T-cell receptor dependent stimuli. The phenotype in some patients is reminiscent of severe combined immunodeficiency. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. A di-leucine motif and a tyrosine-based motif are individually sufficient to induce both endocytosis and delivery to lysosomes.

RefSeq proteins (1): NP_000064* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003110	Phos_immunorcpt_sig_ITAM	Repeat
IPR003598	Ig_sub2	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015484	CD3_esu/gsu/dsu	Family
IPR032052	Ig_4	Domain
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF02189, PF16680

UniProt features (32 total): strand 8, mutagenesis site 7, glycosylation site 2, topological domain 2, helix 2, domain 2, modified residue 2, signal peptide 1, chain 1, disulfide bond 1, sequence variant 1, turn 1, transmembrane region 1, short sequence motif 1

Structure

Experimental structures (PDB)

38 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1SY6	X-RAY DIFFRACTION	2.1
7Q5U	X-RAY DIFFRACTION	2.4
8ES8	ELECTRON MICROSCOPY	2.65
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
9IPD	ELECTRON MICROSCOPY	3.29
9JY4	ELECTRON MICROSCOPY	3.29
8TW4	ELECTRON MICROSCOPY	3.3
9BBC	ELECTRON MICROSCOPY	3.3
9IPE	ELECTRON MICROSCOPY	3.31
9JXZ	ELECTRON MICROSCOPY	3.31
9JY3	ELECTRON MICROSCOPY	3.35
9CIA	ELECTRON MICROSCOPY	3.39
8JC0	ELECTRON MICROSCOPY	3.4
9IPC	ELECTRON MICROSCOPY	3.4
8ZA6	ELECTRON MICROSCOPY	3.43
9C3E	ELECTRON MICROSCOPY	3.5
9IP9	ELECTRON MICROSCOPY	3.64
9JY0	ELECTRON MICROSCOPY	3.69

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P09693-F1	75.05	0.23

Antibody-complex structures (SAbDab): 6 — 1SY6, 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 (2): 145, 148

Disulfide bonds (1): 46–87

Glycosylation sites (2): 52, 92

Mutagenesis-validated functional residues (7):

Position	Phenotype
153	abolishes lysosomal targeting.
153	diminished but persistent lysosomal targeting.
154	abolishes lysosomal targeting.
154	diminished but persistent lysosomal targeting.
154	no effect.
160	abolishes lysosomal targeting.
163	abolishes lysosomal targeting.

Function

Pathways and Gene Ontology

Reactome pathways

29 pathways

ID	Pathway
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-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-9664323	FCGR3A-mediated IL10 synthesis
R-HSA-9664422	FCGR3A-mediated phagocytosis
R-HSA-1280218	Adaptive Immune System
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-199991	Membrane Trafficking
R-HSA-202403	TCR signaling
R-HSA-2029480	Fcgamma receptor (FCGR) dependent phagocytosis
R-HSA-388841	Regulation of T cell activation by CD28 family
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5663205	Infectious disease
R-HSA-9658195	Leishmania infection
R-HSA-9662851	Anti-inflammatory response favouring Leishmania parasite infection
R-HSA-9664407	Parasite infection
R-HSA-9664417	Leishmania phagocytosis
R-HSA-9664433	Leishmania parasite growth and survival
R-HSA-9824443	Parasitic Infection Pathways

MSigDB gene sets: 356 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, BIOCARTA_TCRA_PATHWAY, GOBP_THYMIC_T_CELL_SELECTION, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, MODULE_64, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, GOBP_REGULATION_OF_LYMPHOCYTE_APOPTOTIC_PROCESS, REACTOME_MEMBRANE_TRAFFICKING, GOBP_REGULATION_OF_IMMUNE_RESPONSE, PID_CXCR4_PATHWAY

GO Biological Process (12): adaptive immune response (GO:0002250), establishment or maintenance of cell polarity (GO:0007163), cell surface receptor signaling pathway (GO:0007166), protein transport (GO:0015031), T cell activation (GO:0042110), positive thymic T cell selection (GO:0045059), gamma-delta T cell activation (GO:0046629), alpha-beta T cell activation (GO:0046631), T cell receptor signaling pathway (GO:0050852), protein-containing complex assembly (GO:0065003), regulation of lymphocyte apoptotic process (GO:0070228), immune system process (GO:0002376)

GO Molecular Function (5): transmembrane signaling receptor activity (GO:0004888), signaling receptor complex adaptor activity (GO:0030159), T cell receptor binding (GO:0042608), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (7): cytosol (GO:0005829), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), clathrin-coated endocytic vesicle membrane (GO:0030669), alpha-beta T cell receptor complex (GO:0042105), gamma-delta T cell receptor complex (GO:0042106), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
TCR signaling	4
Fcgamma receptor (FCGR) dependent phagocytosis	3
Adaptive Immune System	2
Immune System	2
Regulation of T cell activation by CD28 family	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
Anti-inflammatory response favouring Leishmania parasite infection	1
Leishmania phagocytosis	1
Vesicle-mediated transport	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
T cell activation	2
signaling receptor binding	2
cellular anatomical structure	2
T cell receptor complex	2
immune response	1
cellular process	1
signal transduction	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
lymphocyte activation	1
positive T cell selection	1
thymic T cell selection	1
antigen receptor-mediated signaling pathway	1
cellular component assembly	1
protein-containing complex organization	1
lymphocyte apoptotic process	1
regulation of leukocyte apoptotic process	1
biological_process	1
signaling receptor activity	1
signaling adaptor activity	1
protein-containing complex binding	1
protein binding	1
binding	1
cytoplasm	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
clathrin-coated vesicle membrane	1
endocytic vesicle membrane	1
clathrin-coated endocytic vesicle	1

Protein interactions and networks

STRING

1566 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD3G	CD3E	P07766	999
CD3G	CD247	P20963	998
CD3G	CD3D	P04234	986
CD3G	HMBS	P08396	857
CD3G	CD4	P01730	850
CD3G	E9PD41	E9PD41	792
CD3G	PTCRA	Q6ISU1	787
CD3G	ZAP70	P43403	759
CD3G	LCK	P06239	743
CD3G	CD8A	P01732	739
CD3G	THY1	P04216	719
CD3G	CD2	P06729	650
CD3G	ETS1	P14921	644
CD3G	PTPRC	P08575	641
CD3G	FCER1G	P30273	611

IntAct

30 interactions, top by confidence:

A	B	Type	Score
CD3G	TMEM19	psi-mi:“MI:0915”(physical association)	0.560
PMP22	CD3G	psi-mi:“MI:0915”(physical association)	0.560
TMEM262	CD3G	psi-mi:“MI:0915”(physical association)	0.560
LAT	CD3G	psi-mi:“MI:0915”(physical association)	0.560
CD3G	EMP1	psi-mi:“MI:0915”(physical association)	0.560
CD3G	MAL	psi-mi:“MI:0915”(physical association)	0.560
CD3G	TMEM203	psi-mi:“MI:0915”(physical association)	0.560
CD3G	KTN1	psi-mi:“MI:0915”(physical association)	0.560
CD3G	PMP22	psi-mi:“MI:0915”(physical association)	0.560
CD3G	TMEM54	psi-mi:“MI:0915”(physical association)	0.560
CD3E	CD3G	psi-mi:“MI:0914”(association)	0.350
CD3G	HKDC1	psi-mi:“MI:0914”(association)	0.350
TMEM262	CD3G	psi-mi:“MI:0915”(physical association)	0.000
LAT	CD3G	psi-mi:“MI:0915”(physical association)	0.000
EMP1	CD3G	psi-mi:“MI:0915”(physical association)	0.000
MAL	CD3G	psi-mi:“MI:0915”(physical association)	0.000
TMEM203	CD3G	psi-mi:“MI:0915”(physical association)	0.000
KTN1	CD3G	psi-mi:“MI:0915”(physical association)	0.000
TMEM54	CD3G	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (20): ZAP70 (Affinity Capture-Western), PIK3R1 (Affinity Capture-Western), GRB2 (Affinity Capture-Western), SHC1 (Affinity Capture-Western), CD3G (Affinity Capture-MS), CD3G (Two-hybrid), CD3G (Two-hybrid), CD3G (Two-hybrid), CD3G (Two-hybrid), CD3G (Two-hybrid), MAL (Two-hybrid), TMEM262 (Two-hybrid), TMEM203 (Two-hybrid), LAT (Two-hybrid), CD3G (Affinity Capture-Western)

ESM2 similar proteins: B7Z8K6, O02757, O09030, O35112, O46634, O46651, O95256, O95727, P01853, P01865, P01867, P01871, P01872, P03985, P03986, P06334, P06335, P09693, P0CF51, P0DSE1, P0DTI4, P10747, P12319, P12371, P13504, P16284, P20489, P23088, P31041, P31042, P31043, P42069, P42292, P43303, P51866, P97710, P97797, Q00609, Q01638, Q02955

Diamond homologs: P04234, P04235, P09693, P11942, P18438, P18439, P19377, Q28072, Q28073, Q28074, Q5PXD3, Q64159, Q764N2, Q95LI7, Q95LI8, Q98910, A4F4L0, O43914, O54885, Q6X9T7, Q8WNQ8, Q95J79, Q9TU45, Q5R1Q1

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
CD3G	up-regulates	RPS6KA4
CD3G	“form complex”	CD3	binding
LCK	“up-regulates activity”	CD3G	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	10
Uncertain significance	67
Likely benign	63
Benign	6

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1070478	NM_000073.3(CD3G):c.178A>T (p.Lys60Ter)	Pathogenic
12754	NC_000011.10:g.118349744_118349760del	Pathogenic
1452317	NM_000073.3(CD3G):c.71C>G (p.Ser24Ter)	Pathogenic
1457956	NM_000073.3(CD3G):c.496C>T (p.Arg166Ter)	Pathogenic
2053595	NM_000073.3(CD3G):c.513C>G (p.Tyr171Ter)	Pathogenic
2833798	NM_000073.3(CD3G):c.109C>T (p.Gln37Ter)	Pathogenic
4709890	NM_000073.3(CD3G):c.80-1G>C	Pathogenic
965164	NM_000073.3(CD3G):c.13A>T (p.Lys5Ter)	Pathogenic
1705260	NM_000073.3(CD3G):c.484-1G>A	Likely pathogenic
1964376	NM_000073.3(CD3G):c.70_79+5del	Likely pathogenic
2429328	NC_000011.9:g.(118215194_118219741)(118224498?)del	Likely pathogenic
2431635	NM_000073.3:c.70_80del	Likely pathogenic
3599122	NM_000073.3(CD3G):c.55+1G>T	Likely pathogenic
3599123	NM_000073.3(CD3G):c.56-1G>A	Likely pathogenic
3652400	NM_000073.3(CD3G):c.2T>A (p.Met1Lys)	Likely pathogenic
4712950	NM_000073.3(CD3G):c.2T>C (p.Met1Thr)	Likely pathogenic
4738867	NM_000073.3(CD3G):c.79+1G>A	Likely pathogenic
4845742	NM_000073.3(CD3G):c.56-2del	Likely pathogenic

SpliceAI

616 predictions. Top by Δscore:

Variant	Effect	Δscore
11:118344475:CAAGG:C	donor_loss	1.0000
11:118344476:AAGGT:A	donor_loss	1.0000
11:118344477:AGGTA:A	donor_loss	1.0000
11:118344478:GGTA:G	donor_loss	1.0000
11:118349887:G:GT	donor_gain	1.0000
11:118349887:G:T	donor_gain	1.0000
11:118349912:G:GT	donor_gain	1.0000
11:118349912:G:T	donor_gain	1.0000
11:118349921:GT:G	donor_gain	1.0000
11:118349968:G:GT	donor_gain	1.0000
11:118349968:GAA:G	donor_gain	1.0000
11:118349971:GTAT:G	donor_gain	1.0000
11:118350550:A:AG	acceptor_gain	1.0000
11:118350550:A:AT	acceptor_loss	1.0000
11:118350550:AGT:A	acceptor_gain	1.0000
11:118350550:AGTGT:A	acceptor_gain	1.0000
11:118350551:G:A	acceptor_loss	1.0000
11:118350551:G:GT	acceptor_gain	1.0000
11:118350551:GT:G	acceptor_gain	1.0000
11:118350551:GTG:G	acceptor_gain	1.0000
11:118350551:GTGT:G	acceptor_gain	1.0000
11:118350551:GTGTG:G	acceptor_gain	1.0000
11:118350680:AGAGG:A	donor_loss	1.0000
11:118350681:GAG:G	donor_gain	1.0000
11:118350681:GAGG:G	donor_loss	1.0000
11:118350682:AGGTA:A	donor_loss	1.0000
11:118350683:GGTA:G	donor_loss	1.0000
11:118350684:G:T	donor_loss	1.0000
11:118350685:T:A	donor_loss	1.0000
11:118352399:TCCA:T	acceptor_loss	1.0000

AlphaMissense

1191 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:118350617:A:C	S125R	0.994
11:118350619:C:A	S125R	0.994
11:118350619:C:G	S125R	0.994
11:118349922:T:A	C87S	0.986
11:118349923:G:C	C87S	0.986
11:118349828:G:C	W55C	0.985
11:118349828:G:T	W55C	0.985
11:118349916:T:G	Y85D	0.985
11:118349826:T:A	W55R	0.978
11:118349826:T:C	W55R	0.978
11:118349922:T:C	C87R	0.978
11:118349917:A:C	Y85S	0.974
11:118350554:T:A	C104S	0.974
11:118350555:G:C	C104S	0.974
11:118349794:T:C	L44P	0.972
11:118350638:G:A	G132R	0.972
11:118350638:G:C	G132R	0.972
11:118349799:T:A	C46S	0.971
11:118349800:G:C	C46S	0.971
11:118350554:T:C	C104R	0.971
11:118349917:A:G	Y85C	0.969
11:118349800:G:A	C46Y	0.964
11:118349799:T:C	C46R	0.963
11:118352408:T:A	L163H	0.963
11:118350565:C:G	C107W	0.960
11:118350563:T:A	C107S	0.959
11:118350564:G:C	C107S	0.959
11:118352432:A:G	Y171C	0.959
11:118349916:T:A	Y85N	0.956
11:118350563:T:C	C107R	0.956

dbSNP variants (sampled 300 via entrez): RS1000017693 (11:118348152 C>A), RS1000174259 (11:118347817 C>T), RS1000290709 (11:118351397 A>G), RS1000309145 (11:118354300 T>G), RS1000685405 (11:118351179 T>C,G), RS1000778716 (11:118344888 G>A), RS1001186408 (11:118348112 G>T), RS1001618801 (11:118348559 T>C), RS1001631135 (11:118352076 C>T), RS1001755145 (11:118354927 T>C), RS1002122472 (11:118355203 G>A), RS1002813795 (11:118342397 C>T), RS1003184050 (11:118345321 A>G), RS1003274770 (11:118346703 C>G,T), RS1003324230 (11:118349623 T>A,C)

Disease associations

OMIM: gene MIM:186740 | disease phenotypes: MIM:615607

GenCC curated gene-disease

Disease	Classification	Inheritance
combined immunodeficiency due to CD3gamma deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
combined immunodeficiency due to CD3gamma deficiency	Definitive	AR

Mondo (2): combined immunodeficiency due to CD3gamma deficiency (MONDO:0014276), severe combined immunodeficiency (MONDO:0015974)

Orphanet (2): Combined immunodeficiency due to CD3gamma deficiency (Orphanet:169082), Severe combined immunodeficiency (Orphanet:183660)

HPO phenotypes

19 total (20 of 19 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000403	Recurrent otitis media
HP:0000964	Eczematoid dermatitis
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001890	Autoimmune hemolytic anemia
HP:0002028	Chronic diarrhea
HP:0002205	Recurrent respiratory infections
HP:0002242	Abnormal intestine morphology
HP:0002721	Immunodeficiency
HP:0002846	Abnormal B cell morphology
HP:0003593	Infantile onset
HP:0003819	Death in childhood
HP:0005218	Anoperineal fistula
HP:0005403	Decreased total T cell count
HP:0005415	Decreased CD8+ T cell proportion
HP:0009098	Chronic oral candidiasis
HP:0031123	Recurrent gastroenteritis
HP:0041063	Chronic decreased circulating IgG2
HP:0004430	Severe combined immunodeficiency

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2364168 (PROTEIN COMPLEX)

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	2
Calcitriol	increases abundance, decreases reaction, affects binding, affects cotreatment, increases expression (+1 more)	2
triphenyl phosphate	affects expression	1
kojic acid	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
theaflavin-3,3’-digallate	affects expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arbutin	decreases expression	1
Benzene	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression	1
Calcifediol	affects binding, affects cotreatment, increases expression, increases reaction, decreases reaction	1
Dimethyl Sulfoxide	affects expression	1
Diuron	decreases expression	1
Ketoconazole	increases reaction, increases abundance, affects binding, affects cotreatment, decreases reaction (+1 more)	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment, decreases expression	1
Nickel	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	increases abundance, increases 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_E1G5	Abcam Jurkat CD3G 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