CD3E

Summary

CD3E (CD3 epsilon subunit of T-cell receptor complex, HGNC:1674) is a protein-coding gene on chromosome 11q23.3, encoding T-cell surface glycoprotein CD3 epsilon chain (P07766). 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-epsilon polypeptide, which together with CD3-gamma, -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. The epsilon polypeptide plays an essential role in T-cell development. Defects in this gene cause immunodeficiency. This gene has also been linked to a susceptibility to type I diabetes in women.

Source: NCBI Gene 916 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 18 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 309 total — 15 pathogenic, 6 likely-pathogenic (top 10% of genes corpus-wide)
• GTEx eGene: eQTL in 10 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 37
• Drug target: yes — 7 curated mechanism-of-action drugs, 16 via a complex or family
• Approved drugs (ChEMBL mechanism of action): 1 — Teplizumab
• Approved drugs acting on a complex or family including it: 10 — Blinatumomab, Catumaxomab, Elranatamab, +7 more (T cell surface glycoprotein CD3)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.47 (intermediate), LOEUF 0.66 (unconstrained)
• MANE Select transcript: NM_000733
• Interaction hub: 2,206 STRING partners (top 6% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1674
Approved symbol	CD3E
Name	CD3 epsilon subunit of T-cell receptor complex
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	CD3epsilon, CD3-epsilon
Ensembl gene	ENSG00000198851
Ensembl biotype	protein_coding
OMIM	186830
Entrez	916

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 4 retained_intron

MANE Select: ENST00000361763

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 4, TSL 5: 1

ENST00000361763, ENST00000526146, ENST00000528435, ENST00000528600, ENST00000529713, ENST00000531913, ENST00000853938, ENST00001003151, ENST00001003152, ENST00001091864, ENST00001130456, ENST00001140014

RefSeq mRNA: 1 — MANE Select: NM_000733 NM_000733

CCDS: CCDS31685

Canonical transcript exons

ENST00000361763 — 9 exons

Exon	Start	End
ENSE00001434986	118312618	118312866
ENSE00002191012	118304730	118304776
ENSE00003458929	118313707	118313874
ENSE00003463111	118314448	118314494
ENSE00003483202	118315486	118316173
ENSE00003502284	118307288	118307308
ENSE00003556358	118312153	118312170
ENSE00003572243	118308427	118308441
ENSE00003583529	118304894	118305001

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 99.17.

FANTOM5 (CAGE): breadth broad, TPM avg 29.2060 / max 1888.5282, expressed in 260 samples.

Highest expression (Bgee): granulocyte, vermiform appendix, lymph node, spleen, blood.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CD3E is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 10 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

11 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	1.3e-18	+0.12	11:118304825:A:G
Liver	eqtl	7.1e-05	+0.34	11:118313018:C:T
Artery Aorta	eqtl	6.5e-04	+0.16	11:118304724:G:A
Thyroid	sqtl	7.3e-03	-1.23	11:118265076:A:C
Brain Cortex	eqtl	1.3e-02	-0.93	11:118437370:CCTCTCGGGCGT:C
Ovary	eqtl	2.2e-02	-0.29	11:118807001:G:A
Spleen	eqtl	2.5e-02	+0.16	11:118282796:T:G
Esophagus Muscularis	eqtl	3.6e-02	-0.17	11:117913999:T:C
Skin Not Sun Exposed Suprapubic	eqtl	3.7e-02	+0.27	11:118170387:G:A
Muscle Skeletal	eqtl	3.9e-02	+0.19	11:118265445:G:A
Pancreas	eqtl	4.8e-02	-0.73	11:118659725:G:T

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
116971	29.0772	260
116974	0.1288	58

Top tissues by expression

showing 100 of 285 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.17	gold quality
vermiform appendix	UBERON:0001154	94.27	gold quality
lymph node	UBERON:0000029	93.65	gold quality
spleen	UBERON:0002106	93.22	gold quality
blood	UBERON:0000178	92.60	gold quality
colonic epithelium	UBERON:0000397	91.89	gold quality
thymus	UBERON:0002370	90.58	gold quality
gall bladder	UBERON:0002110	89.44	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.50	gold quality
rectum	UBERON:0001052	87.38	gold quality
ileal mucosa	UBERON:0000331	86.99	gold quality
mucosa of transverse colon	UBERON:0004991	86.99	gold quality
bone marrow cell	CL:0002092	85.62	gold quality
caecum	UBERON:0001153	85.42	gold quality
small intestine	UBERON:0002108	85.20	gold quality
bone marrow	UBERON:0002371	81.41	gold quality
upper lobe of left lung	UBERON:0008952	81.35	gold quality
superficial temporal artery	UBERON:0001614	79.74	silver quality
right lung	UBERON:0002167	79.39	gold quality
right coronary artery	UBERON:0001625	79.12	gold quality
right uterine tube	UBERON:0001302	78.62	gold quality
body of stomach	UBERON:0001161	78.40	gold quality
upper lobe of lung	UBERON:0008948	77.94	gold quality
omental fat pad	UBERON:0010414	77.17	gold quality
transverse colon	UBERON:0001157	77.16	gold quality
peritoneum	UBERON:0002358	77.07	gold quality
jejunal mucosa	UBERON:0000399	75.89	gold quality
adipose tissue of abdominal region	UBERON:0007808	75.69	gold quality
left uterine tube	UBERON:0001303	75.38	gold quality
tonsil	UBERON:0002372	75.09	gold quality
stomach	UBERON:0000945	74.66	gold quality
right lobe of liver	UBERON:0001114	74.00	gold quality
intestine	UBERON:0000160	73.09	gold quality
smooth muscle tissue	UBERON:0001135	72.68	gold quality
esophagus mucosa	UBERON:0002469	71.77	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	71.60	gold quality
right lobe of thyroid gland	UBERON:0001119	71.45	gold quality
duodenum	UBERON:0002114	71.43	gold quality
vagina	UBERON:0000996	71.19	gold quality
minor salivary gland	UBERON:0001830	70.97	gold quality
left lobe of thyroid gland	UBERON:0001120	70.86	gold quality
ectocervix	UBERON:0012249	70.32	gold quality
colon	UBERON:0001155	69.91	gold quality
thyroid gland	UBERON:0002046	69.73	gold quality
mucosa of stomach	UBERON:0001199	69.69	gold quality
large intestine	UBERON:0000059	69.58	gold quality
thoracic aorta	UBERON:0001515	69.53	gold quality
fundus of stomach	UBERON:0001160	69.37	gold quality
ascending aorta	UBERON:0001496	69.32	gold quality
esophagus	UBERON:0001043	68.65	gold quality
left coronary artery	UBERON:0001626	68.64	gold quality
lung	UBERON:0002048	68.56	gold quality
tibialis anterior	UBERON:0001385	68.30	silver quality
endocervix	UBERON:0000458	68.10	gold quality
urinary bladder	UBERON:0001255	68.09	gold quality
coronary artery	UBERON:0001621	67.93	gold quality
saliva-secreting gland	UBERON:0001044	67.75	gold quality
descending thoracic aorta	UBERON:0002345	67.45	gold quality
mouth mucosa	UBERON:0003729	67.17	gold quality
leukocyte	CL:0000738	66.86	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	66.77	gold quality
prostate gland	UBERON:0002367	66.55	gold quality
skin of abdomen	UBERON:0001416	65.91	gold quality
body of uterus	UBERON:0009853	65.83	gold quality
subcutaneous adipose tissue	UBERON:0002190	65.68	gold quality
right adrenal gland cortex	UBERON:0035827	65.53	gold quality
right atrium auricular region	UBERON:0006631	65.44	gold quality
lower esophagus	UBERON:0013473	64.92	gold quality
lower esophagus muscularis layer	UBERON:0035833	64.89	gold quality
lower esophagus mucosa	UBERON:0035834	64.85	gold quality
body of pancreas	UBERON:0001150	64.62	gold quality
right adrenal gland	UBERON:0001233	64.31	gold quality
spinal cord	UBERON:0002240	64.25	gold quality
left adrenal gland cortex	UBERON:0035825	64.21	gold quality
liver	UBERON:0002107	64.17	gold quality
cardiac atrium	UBERON:0002081	64.10	gold quality
adipose tissue	UBERON:0001013	64.07	gold quality
left adrenal gland	UBERON:0001234	63.97	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	63.85	gold quality
mononuclear cell	CL:0000842	63.76	gold quality
muscle layer of sigmoid colon	UBERON:0035805	63.61	gold quality
connective tissue	UBERON:0002384	63.29	gold quality
skin of leg	UBERON:0001511	63.13	gold quality
uterine cervix	UBERON:0000002	63.09	gold quality
sigmoid colon	UBERON:0001159	62.96	gold quality
aorta	UBERON:0000947	62.83	gold quality
adrenal cortex	UBERON:0001235	62.79	gold quality
monocyte	CL:0000576	62.76	gold quality
metanephros cortex	UBERON:0010533	62.74	gold quality
anatomical system	UBERON:0000467	62.47	gold quality
multicellular organism	UBERON:0000468	62.20	gold quality
material anatomical entity	UBERON:0000465	62.17	gold quality
adrenal gland	UBERON:0002369	62.17	gold quality
tibial nerve	UBERON:0001323	61.86	gold quality
zone of skin	UBERON:0000014	61.77	gold quality
hindlimb stylopod muscle	UBERON:0004252	61.48	gold quality
uterus	UBERON:0000995	61.20	gold quality
adult mammalian kidney	UBERON:0000082	60.93	gold quality
endometrium	UBERON:0001295	60.93	gold quality
right ovary	UBERON:0002118	60.88	gold quality

Single-cell (SCXA)

Detected in 29 experiment(s), a significant marker in 25.

Experiment	Marker?	Max mean expression
E-HCAD-15	yes	1339.00
E-CURD-122	yes	1278.26
E-CURD-88	yes	1155.31
E-MTAB-10042	yes	1147.01
E-MTAB-8142	yes	1061.36
E-GEOD-149689	yes	951.42
E-HCAD-4	yes	786.03
E-MTAB-8410	yes	781.05
E-GEOD-139324	yes	688.70
E-HCAD-1	yes	666.17
E-ANND-5	yes	644.63
E-CURD-112	yes	486.73
E-MTAB-9221	yes	426.04
E-MTAB-6701	yes	119.56
E-MTAB-9467	yes	88.73

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 72 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Thymus	tissue	596.2
Lymph node	tissue	196.3	high
Tonsil	tissue	137.8	high
Appendix	tissue	80.9	high
Spleen	tissue	74.4	medium
Bone marrow	tissue	34.6	medium
Small intestine	tissue	31.8	not detected
Urinary bladder	tissue	23.2	not detected
Stomach 1	tissue	22.9	not detected
Lung	tissue	21.7	not detected
Duodenum	tissue	20.7	not detected
Gallbladder	tissue	18.8	not detected
Rectum	tissue	18.1	not detected
Colon	tissue	14.4	not detected
Salivary gland	tissue	10.9	not detected
Liver	tissue	9.1	not detected
Esophagus	tissue	8.9	not detected
Cervix	tissue	6.7	not detected
Breast	tissue	6.3	not detected
Prostate	tissue	6.2	not detected
Spinal cord	tissue	5.7
Endometrium 1	tissue	5.5	not detected
Adipose tissue	tissue	5.4	not detected
Vagina	tissue	5.3	not detected
Adrenal gland	tissue	5.2	not detected
Skin 1	tissue	5.1	not detected
Fallopian tube	tissue	5.1	not detected
Corpus callosum	tissue	4.9
Smooth muscle	tissue	4.8	not detected
Epididymis	tissue	4.3	not detected
Substantia nigra	tissue	4.0
Olfactory bulb	tissue	3.8
Heart muscle	tissue	3.5	not detected
Amygdala	tissue	3.5
Medulla oblongata	tissue	3.5
Periaqueductal gray	tissue	3.3
Hypothalamus	tissue	3.2
Cerebral cortex	tissue	3.1	not detected
Ventral forebrain	tissue	3.1
Septum	tissue	3.1
Retrosplenial cortex	tissue	3.1
Temporal cortex	tissue	3.1
Insular cortex	tissue	3.1
Cerebellum	tissue	3.0	not detected
Basal ganglia	tissue	2.9	not detected
Hippocampal formation	tissue	2.9
Entorhinal cortex	tissue	2.9
Seminal vesicle	tissue	2.8	not detected
Superior colliculi	tissue	2.8
Thyroid gland	tissue	2.8	not detected
Prefrontal cortex	tissue	2.7
Pons	tissue	2.7
Retrosplenial and cingulate cortex	tissue	2.7
Putamen	tissue	2.6
Midbrain	tissue	2.6
Ovary	tissue	2.5	not detected
Thalamus	tissue	2.5
Motor cortex	tissue	2.4
Kidney	tissue	2.4	not detected
Occipital cortex	tissue	2.4

Brain sub-regions (HPA Brain Atlas): detected in 185; highest nTPM — Dorsal spinal cord (5.7), White matter (4.9), Blood vessel (4.8), Ventral spinal cord (4.3), Subiculum (2.8).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, DNMT1, FOS, GATA3, HAND2, HES1, HNF1A, NFATC2, NFIL3, NFKB1, NFKB, PAX3, STAT5A

miRNA regulators (miRDB)

Targeting CD3E by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 48 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-1207-5P	99.49	69.11	2983

Functional genomics

gnomAD constraint: pLI 0.469, LOEUF 0.659, missense Z 0.886 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000361763 — one region, missense o/e 0.88. ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 36)

• Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. (PMID:12110186)
• CD3 epsilon undergoes a conformational change after dimerization with CD3 gamma or CD3 delta (PMID:12410792)
• T cell receptor can be recruited to a subset of plasma membrane rafts, independently of cell signaling and attendantly to raft clustering (PMID:12499387)
• crystal structure at 1.9-A resolution of a complex between a CD3-epsilon/delta ectodomain heterodimer and a single-chain fragment of the UCHT1 antibody (PMID:15534202)
• SCID is caused by a CD3E deficiency. (PMID:15546002)
• CD3 expression was strong in normal proximal and distal tubular epithelium and in renal oncocytomas, weak in chromophobe carcinoma, and negative in clear cell carcinomas, in papillary renal cell carcinoma, and in a transitional cell carcinoma. (PMID:16308105)
• A human CD3 transgene that encodes full length CD3delta and a truncated but functional form of CD3epsilon restored the defective preTCR function in not only CD3epsilon- but CD3gamma- and CD3gammadelta-deficient mice as well. (PMID:16412509)
• analysis of TCRalpha-CD3deltaepsilon and TCRbeta-CD3gammaepsilon dimers and the role of the membrane-proximal tetracysteine motif (PMID:17023417)
• The CD3 epsilon 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)
• CD3epsilon-mediated signal transduction pathway is essential for this transformation process (PMID:17507663)
• Notch-dependent cytoplasmic CD3 expression can only be achieved during the early phase of NK-cell differentiation. (PMID:17630354)
• In lung adenocarcinoma patients, significant decreases of MFI values for CD3epsilon, but not CD3zeta, were found in CD4+T and CD8+T cells from pleural effusion compared to peripheral blood and in peripheral blood of patients compared to healthy donors. (PMID:17668204)
• Data show that Nck forms a complex with an atypical PxxDY motif of the CD3epsilon tail, which encompasses Tyr166 within the activation motif and a T-cell receptor endocytosis signal. (PMID:18555270)
• Data show that anti-CD3 monoclonal antibody (MAb)-mediated chimpanzee T-cell activation is a function of the anti-CD3 MAb isotype and is not governed by Siglec expression. (PMID:18667496)
• Results suggest that generation of CD3varepsilon chain isoforms with different N-terminal sequence and pI is a general phenomenon. (PMID:19616027)
• Results revealed that the human CD3 epsilon subunit forms a homodimer structure, which provide insight into our understanding of the molecular assembly of the CD3 molecular complex. (PMID:19724882)
• analysis of the transgenic integration site in immunodeficient tgepsilon26 human CD3epsilon transgenic mice (PMID:21203507)
• 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)
• Results show that levels of CD3epsilon, CD25, CD68, and ICAM-1 mRNA in BCC biopsies may predict risk for new basal cell carcinomas. (PMID:21980389)
• Altered expression of the TCR signaling related genes CD3 and FcepsilonRIgamma in patients with aplastic anemia. (PMID:22401598)
• Local changes in the lipid composition of TCR microclusters render the CD3epsilon cytoplasmic domain accessible during early stages of T cell activation. (PMID:23166358)
• ABCB1 homozygous 3435 TT carrier subjects showed the lowest Pgp activity compared with 3435 CT and CC carriers of renal transplant patients. (PMID:23216707)
• that Nck recruitment to the TCR is fundamental to mount an efficient T cell response in vivo, and that the Nck-CD3epsilon interaction may represent a target for pharmacological modulation of the immune response. (PMID:24470497)
• analysis of the molecular organization of the TCR-CD3 complex (PMID:25422432)
• The docking site for CD3 subunits on the T Cell receptor beta chain has been identified by solution NMR. (PMID:26109064)
• The inducible recruitment of WASp to the TCR-CD3 complex is partially dependent of tyrosine phosphorylation of Cd3e. (PMID:26342115)
• Data suggest that HIV-1 gp41 transmembrane domain (TMD) directly interacts with TMDs of the T-cell receptor and it’s CD3-antigen co-receptors (delta, gamma, and epsilon); these interactions appear to be involved in immune evasion mechanism of HIV-1. (PMID:26828096)
• increase. Our results indicate that the change in CD3zeta-chain expression from the baseline is an independent predictor of residual and recurrent head and neck squamous cell carcinoma. (PMID:26888626)
• the stalk domains of NKp30 and NKp46, another NCR employing CD3zeta for signaling, were not exchangeable without drastic deficiencies in folding, plasma membrane targeting, and/or ligand-induced receptor signaling. (PMID:27754869)
• A novel pathogenic frameshift variant of CD3E gene has been found in two unrelated T-B+ NK+ severe combined immunodeficiency infants from Turkey. (PMID:28597365)
• The ionic CD3-epsilon -Lck interaction controls the phosphorylation level of the T-cell receptor. (PMID:28659468)
• Actin polymerization promotes the recruitment of Nck to the TCR, enhancing downstream signaling, such as phosphorylation of CD3epsilon and lymphocyte activation. (PMID:31674657)
• Biallelic Form of a Known CD3E Mutation in a Patient with Severe Combined Immunodeficiency. (PMID:32016651)
• Multiple Signaling Roles of CD3epsilon and Its Application in CAR-T Cell Therapy. (PMID:32730808)
• Low transcriptomic of PTPRCv1 and CD3E is an independent predictor of mortality in HIV and tuberculosis co-infected patient. (PMID:35710869)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cd3e	ENSMUSG00000032093
rattus_norvegicus	Cd3e	ENSRNOG00000016069

Paralogs (2): CD3G (ENSG00000160654), CD3D (ENSG00000167286)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88332) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 26 distinct phenotype terms.

Mouse phenotype (MP)	Records
arrested T cell differentiation	4
absent T cells	3
abnormal T cell differentiation	2
decreased double-positive T cell number	2
abnormal thymus morphology	1
small thymus	1
absent CD8-positive, alpha-beta T cells	1
thymus hypoplasia	1
seizures	1
abnormal double-negative T cell morphology	1
abnormal double-positive T cell morphology	1
absent CD4-positive, alpha-beta T cells	1
abnormal class switch recombination	1
abnormal B cell morphology	1
abnormal regulatory T cell physiology	1
increased double-negative T cell number	1
abnormal T cell number	1
increased T cell apoptosis	1
abnormal T cell morphology	1
decreased CD4-positive, alpha-beta T cell number	1
increased CD8-positive, alpha-beta T cell number	1
abnormal CD8-positive, alpha-beta T cell differentiation	1
increased susceptibility to induced morbidity/mortality	1
increased DN3 thymocyte number	1
increased central memory CD8-positive, alpha-beta T cell number	1

+1 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Ovis aries	P29328	84.9%	Diamond
Bos taurus	Q28073	84.9%	Diamond
Macaca fascicularis	Q95LI5	68.1%	Diamond
Sus scrofa	Q7YRN2	67.7%	Diamond
Oryctolagus cuniculus	Q9TUF9	60.6%	Diamond
Canis lupus familiaris	P27597	60.4%	Diamond
Felis catus	Q5R1Q1	60.4%	Diamond
Gallus gallus	Q98910	42.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
JAML	protein-coding	120425
MPZL3	protein-coding	196264
CD3D	protein-coding	915
MPZL2	protein-coding	10205
SCN2B	protein-coding	6327
ATP5MG	protein-coding	10632
CD3G	protein-coding	917
UBE4A	protein-coding	9354

Protein

Protein identifiers

T-cell surface glycoprotein CD3 epsilon chain — P07766 (reviewed: P07766)

Alternative names: T-cell surface antigen T3/Leu-4 epsilon chain

All UniProt accessions (2): E9PSH8, P07766

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. CD3E ITAM phosphorylation creates docking sites for the protein kinase ZAP70 leading to ZAP70 phosphorylation and its conversion into a catalytically active enzyme. In addition of this role of signal transduction in T-cell activation, CD3E plays an essential role in correct T-cell development. Also participates in internalization and cell surface down-regulation of TCR-CD3 complexes via endocytosis sequences present in CD3E cytosolic region. In addition to its role as a TCR coreceptor, it serves as a receptor for ITPRIPL1. Ligand recognition inhibits T-cell activation by promoting interaction with NCK1, which prevents CD3E-ZAP70 interaction and blocks the ERK-NFkB signaling cascade and calcium influx.

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 CD6. Interacts (via Proline-rich sequence) with NCK1; the interaction is ligand dependent but independent of tyrosine kinase activation. Interacts with NUMB; this interaction is important for TCR-CD3 internalization and subsequent degradation. Interacts (when tyrosine phosphorylated) with LAG3; disrupting the association between CD3E and LCK and preventing TCR activation.

Subcellular location. Cell membrane.

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

Disease relevance. Immunodeficiency 18 (IMD18) [MIM:615615] An autosomal recessive primary immunodeficiency characterized by onset in infancy or early childhood of recurrent infections. The severity is variable, encompassing both a mild immunodeficiency and severe combined immunodeficiency (SCID), resulting in early death without bone marrow transplantation in some patients. Immunologic work-up of the IMD18 SCID patients shows a T cell-negative, B cell-positive, natural killer (NK) cell-positive phenotype, whereas T-cell development is not impaired in the mild form of IMD18. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_000724* (*=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
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF02189, PF16681

UniProt features (30 total): strand 10, helix 7, region of interest 3, modified residue 2, topological domain 2, domain 2, signal peptide 1, chain 1, disulfide bond 1, transmembrane region 1

Structure

Experimental structures (PDB)

showing 30 of 44 structures by resolution:

PDB	Title	Method	Resolution (Å)
5QU2	Crystal Structure of human Nck SH3.1 in complex with peptide PPPVPNPDY	X-RAY DIFFRACTION	1.04
9T46	Crystal structure of the Fab 40G5c in complex with a CD3 epsilon peptide	X-RAY DIFFRACTION	1.65
8VY4	Engineering a Tumor-Selective Prodrug T Cell Engager Bispecific Antibody for Safer …	X-RAY DIFFRACTION	1.7
8F0L	Crystal Structure of the Human T cell Receptor CD3(EPSILON) N-Terminal Peptide Complexed …	X-RAY DIFFRACTION	1.81
1XIW	Crystal structure of human CD3-e/d dimer in complex with a UCHT1 single-chain antibody …	X-RAY DIFFRACTION	1.9
1SY6	Crystal Structure of CD3gammaepsilon Heterodimer in Complex with OKT3 Fab Fragment	X-RAY DIFFRACTION	2.1
8ES8	CryoEM structure of PN45545 TCR-CD3 in complex with HLA-A2 MAGEA4 (230-239)	ELECTRON MICROSCOPY	2.65
1A81	CRYSTAL STRUCTURE OF THE TANDEM SH2 DOMAIN OF THE SYK KINASE BOUND TO A DUALLY …	X-RAY DIFFRACTION	3
7FJE	Cryo-EM structure of a membrane protein(LL)	ELECTRON MICROSCOPY	3
9CI8	T cell receptor complex	ELECTRON MICROSCOPY	3.01
8ES7	CryoEM structure of PN45545 TCR-CD3 complex	ELECTRON MICROSCOPY	3.04
7PHR	Structure of a fully assembled T-cell receptor engaging a tumor-associated peptide-MHC I	ELECTRON MICROSCOPY	3.08
9JY1	delta epsilon/delta epsilon Fab-TCR tetramer	ELECTRON MICROSCOPY	3.08
7FJF	Cryo-EM structure of a membrane protein(CS)	ELECTRON MICROSCOPY	3.1
8TW6	TCR in nanodisc ND-II	ELECTRON MICROSCOPY	3.1
9IRU	Cryo-em structure of TCR-4B1 complex	ELECTRON MICROSCOPY	3.14
9IRS	Cryo-EM structure of the TCR-OKT3 complex	ELECTRON MICROSCOPY	3.18
7FJD	Cryo-EM structure of a membrane protein(WT)	ELECTRON MICROSCOPY	3.2
9JY2	Fab-CD3-delta epsilon-TCR complex	ELECTRON MICROSCOPY	3.24
8ES9	CryoEM structure of PN45428 TCR-CD3 in complex with HLA-A2 MAGEA4	ELECTRON MICROSCOPY	3.25
9CQ4	G115 gamma delta TCR/CD3 complex bound by OKT3 Fab	ELECTRON MICROSCOPY	3.27
9IPD	Poly-alanine model for LH-type bispecific diabody Ex3 composed of 528 and OKT3 Fvs in …	ELECTRON MICROSCOPY	3.29
9JY4	gamma epsilon/gamma epsilon Fab-TCR tetramer	ELECTRON MICROSCOPY	3.29
8TW4	TCR in nanodisc ND-I	ELECTRON MICROSCOPY	3.3
9BBC	TCR GDN detergent micelle	ELECTRON MICROSCOPY	3.3
9IPE	Poly-alanine model for LH-type bispecific diabody Ex3 composed of 528 and OKT3 Fvs in …	ELECTRON MICROSCOPY	3.31
9JXZ	V gamma9 V delta2 TCR and CD3 complex	ELECTRON MICROSCOPY	3.31
9JY3	delta epsilon/gamma epsilon Fab-TCR tetramer	ELECTRON MICROSCOPY	3.35
9CIA	T cell receptor complex	ELECTRON MICROSCOPY	3.39
8JC0	V gamma9 V delta2 TCR and CD3 complex in LMNG	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07766-F1	73.56	0.30

Antibody-complex structures (SAbDab)

11 antibodies co-crystallized with this protein: 1SY6, 1XIW, 8F0L, 8VY4, 9CIA, 9CQ4, 9JY0, 9JY1, 9JY2, BLONTUVETMAB, MUROMONAB

Human Protein Atlas

Protein class: CD markers, Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Disease related genes, FDA approved drug targets, Biotech drugs, Human disease related genes, Primary immunodeficiency

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): endoplasmic reticulum; plasma membrane; golgi apparatus

Antibody reliability (HPA): IH enhanced · IF supported

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)

Type	Positions
Phosphotyrosine	188, 199

Disulfide bonds (1)

Type	Positions
Disulfide bond	49–98

Function

Pathways and Gene Ontology

Reactome pathways

6 curated (TAS) of 10; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

10 pathways:

ID	Pathway	Evidence
R-HSA-389948	Co-inhibition by PD-1	curated
R-HSA-202424	Downstream TCR signaling	curated
R-HSA-202433	Generation of second messenger molecules	curated
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	curated
R-HSA-202427	Phosphorylation of CD3 and TCR zeta chains	curated
R-HSA-202430	Translocation of ZAP-70 to Immunological synapse	curated
R-HSA-1280218	Adaptive Immune System	—
R-HSA-168256	Immune System	—
R-HSA-388841	Regulation of T cell activation by CD28 family	—
R-HSA-202403	TCR signaling	—

MSigDB gene sets: 446 (showing top): FERRANDO_TAL1_NEIGHBORS, GOBP_DENDRITE_DEVELOPMENT, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, MORF_FLT1, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_TOLERANCE_INDUCTION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, BIOCARTA_TCRA_PATHWAY, GOBP_THYMIC_T_CELL_SELECTION, MODULE_45, MODULE_64

GO Biological Process (21): positive regulation of cell-matrix adhesion (GO:0001954), adaptive immune response (GO:0002250), cell surface receptor signaling pathway (GO:0007166), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), signal complex assembly (GO:0007172), G protein-coupled receptor signaling pathway (GO:0007186), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), dendrite development (GO:0016358), cerebellum development (GO:0021549), positive regulation of cell-cell adhesion mediated by integrin (GO:0033634), positive regulation of T cell proliferation (GO:0042102), T cell activation (GO:0042110), regulation of apoptotic process (GO:0042981), 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), immune system process (GO:0002376), regulation of signal transduction (GO:0009966)

GO Molecular Function (9): transmembrane signaling receptor activity (GO:0004888), SH3 domain binding (GO:0017124), protein kinase binding (GO:0019901), signaling receptor complex adaptor activity (GO:0030159), protein-macromolecule adaptor activity (GO:0030674), T cell receptor binding (GO:0042608), identical protein binding (GO:0042802), protein binding (GO:0005515), MHC class II receptor activity (GO:0032395)

GO Cellular Component (9): immunological synapse (GO:0001772), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), external side of plasma membrane (GO:0009897), T cell receptor complex (GO:0042101), alpha-beta T cell receptor complex (GO:0042105), dendritic spine (GO:0043197), cell body (GO:0044297), membrane (GO:0016020)

Reactome top-level categories

4 top-level categories:

Category	Pathways
TCR signaling	4
Adaptive Immune System	3
Regulation of T cell activation by CD28 family	1
Immune System	1

GO top-level categories

59 GO namespaces:

Category	Terms
cellular anatomical structure	3
signal transduction	2
gene expression	2
regulation of gene expression	2
T cell activation	2
signaling receptor binding	2
protein binding	2
plasma membrane	2
regulation of cell-matrix adhesion	1
cell-matrix adhesion	1
positive regulation of cell-substrate adhesion	1
immune response	1
enzyme-linked receptor protein signaling pathway	1
regulation of signal transduction	1
protein-containing complex assembly	1
G protein-coupled receptor activity	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
neuron projection development	1
anatomical structure development	1
metencephalon development	1
animal gross anatomical part developmental process	1
positive regulation of cell-cell adhesion	1
positive regulation of cell adhesion mediated by integrin	1
cell-cell adhesion mediated by integrin	1
regulation of cell-cell adhesion mediated by integrin	1
T cell proliferation	1
regulation of T cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of T cell activation	1
lymphocyte activation	1
apoptotic process	1
regulation of programmed cell death	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
biological_process	1
signaling receptor activity	1
protein domain specific binding	1
kinase binding	1
signaling adaptor activity	1
molecular adaptor activity	1
protein-containing complex binding	1
binding	1
transmembrane signaling receptor activity	1
MHC class II protein binding	1
immune receptor activity	1
membrane	1
cell periphery	1
anchoring junction	1
cell surface	1
side of membrane	1
plasma membrane signaling receptor complex	1
T cell receptor complex	1
dendrite	1
neuron spine	1
postsynapse	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 39 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
T cell receptor signaling pathway	BP	direct assay
negative regulation of gene expression	BP	mutant phenotype
positive regulation of T cell proliferation	BP	mutant phenotype
positive regulation of gene expression	BP	mutant phenotype
T cell receptor complex	CC	direct assay
alpha-beta T cell receptor complex	CC	direct assay
external side of plasma membrane	CC	direct assay
plasma membrane	CC	direct assay
SH3 domain binding	MF	physical interaction
identical protein binding	MF	direct assay
protein-macromolecule adaptor activity	MF	direct assay
transmembrane signaling receptor activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,206 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD3E	CD3D	P04234	974
CD3E	CD3G	P09693	959
CD3E	CD4	P01730	868
CD3E	CD247	P20963	857
CD3E	CD8A	P01732	850
CD3E	PTPRC	P08575	822
CD3E	AOC3	Q16853	800
CD3E	FOXP3	Q9BZS1	788
CD3E	THY1	P04216	785
CD3E	CD19	P15391	779
CD3E	LCK	P06239	773
CD3E	ITGAM	P11215	757
CD3E	CD28	P10747	749
CD3E	CD79A	P11912	735
CD3E	E9PD41	E9PD41	735

IntAct

Human interaction partners of CD3E in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

23 partners by confidence:

Partner	Interaction type	MIscore	Records
EPS8L1	physical association	0.750	6
NCK1	physical association	0.740	6
NCK2	physical association	0.680	4
SYK	association	0.600	6
ADAM33	physical association	0.560	3
BNIP3	physical association	0.560	3
MUC15	physical association	0.560	3
PKMYT1	physical association	0.560	3
ZFPL1	physical association	0.560	3
ZAP70	association	0.530	3
EPS8	physical association	0.400	1
EPS8L2	physical association	0.400	1
EPS8L3	physical association	0.400	1
NCR1	physical association	0.400	1
CCR7	physical association	0.370	1
CD3D	association	0.350	1
CD3G	association	0.350	1
GHDC	association	0.350	1
HLA-A	association	0.350	1
LCK	association	0.350	1
SHC1	association	0.350	1
TMEM131L	association	0.350	1
CD247	proximity	0.270	1

BioGRID (89 interactions; top human partners by supporting records): NCK2 (Two-hybrid; 4 records), C10orf35 (Affinity Capture-MS; 3 records), CD247 (Co-localization; 3 records), GHDC (Affinity Capture-MS; 3 records), LNPEP (Affinity Capture-MS; 3 records), NCK1 (Affinity Capture-Western; 3 records), UBASH3A (Affinity Capture-Western; 3 records), ZAP70 (Affinity Capture-Western; 3 records), CD38 (Affinity Capture-Western; 2 records), CD3EAP (Affinity Capture-Western; 2 records), EPS8L1 (Affinity Capture-Western; 2 records), FCRL3 (Proximity Label-MS; 2 records), GP1BB (Affinity Capture-MS; 2 records), ITPRIPL1 (Affinity Capture-MS; 2 records), LCK (Affinity Capture-Western; 2 records)

SIGNOR signaling

showing 4 of 6 signaling interactions:

A	Effect	B	Mechanism
CD3E	“form complex”	CD3	binding
CD3E	“up-regulates activity”	NCK1	relocalization
STOML2	“up-regulates activity”	CD3E	binding
LCK	“up-regulates activity”	CD3E	phosphorylation

Protein complexes (CORUM) (2)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

2 complexes by size:

Complex	Subunits	Members
★ TCR-CD3 complex	6	CD247, CD3D, CD3E, CD3G, TRA, TRB
★ CD3-LAG3-TCR complex	6	CD3D, CD3E, CD3G, LAG3, TRA, TRB

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 23 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
Translocation of ZAP-70 to Immunological synapse	5	176.2×	5e-09
Generation of second messenger molecules	6	115.3×	1e-09
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	5	24.2×	4e-05
Adaptive Immune System	6	9.9×	2e-04
Innate Immune System	5	7.1×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
T cell activation	5	61.7×	1e-06
T cell receptor signaling pathway	6	43.4×	6e-07
adaptive immune response	5	20.1×	1e-04

Disease & clinical

Genetic variants

Variant evidence for CD3E: 309 ClinVar records (21 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	6
Uncertain significance	87
Likely benign	151
Benign	25

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 21 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
2735762	NM_000733.4(CD3E):c.49+1G>C	Pathogenic	criteria provided, multiple submitters, no conflicts	2
3340358	NM_000733.4(CD3E):c.173del (p.Leu58fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
835442	NM_000733.4(CD3E):c.103+1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	4
847887	NM_000733.4(CD3E):c.261_262del (p.Ser88fs)	Pathogenic	criteria provided, single submitter	1
847888	NM_000733.4(CD3E):c.490C>T (p.Arg164Ter)	Pathogenic	criteria provided, single submitter	1
2704456	NM_000733.4(CD3E):c.190A>T (p.Lys64Ter)	Pathogenic	criteria provided, single submitter	1
2735763	NM_000733.4(CD3E):c.428del (p.Gly143fs)	Pathogenic	criteria provided, single submitter	1
2786487	NM_000733.4(CD3E):c.49+1G>A	Pathogenic	criteria provided, single submitter	1
2864291	NM_000733.4(CD3E):c.472A>T (p.Lys158Ter)	Pathogenic	criteria provided, single submitter	1
3647560	NM_000733.4(CD3E):c.310A>T (p.Lys104Ter)	Pathogenic	criteria provided, single submitter	1
4721598	NM_000733.4(CD3E):c.416dup (p.Cys139fs)	Pathogenic	criteria provided, single submitter	1
12744	NM_000733.4(CD3E):c.520+2T>C	Likely pathogenic	criteria provided, single submitter	2
570046	NM_000733.4(CD3E):c.103+1G>T	Likely pathogenic	criteria provided, single submitter	1
2700001	NM_000733.4(CD3E):c.353-1G>A	Likely pathogenic	criteria provided, single submitter	1
2708832	NM_000733.4(CD3E):c.520+1G>A	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CD3E’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 37 predictions of 539):

Position(s)	Effect	Δscore	Sites
11:118307489	donor_gain	0.9900
11:118308547	donor_gain	0.9900
11:118313697	acceptor_gain	0.9900
11:118313705–118313706	acceptor_loss	0.9900	6
11:118313875–118313876	donor_loss	0.9900	6
11:118314446–118314447	acceptor_loss	0.9900	6
11:118314495–118314496	donor_loss	0.9900	5
11:118305002–118305003	donor_loss	0.9800	5
11:118314496	donor_loss	0.9800
11:118304777–118304778	donor_loss	0.9700	5

AlphaMissense

364 missense substitutions predicted likely pathogenic (of 1,342 scored), across 100 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D187	8	0.932	0.961
D137	8	0.900	0.965
C98	7	0.974	0.985
C49	7	0.966	0.984
C122	7	0.955	0.976
W59	7	0.951	0.994
C119	7	0.948	0.976
F87	7	0.940	0.991
E189	7	0.874	0.954
E124	7	0.677	0.822
Y188	6	0.904	0.987
P184	6	0.865	0.933
G94	6	0.830	0.954
T141	6	0.801	0.939
I40	6	0.797	0.978
N185	6	0.783	0.956
P186	6	0.744	0.833
D197	6	0.702	0.838
E89	6	0.651	0.725
Y96	5	0.908	0.971

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Breast Invasive Carcinoma (TCGA)	favorable	0.000161
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	favorable	0.000243
Head and Neck Squamous Cell Carcinoma (TCGA)	favorable	0.000377

Disease associations

OMIM: gene MIM:186830 | disease phenotypes: MIM:615615

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
immunodeficiency 18	Definitive	Autosomal recessive	2
T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
immunodeficiency 18	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (2 panels, 2 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

2 panels:

Panel	Rating
COVID-19 research	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green

Mondo (3): immunodeficiency 18 (MONDO:0014278), 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

37 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000388	Otitis media
HP:0000403	Recurrent otitis media
HP:0001019	Erythroderma
HP:0001433	Hepatosplenomegaly
HP:0001880	Increased total eosinophil count
HP:0001888	Decreased total lymphocyte count
HP:0001945	Fever
HP:0002014	Diarrhea
HP:0002039	Anorexia
HP:0002090	Pneumonia
HP:0002205	Recurrent respiratory infections
HP:0002719	Recurrent infections
HP:0002721	Immunodeficiency
HP:0002722	Recurrent abscess formation
HP:0002850	Decreased circulating IgM concentration
HP:0003460	Chronic decreased circulating IgA concentration
HP:0003593	Infantile onset
HP:0004315	Decreased circulating IgG concentration
HP:0004385	Protracted diarrhea
HP:0005353	Recurrent herpes
HP:0005401	Recurrent Candida infection
HP:0005403	Decreased total T cell count
HP:0006532	Recurrent pneumonia
HP:0008866	Failure to thrive secondary to recurrent infections
HP:0009098	Recurrent oral thrush
HP:0010702	Increased circulating immunoglobulin concentration
HP:0010975	Abnormal total B cell count
HP:0011463	Childhood onset
HP:0012115	Hepatitis
HP:0031123	Recurrent gastroenteritis
HP:0031379	Abnormal T cell proliferation
HP:0031381	Decreased mitogen-induced T-cell proliferation
HP:0032218	Decreased total CD4+ T cell proportion
HP:0040088	Abnormal lymphocyte count
HP:0040218	Reduced total natural killer cell count
HP:0410242	Abnormal circulating IgG concentration

GWAS associations

2 associations:

Study	Trait	p-value
GCST007096_147	Pulse pressure	3e-8
GCST004749_54	Lung cancer in ever smokers	4e-7

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0005763	pulse pressure measurement

MeSH disease descriptors

1 disease descriptors:

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 (2): CHEMBL1975 (SINGLE PROTEIN), CHEMBL2364168 (PROTEIN COMPLEX)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the CD3E protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

7 curated-mechanism drugs:

Drug	Modality	Max phase
TEPLIZUMAB	Antibody	4
HOKT3	Unknown	3
OTELIXIZUMAB	Antibody	3
VISILIZUMAB	Antibody	3
ERTUMAXOMAB	Antibody	2
RESIMMUNE	Unknown	2
MEDI-565	Unknown	1

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes CD3E — the drug acts on the assembly or class, not necessarily on this subunit alone.

16 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
BLINATUMOMAB	T cell surface glycoprotein CD3	3	4
CATUMAXOMAB	T cell surface glycoprotein CD3	3	4
ELRANATAMAB	T cell surface glycoprotein CD3	3	4
EPCORITAMAB	T cell surface glycoprotein CD3	3	4
GLOFITAMAB	T cell surface glycoprotein CD3	3	4
MOSUNETUZUMAB	T cell surface glycoprotein CD3	3	4
MUROMONAB-CD3	T cell surface glycoprotein CD3	3	4
TALQUETAMAB	T cell surface glycoprotein CD3	3	4
TARLATAMAB	T cell surface glycoprotein CD3	3	4
TECLISTAMAB	T cell surface glycoprotein CD3	3	4
ODRONEXTAMAB	T cell surface glycoprotein CD3	3	3
FLOTETUZUMAB	T cell surface glycoprotein CD3	3	2
FORALUMAB	T cell surface glycoprotein CD3	3	2
SOLITOMAB	T cell surface glycoprotein CD3	3	2
FBT-A05	T cell surface glycoprotein CD3	3	1
IMC-GP100	T cell surface glycoprotein CD3	3	—

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — CD molecules

Most potent curated ligand interactions (9 total), top 9:

Ligand	Action	Affinity	Parameter
AX-024	Binding	9.0	pIC50
xaluritamig	Binding	8.56	pKd
tarlatamab	Binding	8.36	pKd
ZWB67	Binding	8.0	pKd
PF-07062119	Binding	7.62	pKd
gamgertamig	Binding	7.51	pKd
blinatumomab	Binding	7.0	pKd
linvoseltamab	Binding	6.92	pEC50
tepoditamab	Binding	6.75	pKd

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
perfluorooctanoic acid	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
Fingolimod Hydrochloride	decreases expression	1
Antineoplastic Agents, Immunological	increases expression, affects binding	1
Resveratrol	affects cotreatment, decreases expression	1
Allergens	affects cotreatment, increases expression	1
Amphotericin B	increases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	affects cotreatment, increases expression	1
Benzene	decreases expression, increases expression	1
Benzo(a)pyrene	increases methylation	1
Calcifediol	increases reaction, decreases reaction, affects binding, affects cotreatment, increases expression	1
Calcitriol	increases reaction, increases abundance, decreases reaction, affects binding, affects cotreatment (+1 more)	1
Cycloheximide	decreases expression, decreases reaction	1
Ketoconazole	increases reaction, increases abundance, affects binding, affects cotreatment, decreases reaction (+1 more)	1
Nickel	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tetrachlorodibenzodioxin	decreases expression, decreases reaction	1

Cellosaurus cell lines

12 cell lines: 9 cancer cell line, 2 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8D1	Abcam HCT 116 CD3E KO	Cancer cell line	Male
CVCL_B8TN	Abcam MCF-7 CD3E KO	Cancer cell line	Female
CVCL_B9UM	Abcam A-549 CD3E KO	Cancer cell line	Male
CVCL_E1G4	Abcam Jurkat CD3E 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
CVCL_E8IP	Jurkat-NFAT-Luc2-CD3D-CD3E-KO-1C4	Cancer cell line	Male
CVCL_E8IQ	Jurkat-NFAT-Luc2-CD3D-CD3E-KO-2A3	Cancer cell line	Male
CVCL_E8IR	Jurkat-NFAT-Luc2-CD3E-KO-1A1	Cancer cell line	Male
CVCL_E8IS	Jurkat-NFAT-Luc2-CD3E-KO-1B3	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

44 trials:

NCT	Phase	Status	Title
NCT00220766	Phase 3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT01420627	Phase 3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	Phase 3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT00000603	Phase 2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00794508	Phase 2	COMPLETED	MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
NCT01182675	Phase 2	TERMINATED	Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim
NCT01529827	Phase 2	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	Phase 2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02177760	Phase 2	WITHDRAWN	Sirolimus Prophylaxis for aGVHD in TME SCID
NCT03619551	Phase 2	ACTIVE_NOT_RECRUITING	Conditioning SCID Infants Diagnosed Early
NCT00008450	Phase 1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT00028236	Phase 1	COMPLETED	Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)
NCT00152100	Phase 1	COMPLETED	Transplantation of Hematopoietic Cells in Children With Severe Combined Immunodeficiency Syndrome
NCT02860559	Phase 1	UNKNOWN	Safety and Early Efficacy Study of TBX-1400 in Patients With Severe Combined Immunodeficiency
NCT01019876	Phase 2/3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT00228852	Phase 1/2	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	Phase 1/2	TERMINATED	Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders
NCT01129544	Phase 1/2	COMPLETED	Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
NCT01852370	Phase 1/2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT02127892	Phase 1/2	TERMINATED	SCID Bu/Flu/ATG Study With T Cell Depletion
NCT02963064	Phase 1/2	TERMINATED	JSP191 Antibody Targeting Conditioning in SCID Patients
NCT03513328	Phase 1/2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT03538899	Phase 1/2	RECRUITING	Autologous Gene Therapy for Artemis-Deficient SCID
NCT03597594	Phase 1/2	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
NCT05298930	Not specified	COMPLETED	Feasibility Study to Assess an Adapted Physical Activity Program in Children, Adolescents and Young Adults Requiring Hematopoietic Stem Cell Transplantation
NCT05651113	Not specified	RECRUITING	The Experience of Screening for SCID
NCT06659588	Not specified	RECRUITING	Study of Populations at Risk of Developing Chronic Hepatitis Linked to Chronic Enteric Virus Infection in Patients With Primary Immunodeficiency and Secondary Humoral Deficiency
NCT06731036	Not specified	AVAILABLE	Expanded Access to CD34+ Selection Utilizing Miltenyi CliniMACS Prodigy® for Patients Receiving Peripheral Blood Stem Cell Transplantations and Stem Cell Boosts