CD3D

Summary

CD3D (CD3 delta subunit of T-cell receptor complex, HGNC:1673) is a protein-coding gene on chromosome 11q23.3, encoding T-cell surface glycoprotein CD3 delta chain (P04234). 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 part of the T-cell receptor/CD3 complex (TCR/CD3 complex) and is involved in T-cell development and signal transduction. The encoded membrane protein represents the delta subunit of the CD3 complex, and along with four other CD3 subunits, binds either TCR alpha/beta or TCR gamma/delta to form the TCR/CD3 complex on the surface of T-cells. Defects in this gene are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-positive (SCIDBNK). Two transcript variants encoding different isoforms have been found for this gene. Other variants may also exist, but the full-length natures of their transcripts has yet to be defined.

Source: NCBI Gene 915 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 19 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 230 total — 10 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 33
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000732

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1673
Approved symbol	CD3D
Name	CD3 delta subunit of T-cell receptor complex
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	CD3DELTA, CD3-DELTA
Ensembl gene	ENSG00000167286
Ensembl biotype	protein_coding
OMIM	186790
Entrez	915

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 retained_intron, 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000300692, ENST00000392884, ENST00000526561, ENST00000529594, ENST00000534687, ENST00000695666, ENST00000695667, ENST00000695668

RefSeq mRNA: 2 — MANE Select: NM_000732 NM_000732, NM_001040651

CCDS: CCDS41724, CCDS8394

Canonical transcript exons

ENST00000300692 — 5 exons

Exon	Start	End
ENSE00001111779	118339775	118339906
ENSE00001275643	118342553	118342705
ENSE00002189483	118339075	118339227
ENSE00003619361	118339451	118339494
ENSE00003964668	118340375	118340593

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 99.39.

FANTOM5 (CAGE): breadth broad, TPM avg 18.6406 / max 1352.3661, expressed in 289 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122601	8.0280	196
122600	5.8575	224
122602	4.1248	139
206460	0.2873	102
122604	0.2490	64
122603	0.0941	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	99.39	gold quality
granulocyte	CL:0000094	98.67	gold quality
lymph node	UBERON:0000029	97.71	gold quality
vermiform appendix	UBERON:0001154	96.45	gold quality
blood	UBERON:0000178	95.33	gold quality
spleen	UBERON:0002106	93.94	gold quality
epithelium of nasopharynx	UBERON:0001951	93.55	gold quality
caecum	UBERON:0001153	93.50	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.15	gold quality
ileal mucosa	UBERON:0000331	90.83	gold quality
bone marrow	UBERON:0002371	90.64	gold quality
superficial temporal artery	UBERON:0001614	89.71	gold quality
bone marrow cell	CL:0002092	89.48	gold quality
tonsil	UBERON:0002372	89.01	gold quality
rectum	UBERON:0001052	88.72	gold quality
jejunal mucosa	UBERON:0000399	88.61	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.62	gold quality
gall bladder	UBERON:0002110	86.89	gold quality
mucosa of transverse colon	UBERON:0004991	86.78	gold quality
palpebral conjunctiva	UBERON:0001812	86.40	gold quality
colonic epithelium	UBERON:0000397	85.91	gold quality
small intestine	UBERON:0002108	85.83	gold quality
periodontal ligament	UBERON:0008266	85.69	gold quality
duodenum	UBERON:0002114	84.55	gold quality
amniotic fluid	UBERON:0000173	84.37	gold quality
nasal cavity epithelium	UBERON:0005384	84.17	gold quality
buccal mucosa cell	CL:0002336	83.30	gold quality
trabecular bone tissue	UBERON:0002483	82.80	gold quality
pylorus	UBERON:0001166	82.56	gold quality
oral cavity	UBERON:0000167	82.03	gold quality

Single-cell (SCXA)

Detected in 47 experiment(s), a significant marker in 38.

Experiment	Marker?	Max mean expression
E-GEOD-139324	yes	2905.58
E-MTAB-8410	yes	2084.80
E-GEOD-111727	yes	1958.14
E-MTAB-6653	yes	1727.63
E-HCAD-1	yes	1612.25
E-MTAB-6308	yes	1323.92
E-MTAB-9906	yes	1318.37
E-HCAD-15	yes	1262.78
E-MTAB-8322	yes	1241.33
E-MTAB-8221	yes	1201.05
E-HCAD-4	yes	1163.17
E-CURD-46	yes	1128.20
E-MTAB-10042	yes	1108.02
E-HCAD-36	yes	1075.20
E-CURD-122	yes	1061.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, ELF1, ELF2, ETS1, IKZF1, YY1

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 30)

• CD3 epsilon undergoes a conformational change after dimerization with CD3 gamma or CD3 delta (PMID:12410792)
• defect in CD3delta gene in severe combined immunodeficiency is characterized by the absence of T cells but normal B cells (PMID:14602880)
• 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 CD3D deficiency. (PMID:15546002)
• a single, membrane-distal YxxO motif in CD3delta could mediate approximately 75% of receptor internalization, whereas its removal only reduced internalization by approximately 20% (PMID:15778375)
• 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)
• CD3delta and CD3gamma play a different role in humans and mice in pre-TCR and TCR function during alphabeta T-cell development (PMID:16888097)
• analysis of TCRalpha-CD3deltaepsilon and TCRbeta-CD3gammaepsilon dimers and the role of the membrane-proximal tetracysteine motif (PMID:17023417)
• The CD3 delta 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)
• 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)
• Enumeration of NK cells and of T lymphocytes expressing TCR alpha/beta in human body effusions is not helpful in attempting to distinguish between benign and malignant effusions. (PMID:18803280)
• Stage-dependent molecular changes in Notch signaling that are critical for normal human T-cell development. (PMID:19056690)
• 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)
• 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)
• Protein sequence comparison indicates that the CD3elta and CD3gamma subunits evolved with highly homologous heterodimeric interfaces and membrane proximal segments for efficient and specific signaling transfer when paired with CD3epsilon. (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)
• report 2 unrelated cases of SCID with a selective block in alphabeta but not in gammadelta T cell development, associated with a new splicing mutation in the CD3D gene (PMID:21926461)
• A transgenic T cell receptor gammadelta-low expressing subset of T cells accumulates in mouse ear keratinocytes after IL-23 injections. (PMID:21984702)
• Altered expression of the TCR signaling related genes CD3 and FcepsilonRIgamma in patients with aplastic anemia. (PMID:22401598)
• 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)
• Two cases of SCID with CD3delta gene mutation in Mexican Mennonite infants are described. (PMID:24288697)
• 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)
• A FOXP3(+)CD3(+)CD56(+)-expressed T-cell population with immunosuppressive function and reduced patient survival has been identified in cancer tissues of human hepatocellular carcinoma. (PMID:26437631)
• PCR and transcriptome analysis suggest that the genes CD3D and PKRCQ together can be used as a model for differentiating between B-cell and T-cell acute lymphoblastic leukemia. (PMID:27494091)
• we demonstrate that the incorporation of a 2A self-processing peptide derived from foot-and-mouth disease virus conveying co-translational cleavage into a two-chain anti-CD3 x anti-CEA diabody gene enables near-equimolar expression of diabody chains 1 and 2, and thus increases the final amount of assembled diabody. (PMID:28075428)
• Comprehensive analysis reveals a prognostic and therapeutic biomarker CD3D in the breast carcinoma microenvironment. (PMID:33350431)
• Hypomethylation of CD3D promoter induces immune cell infiltration and supports malignant phenotypes in uveal melanoma. (PMID:37651092)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cd3d	ENSMUSG00000032094
rattus_norvegicus	Cd3d	ENSRNOG00000015994

Paralogs (2): CD3G (ENSG00000160654), CD3E (ENSG00000198851)

Protein

Protein identifiers

T-cell surface glycoprotein CD3 delta chain — P04234 (reviewed: P04234)

Alternative names: T-cell receptor T3 delta chain

All UniProt accessions (3): B0YIY4, E9PMT5, P04234

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 of this role of signal transduction in T-cell activation, CD3D plays an essential role in thymocyte differentiation. Indeed, participates in correct intracellular TCR-CD3 complex assembly and surface expression. In absence of a functional TCR-CD3 complex, thymocytes are unable to differentiate properly. Interacts with CD4 and CD8 and thus serves to establish a functional link between the TCR and coreceptors CD4 and CD8, which is needed for activation and positive selection of CD4 or CD8 T-cells.

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 coreceptors CD4 and CD8.

Subcellular location. Cell membrane.

Tissue specificity. CD3D is mostly present on T-lymphocytes with its TCR-CD3 partners. Present also in fetal NK-cells.

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

Disease relevance. Immunodeficiency 19, severe combined (IMD19) [MIM:615617] An autosomal recessive form of severe combined immunodeficiency characterized by onset in early infancy of recurrent bacterial, viral, and fungal infections. Patients usually have chronic diarrhea, recurrent respiratory infections, and failure to thrive. Immunologic work-up shows a T-cell negative, B-cell positive, NK-cell positive phenotype. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
P04234-1	1	yes
P04234-2	2

RefSeq proteins (2): NP_000723, NP_001035741 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003110	Phos_immunorcpt_sig_ITAM	Repeat
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 (26 total): strand 9, helix 4, topological domain 2, modified residue 2, glycosylation site 2, signal peptide 1, chain 1, disulfide bond 1, splice variant 1, sequence variant 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

31 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1XIW	X-RAY DIFFRACTION	1.9
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
9JY4	ELECTRON MICROSCOPY	3.29
8TW4	ELECTRON MICROSCOPY	3.3
9BBC	ELECTRON MICROSCOPY	3.3
9JXZ	ELECTRON MICROSCOPY	3.31
9JY3	ELECTRON MICROSCOPY	3.35
9CIA	ELECTRON MICROSCOPY	3.39
8JC0	ELECTRON MICROSCOPY	3.4
8ZA6	ELECTRON MICROSCOPY	3.43
9C3E	ELECTRON MICROSCOPY	3.5
9JY0	ELECTRON MICROSCOPY	3.69
6JXR	ELECTRON MICROSCOPY	3.7
8WY0	ELECTRON MICROSCOPY	3.8
8WYI	ELECTRON MICROSCOPY	3.9
8WXE	ELECTRON MICROSCOPY	4
8YC0	ELECTRON MICROSCOPY	4.12

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04234-F1	77.57	0.39

Antibody-complex structures (SAbDab): 6 — 1XIW, 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): 149, 160

Disulfide bonds (1): 37–73

Glycosylation sites (2): 38, 74

Function

Pathways and Gene Ontology

Reactome pathways

14 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-389948	Co-inhibition by PD-1
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-199991	Membrane Trafficking
R-HSA-202403	TCR signaling
R-HSA-388841	Regulation of T cell activation by CD28 family
R-HSA-5653656	Vesicle-mediated transport

MSigDB gene sets: 363 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, WALLACE_PROSTATE_CANCER_RACE_UP, MODULE_169, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, BIOCARTA_TCRA_PATHWAY, GOBP_THYMIC_T_CELL_SELECTION, MODULE_45, MODULE_64, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, REACTOME_MEMBRANE_TRAFFICKING, WIELAND_UP_BY_HBV_INFECTION, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_2NM_UP, HERNANDEZ_MITOTIC_ARREST_BY_DOCETAXEL_2_UP, MODULE_118

GO Biological Process (6): adaptive immune response (GO:0002250), cell surface receptor signaling pathway (GO:0007166), positive thymic T cell selection (GO:0045059), alpha-beta T cell activation (GO:0046631), T cell receptor signaling pathway (GO:0050852), immune system process (GO:0002376)

GO Molecular Function (3): transmembrane signaling receptor activity (GO:0004888), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (7): cytoplasm (GO:0005737), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), clathrin-coated endocytic vesicle membrane (GO:0030669), T cell receptor complex (GO:0042101), alpha-beta T cell receptor complex (GO:0042105), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
TCR signaling	4
Adaptive Immune System	3
Regulation of T cell activation by CD28 family	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
Immune System	1
Vesicle-mediated transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
immune response	1
signal transduction	1
positive T cell selection	1
thymic T cell selection	1
T cell activation	1
antigen receptor-mediated signaling pathway	1
biological_process	1
signaling receptor activity	1
protein binding	1
binding	1
intracellular anatomical structure	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
plasma membrane signaling receptor complex	1
T cell receptor complex	1

Protein interactions and networks

STRING

4689 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD3D	CD3E	P07766	999
CD3D	CD247	P20963	998
CD3D	CD3G	P09693	986
CD3D	CD8A	P01732	919
CD3D	LCK	P06239	853
CD3D	ZAP70	P43403	852
CD3D	E9PD41	E9PD41	832
CD3D	HMBS	P08396	785
CD3D	CD4	P01730	758
CD3D	PTPRC	P08575	758
CD3D	CD2	P06729	749
CD3D	GZMK	P49863	739
CD3D	GZMA	P12544	726
CD3D	THY1	P04216	721
CD3D	LCP2	Q13094	716

IntAct

13 interactions, top by confidence:

A	B	Type	Score
CD3D	SGTB	psi-mi:“MI:0915”(physical association)	0.560
CD3D	CANX	psi-mi:“MI:2364”(proximity)	0.480
CD3D	AMFR	psi-mi:“MI:0915”(physical association)	0.400
CD3D		psi-mi:“MI:0915”(physical association)	0.400
CD3D	FYN	psi-mi:“MI:0915”(physical association)	0.400
NR3C1	CD3D	psi-mi:“MI:0915”(physical association)	0.400
CD3E	CD3D	psi-mi:“MI:0914”(association)	0.350
CD3D	CLGN	psi-mi:“MI:0914”(association)	0.350
CD3D	TAP2	psi-mi:“MI:0914”(association)	0.350
CD3D	ITGB8	psi-mi:“MI:0914”(association)	0.350
CD3D	SGTB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (87): CD3D (Affinity Capture-Western), CANX (Co-localization), WDR20 (Affinity Capture-Western), SYVN1 (Affinity Capture-Western), CD3D (Affinity Capture-Western), ZAP70 (Affinity Capture-Western), FYN (Affinity Capture-Western), PIK3R1 (Affinity Capture-Western), GRB2 (Affinity Capture-Western), SHC1 (Affinity Capture-Western), CD3D (Affinity Capture-MS), CD3D (Synthetic Lethality), SGTB (Two-hybrid), CD8A (FRET), CD8A (Affinity Capture-Western)

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

Diamond homologs: P04234, P04235, P09693, P11942, P18438, P18439, P19377, Q28072, Q28073, Q28074, Q5PXD3, Q64159, Q764N2, Q95LI7, Q95LI8, Q98910, A4F4L0, O43914, O54885, Q6X9T7, Q8WNQ8, Q95J79, Q9TU45, Q5R1Q1, P07766, P27597, P29328, Q7YRN2, Q9TUF9

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
CD3D	“form complex”	CD3	binding
TRIM13	“down-regulates quantity by destabilization”	CD3D	polyubiquitination
AMFR	“down-regulates quantity by destabilization”	CD3D	polyubiquitination
LCK	“up-regulates activity”	CD3D	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	5
Uncertain significance	84
Likely benign	107
Benign	12

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1075708	NM_000732.6(CD3D):c.51_52del (p.Gln18fs)	Pathogenic
12747	NM_000732.6(CD3D):c.202C>T (p.Arg68Ter)	Pathogenic
12748	NM_000732.6(CD3D):c.279C>A (p.Cys93Ter)	Pathogenic
2691273	NM_000732.6(CD3D):c.107del (p.Asn36fs)	Pathogenic
2697867	NM_000732.6(CD3D):c.9_10del (p.His3fs)	Pathogenic
2754021	NM_000732.6(CD3D):c.237C>G (p.Tyr79Ter)	Pathogenic
2766936	NM_000732.6(CD3D):c.15del (p.Leu7fs)	Pathogenic
2772341	NM_000732.6(CD3D):c.40_41dup (p.Leu15fs)	Pathogenic
2869561	NM_000732.6(CD3D):c.271C>T (p.Arg91Ter)	Pathogenic
643120	NM_000732.6(CD3D):c.128G>A (p.Trp43Ter)	Pathogenic
1468778	NM_000732.6(CD3D):c.407-2A>G	Likely pathogenic
1508408	NM_000732.6(CD3D):c.407-1G>A	Likely pathogenic
2759883	NM_000732.6(CD3D):c.274+2T>C	Likely pathogenic
2810710	NM_000732.6(CD3D):c.406+1G>T	Likely pathogenic
3599120	NM_000732.6(CD3D):c.450+1G>A	Likely pathogenic

SpliceAI

617 predictions. Top by Δscore:

Variant	Effect	Δscore
11:118339228:C:CC	acceptor_gain	1.0000
11:118339445:GCTCA:G	donor_loss	1.0000
11:118339447:TCACC:T	donor_loss	1.0000
11:118339448:CACCT:C	donor_loss	1.0000
11:118339449:A:AG	donor_loss	1.0000
11:118339450:C:T	donor_loss	1.0000
11:118339492:CAG:C	acceptor_gain	1.0000
11:118339493:AG:A	acceptor_gain	1.0000
11:118339495:C:CC	acceptor_gain	1.0000
11:118339505:C:CT	acceptor_gain	1.0000
11:118339766:T:TA	donor_gain	1.0000
11:118339770:CTAA:C	donor_loss	1.0000
11:118339771:TAA:T	donor_loss	1.0000
11:118339773:A:AG	donor_loss	1.0000
11:118339773:AC:A	donor_gain	1.0000
11:118339773:ACC:A	donor_gain	1.0000
11:118339773:ACCC:A	donor_gain	1.0000
11:118339774:CC:C	donor_gain	1.0000
11:118339774:CCC:C	donor_gain	1.0000
11:118339774:CCCC:C	donor_gain	1.0000
11:118339784:G:GA	donor_gain	1.0000
11:118339788:T:TA	donor_gain	1.0000
11:118339789:C:A	donor_gain	1.0000
11:118339797:ATGT:A	donor_gain	1.0000
11:118339800:T:TA	donor_gain	1.0000
11:118339819:C:CA	donor_gain	1.0000
11:118339820:C:A	donor_gain	1.0000
11:118339903:CACA:C	acceptor_gain	1.0000
11:118339905:CA:C	acceptor_gain	1.0000
11:118339906:ACT:A	acceptor_loss	1.0000

AlphaMissense

1098 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:118340431:C:G	C73S	0.975
11:118340432:A:T	C73S	0.975
11:118340438:A:C	Y71D	0.968
11:118339840:G:T	A114D	0.959
11:118340432:A:G	C73R	0.955
11:118340539:C:G	C37S	0.951
11:118340540:A:T	C37S	0.951
11:118339903:C:G	C93S	0.950
11:118339904:A:T	C93S	0.950
11:118340539:C:T	C37Y	0.944
11:118339904:A:G	C93R	0.943
11:118340538:G:C	C37W	0.942
11:118339820:C:G	G121R	0.941
11:118339820:C:T	G121R	0.941
11:118339828:A:T	L118H	0.938
11:118340540:A:G	C37R	0.937
11:118340431:C:T	C73Y	0.928
11:118340386:A:T	V88D	0.924
11:118340377:C:G	R91P	0.921
11:118340438:A:T	Y71N	0.918
11:118340430:A:C	C73W	0.917
11:118339828:A:C	L118R	0.916
11:118340446:C:G	R68P	0.915
11:118339894:C:G	C96S	0.912
11:118339895:A:T	C96S	0.912
11:118339894:C:T	C96Y	0.907
11:118339819:C:T	G121E	0.906
11:118340467:C:A	G61V	0.906
11:118339895:A:G	C96R	0.905
11:118339825:G:T	A119D	0.904

dbSNP variants (sampled 300 via entrez): RS1000661989 (11:118341581 T>C,G), RS1001061094 (11:118338974 G>A), RS1002624367 (11:118338692 A>C,T), RS1002813795 (11:118342397 C>T), RS1003220858 (11:118340698 G>A), RS1003779647 (11:118343732 A>T), RS1006186853 (11:118342940 G>A), RS1006260323 (11:118342684 C>T), RS1006655330 (11:118344278 A>T), RS1006688266 (11:118344030 C>T), RS1007656598 (11:118343301 G>A), RS1007687584 (11:118343014 C>T), RS1007836348 (11:118343116 C>T), RS1008116599 (11:118343436 G>A), RS1009711254 (11:118340685 T>C)

Disease associations

OMIM: gene MIM:186790 | disease phenotypes: MIM:615617, MIM:615607, MIM:608971

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 19	Strong	Autosomal recessive
T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunodeficiency 19	Definitive	AR

Mondo (5): immunodeficiency 19 (MONDO:0014280), combined immunodeficiency due to CD3gamma deficiency (MONDO:0014276), severe combined immunodeficiency (MONDO:0015974), immunodeficiency 104 (MONDO:0012163), T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta (MONDO:0015703)

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

HPO phenotypes

33 total (30 of 33 shown, 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:0001508	Failure to thrive
HP:0001880	Increased total eosinophil count
HP:0001888	Decreased total lymphocyte count
HP:0001945	Fever
HP:0002014	Diarrhea
HP:0002028	Chronic diarrhea
HP:0002039	Anorexia
HP:0002090	Pneumonia
HP:0002205	Recurrent respiratory infections
HP:0002719	Recurrent infections
HP:0002722	Recurrent abscess formation
HP:0002846	Abnormal B cell morphology
HP:0003460	Decreased circulating total IgA
HP:0003593	Infantile onset
HP:0004315	Decreased circulating IgG concentration
HP:0004385	Protracted diarrhea
HP:0004430	Severe combined immunodeficiency
HP:0005353	Recurrent herpes
HP:0005401	Recurrent candida infections
HP:0005403	Decreased total T cell count
HP:0006532	Recurrent pneumonia
HP:0008866	Failure to thrive secondary to recurrent infections
HP:0009098	Chronic oral candidiasis
HP:0010702	Increased circulating immunoglobulin concentration
HP:0012115	Hepatitis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007096_210	Pulse pressure	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750
C563822	Severe Combined Immunodeficiency, Autosomal Recessive, T Cell Negative, B Cell Positive, NK Cell Positive (supp.)

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

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	4
Aflatoxin B1	increases expression, increases methylation, affects expression	4
(+)-JQ1 compound	decreases expression	3
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Valproic Acid	decreases methylation, increases expression	2
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
dorsomorphin	increases expression, affects cotreatment	1
nabiximols	increases expression	1
Acetaminophen	increases expression	1
Benzene	increases expression	1
Cadmium	decreases expression	1
Calcifediol	affects binding, affects cotreatment, increases expression, increases reaction, decreases reaction	1
Calcitriol	affects binding, affects cotreatment, increases expression, increases reaction, increases abundance (+1 more)	1
Diuron	decreases expression	1
Hydroxychloroquine	affects cotreatment, decreases expression	1
Ketoconazole	decreases reaction, increases expression, increases reaction, increases abundance, affects binding (+1 more)	1
Methamphetamine	affects reaction, increases expression	1
Methotrexate	affects cotreatment, decreases expression	1
N-Nitrosopyrrolidine	increases expression	1
Nickel	increases expression	1
Quercetin	increases expression	1
Sulfasalazine	decreases expression, affects cotreatment	1
Dronabinol	increases methylation	1
Tretinoin	decreases expression	1
Isotretinoin	increases expression	1
Antirheumatic Agents	decreases expression	1
Copper Sulfate	increases expression	1

Cellosaurus cell lines

5 cell lines: 3 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_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_E8IY	Jurkat-NFAT-Luc2-CD3D-KO-1B1	Cancer cell line	Male

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