ZAP70

Summary

ZAP70 (zeta chain of T cell receptor associated protein kinase 70, HGNC:12858) is a protein-coding gene on chromosome 2q11.2, encoding Tyrosine-protein kinase ZAP-70 (P43403). Tyrosine kinase that plays an essential role in regulation of the adaptive immune response.

This gene encodes an enzyme belonging to the protein tyrosine kinase family, and it plays a role in T-cell development and lymphocyte activation. This enzyme, which is phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation, functions in the initial step of TCR-mediated signal transduction in combination with the Src family kinases, Lck and Fyn. This enzyme is also essential for thymocyte development. Mutations in this gene cause selective T-cell defect, a severe combined immunodeficiency disease characterized by a selective absence of CD8-positive T-cells. Two transcript variants that encode different isoforms have been found for this gene.

Source: NCBI Gene 7535 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined immunodeficiency due to ZAP70 deficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 596 total — 24 pathogenic, 13 likely-pathogenic (top 6% of genes corpus-wide)
• GTEx eGene: eQTL in 37 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 59
• ChEMBL bioactivity: 14 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.01 (LoF-tolerant), LOEUF 0.62 (unconstrained)
• MANE Select transcript: NM_001079
• Interaction hub: 2,302 STRING partners (top 5% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12858
Approved symbol	ZAP70
Name	zeta chain of T cell receptor associated protein kinase 70
Location	2q11.2
Locus type	gene with protein product
Status	Approved
Aliases	ZAP-70, STD
Ensembl gene	ENSG00000115085
Ensembl biotype	protein_coding
OMIM	176947
Entrez	7535

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 9 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000264972

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 3, TSL 3: 1, TSL 4: 1

ENST00000264972, ENST00000451498, ENST00000463643, ENST00000483781, ENST00000487283, ENST00000489250, ENST00000495754, ENST00000498836, ENST00000698508, ENST00000698509, ENST00000718250, ENST00000885385, ENST00000885386, ENST00000885387, ENST00001001950, ENST00001001951, ENST00001001952, ENST00001145268

RefSeq mRNA: 3 — MANE Select: NM_001079 NM_001079, NM_001378594, NM_207519

CCDS: CCDS33254, CCDS33255

Canonical transcript exons

ENST00000264972 — 14 exons

Exon	Start	End
ENSE00001267184	97739375	97739860
ENSE00001346286	97713916	97713994
ENSE00001915964	97713576	97713674
ENSE00003467221	97735250	97735456
ENSE00003502647	97733297	97733343
ENSE00003503894	97733544	97733595
ENSE00003510686	97724016	97724438
ENSE00003540216	97725092	97725252
ENSE00003547939	97737995	97738107
ENSE00003599670	97737473	97737665
ENSE00003618162	97732883	97733021
ENSE00003637033	97733125	97733212
ENSE00003638273	97737757	97737897
ENSE00003646213	97734520	97734712

Expression profiles

Bgee: expression breadth ubiquitous, 182 present calls, max score 99.28.

FANTOM5 (CAGE): breadth broad, TPM avg 9.6180 / max 696.4163, expressed in 290 samples.

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

Genetic regulation across tissues (GTEx eQTL / sQTL)

ZAP70 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 37 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 37 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cerebellar Hemisphere	eqtl	1.7e-59	-1.23	2:97701308:C:A
Brain Cerebellum	eqtl	8.1e-52	-1.20	2:97701308:C:A
Testis	eqtl	3.2e-49	-0.91	2:97701308:C:A
Nerve Tibial	eqtl	3.9e-39	-0.55	2:97701308:C:A
Cells Cultured fibroblasts	eqtl	4.9e-18	-0.55	2:97701308:C:A
Skin Sun Exposed Lower leg	eqtl	9.9e-17	-0.30	2:97701308:C:A
Brain Nucleus accumbens basal ganglia	eqtl	3.4e-14	-0.62	2:97698446:T:C
Muscle Skeletal	eqtl	3.0e-13	-0.25	2:97735523:T:C
Thyroid	eqtl	2.1e-12	-0.17	2:97694802:A:C
Brain Cortex	eqtl	1.3e-10	-0.58	2:97698446:T:C
Breast Mammary Tissue	eqtl	3.8e-10	-0.25	2:97676529:T:C
Brain Anterior cingulate cortex BA24	eqtl	9.7e-10	-0.56	2:97698446:T:C
Brain Frontal Cortex BA9	eqtl	9.4e-09	-0.54	2:97630482:C:T
Skin Not Sun Exposed Suprapubic	eqtl	1.1e-08	-0.23	2:97671334:C:CG
Artery Tibial	eqtl	1.6e-08	-0.21	2:97701308:C:A
Brain Hypothalamus	eqtl	4.2e-08	-0.39	2:97633376:A:C
Brain Hippocampus	eqtl	2.8e-07	-0.50	2:97632177:A:C
Brain Putamen basal ganglia	eqtl	6.0e-07	-0.42	2:97630482:C:T
Brain Caudate basal ganglia	eqtl	2.9e-06	-0.35	2:97701308:C:A
Pancreas	eqtl	3.0e-06	-0.36	2:97694802:A:C

FANTOM5 promoters

showing 10 of 13 alternative TSS:

Promoter ID	TPM avg	Samples expressed
21520	5.6167	226
21521	2.2848	140
21527	0.4039	56
21524	0.2428	76
21519	0.2245	77
21526	0.2123	49
21525	0.1943	60
21523	0.1877	66
21522	0.1532	65
21518	0.0525	33

Top tissues by expression

showing 100 of 289 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.28	gold quality
lymph node	UBERON:0000029	93.72	gold quality
blood	UBERON:0000178	93.26	gold quality
spleen	UBERON:0002106	92.98	gold quality
vermiform appendix	UBERON:0001154	90.38	gold quality
thymus	UBERON:0002370	88.34	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.77	gold quality
caecum	UBERON:0001153	83.83	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.57	gold quality
gall bladder	UBERON:0002110	82.61	gold quality
small intestine	UBERON:0002108	82.39	gold quality
upper lobe of left lung	UBERON:0008952	81.98	gold quality
mucosa of transverse colon	UBERON:0004991	81.53	gold quality
bone marrow cell	CL:0002092	80.01	gold quality
tonsil	UBERON:0002372	79.81	gold quality
upper lobe of lung	UBERON:0008948	79.24	gold quality
bone marrow	UBERON:0002371	79.04	gold quality
right lobe of liver	UBERON:0001114	78.23	gold quality
right lung	UBERON:0002167	78.13	gold quality
right uterine tube	UBERON:0001302	76.89	gold quality
omental fat pad	UBERON:0010414	76.41	gold quality
peritoneum	UBERON:0002358	76.31	gold quality
adipose tissue of abdominal region	UBERON:0007808	75.80	gold quality
superficial temporal artery	UBERON:0001614	75.37	silver quality
body of stomach	UBERON:0001161	74.90	gold quality
right coronary artery	UBERON:0001625	74.66	gold quality
transverse colon	UBERON:0001157	74.14	gold quality
apex of heart	UBERON:0002098	73.94	gold quality
jejunal mucosa	UBERON:0000399	73.42	silver quality
rectum	UBERON:0001052	73.21	gold quality
left uterine tube	UBERON:0001303	72.46	gold quality
leukocyte	CL:0000738	72.12	gold quality
colonic epithelium	UBERON:0000397	72.05	gold quality
ectocervix	UBERON:0012249	72.02	gold quality
left lobe of thyroid gland	UBERON:0001120	71.78	gold quality
intestine	UBERON:0000160	71.61	gold quality
stomach	UBERON:0000945	71.37	gold quality
esophagus mucosa	UBERON:0002469	71.23	gold quality
thyroid gland	UBERON:0002046	71.08	gold quality
fundus of stomach	UBERON:0001160	70.78	gold quality
vagina	UBERON:0000996	70.64	gold quality
right lobe of thyroid gland	UBERON:0001119	70.61	gold quality
subcutaneous adipose tissue	UBERON:0002190	70.11	gold quality
mononuclear cell	CL:0000842	69.87	gold quality
duodenum	UBERON:0002114	69.72	gold quality
skin of abdomen	UBERON:0001416	69.69	gold quality
monocyte	CL:0000576	69.67	gold quality
minor salivary gland	UBERON:0001830	69.65	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	69.62	gold quality
ileal mucosa	UBERON:0000331	69.12	gold quality
colon	UBERON:0001155	68.83	gold quality
large intestine	UBERON:0000059	68.69	gold quality
lung	UBERON:0002048	68.53	gold quality
ascending aorta	UBERON:0001496	68.52	gold quality
urinary bladder	UBERON:0001255	68.34	gold quality
thoracic aorta	UBERON:0001515	68.22	gold quality
saliva-secreting gland	UBERON:0001044	68.08	gold quality
esophagus	UBERON:0001043	68.07	gold quality
body of uterus	UBERON:0009853	68.00	gold quality
mucosa of stomach	UBERON:0001199	67.97	gold quality
gluteal muscle	UBERON:0002000	67.86	silver quality
right atrium auricular region	UBERON:0006631	67.86	gold quality
skin of leg	UBERON:0001511	67.83	gold quality
endocervix	UBERON:0000458	67.81	gold quality
lower esophagus mucosa	UBERON:0035834	67.80	gold quality
mouth mucosa	UBERON:0003729	67.68	gold quality
metanephros cortex	UBERON:0010533	67.63	gold quality
hindlimb stylopod muscle	UBERON:0004252	67.44	gold quality
palpebral conjunctiva	UBERON:0001812	67.12	silver quality
zone of skin	UBERON:0000014	66.82	gold quality
liver	UBERON:0002107	66.82	gold quality
triceps brachii	UBERON:0001509	66.73	silver quality
left coronary artery	UBERON:0001626	66.73	gold quality
tibial nerve	UBERON:0001323	66.69	gold quality
adipose tissue	UBERON:0001013	66.53	gold quality
coronary artery	UBERON:0001621	66.45	gold quality
amniotic fluid	UBERON:0000173	66.43	silver quality
nasal cavity mucosa	UBERON:0001826	66.31	gold quality
cardiac atrium	UBERON:0002081	66.31	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	66.31	gold quality
anatomical system	UBERON:0000467	66.24	gold quality
gastrocnemius	UBERON:0001388	66.12	gold quality
muscle of leg	UBERON:0001383	66.06	gold quality
connective tissue	UBERON:0002384	66.06	gold quality
skin of hip	UBERON:0001554	65.98	gold quality
multicellular organism	UBERON:0000468	65.92	gold quality
material anatomical entity	UBERON:0000465	65.91	gold quality
prostate gland	UBERON:0002367	65.64	gold quality
adenohypophysis	UBERON:0002196	65.50	gold quality
lower esophagus	UBERON:0013473	65.19	gold quality
lower esophagus muscularis layer	UBERON:0035833	65.16	gold quality
decidua	UBERON:0002450	65.05	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	65.01	gold quality
muscle layer of sigmoid colon	UBERON:0035805	64.75	gold quality
descending thoracic aorta	UBERON:0002345	64.74	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	64.71	gold quality
left testis	UBERON:0004533	64.44	gold quality
left adrenal gland cortex	UBERON:0035825	64.40	gold quality
sigmoid colon	UBERON:0001159	64.08	gold quality
right ovary	UBERON:0002118	64.00	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	44.41
E-MTAB-6678	yes	23.32
E-ANND-3	yes	14.88
E-MTAB-9067	yes	4.32
E-CURD-112	yes	3.75

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 75 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Thymus	tissue	74.4
Lymph node	tissue	49.6	high
Spleen	tissue	25.7	medium
Appendix	tissue	24.5	high
Bone marrow	tissue	22.6	medium
Tonsil	tissue	16.6	high
Small intestine	tissue	7.2	not detected
Stomach 1	tissue	6.0	not detected
Lung	tissue	5.8	low
Duodenum	tissue	5.4	not detected
Olfactory bulb	tissue	4.8
Gallbladder	tissue	4.5	not detected
Urinary bladder	tissue	4.1	not detected
Cerebellum	tissue	3.8	not detected
Corpus callosum	tissue	3.8
Cerebral cortex	tissue	3.6	not detected
Insular cortex	tissue	3.6
Amygdala	tissue	3.4
Hippocampal formation	tissue	3.4
Retrosplenial cortex	tissue	3.3
Basal ganglia	tissue	3.1	not detected
Ventral forebrain	tissue	3.1
Temporal cortex	tissue	3.1
Retrosplenial and cingulate cortex	tissue	3.0
Prefrontal cortex	tissue	2.9
Spinal cord	tissue	2.9
Entorhinal cortex	tissue	2.9
Periaqueductal gray	tissue	2.9
Septum	tissue	2.8
Hypothalamus	tissue	2.7
Vagina	tissue	2.6	not detected
Tongue	tissue	2.6
Putamen	tissue	2.6
Medulla oblongata	tissue	2.6
Substantia nigra	tissue	2.6
Occipital cortex	tissue	2.6
Midbrain	tissue	2.5
Somatosensory cortex	tissue	2.5
Motor cortex	tissue	2.4
Skin 1	tissue	2.3	not detected
Colon	tissue	2.3	not detected
Salivary gland	tissue	2.0	not detected
Thalamus	tissue	2.0
Superior colliculi	tissue	2.0
Pons	tissue	1.9
Adipose tissue	tissue	1.7	not detected
Skeletal muscle	tissue	1.5	not detected
Rectum	tissue	1.4	not detected
Liver	tissue	1.4	not detected
Testis	tissue	1.3	medium
Endometrium 1	tissue	1.3	not detected
Pituitary gland	tissue	1.1
Prostate	tissue	1.1	not detected
Adrenal gland	tissue	1.1	not detected
Heart muscle	tissue	0.9	not detected
Esophagus	tissue	0.9	not detected
Pancreas	tissue	0.9	not detected
Placenta	tissue	0.8	not detected
Seminal vesicle	tissue	0.7	not detected
Choroid plexus	tissue	0.7

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — White matter (3.8), Subiculum (3.4), Ventral hippocampus (3.1), Ventral spinal cord (2.9), Dorsal spinal cord (2.8).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREM, MTF1, SPI1, TBPL1

miRNA regulators (miRDB)

Targeting ZAP70 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

5 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-629-5P	98.78	68.72	1032
HSA-MIR-5589-5P	98.34	64.82	1148
HSA-MIR-3918	96.13	64.65	1300

Functional genomics

gnomAD constraint: pLI 0.0095, LOEUF 0.624, missense Z 1.84 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000264972 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:97,724,037–97,737,524	551 / 630.0	0.87	no
2:97,737,525–97,738,034	67 / 151.9	0.44	no
2:97,738,035–97,739,495	78 / 88.6	0.88	no

Literature-anchored findings (GeneRIF, showing 40)

• association of Zap-70 induced by T cell activation in plasma membrane microdomains with GM3 (PMID:11781312)
• Signaling through ZAP-70 is required for CXCL12-mediated T-cell transendothelial migration. (PMID:11964272)
• ZAP-70, a tyrosine kinase known to be crucial for T cell activation, as a key player in TCR down-modulation and zeta degradation. (PMID:12165490)
• ZAP-70 signaling drives the TCR-dependent reorientation of the microtubule-organizing center (PMID:12387734)
• Expression of ZAP-70 is associated with enhanced signal transduction via the BCR complex, which may contribute to the more aggressive clinical course associated with CLL cells that express nonmutated immunoglobulin receptors. (PMID:12393534)
• VHR, a Vaccinia virus VH1-related dual-specific protein phosphatase, is phosphorylated at Y138 by ZAP-70. (PMID:12447358)
• profiling of gene expression in purified chronic lymphocytic leukemia(CLL)samples from 107 patients showed that ZAP-70 expression is the best discriminator of Ig-mutated and Ig-unmutated CLL (PMID:12595313)
• Impaired ZAP-70 activation is associated with a unique signaling pathway coupling TCR ligation with T cell proliferation. (PMID:12778467)
• ZAP-70 is required for intracellular calcium ion mobilization in response to SDF-1alpha/CXCL12-induced prolonged activation of extracellular signal-related protein kinase in Jurkat T lymphocytes. (PMID:12817019)
• The requirement for ZAP-70 is clearly demonstrated in T cell receptor-induced polarization of the T cell’s microtubule-organizing center, as it moves toward the interface of the T cell and antigen-presenting cell. (PMID:12847255)
• concluded that phosphorylation of ZAP-70 at Ser-520 plays an important role in the correct localization of ZAP-70 and in priming ZAP-70 for its acute recruitment and activation upon antigen receptor ligation (PMID:14560012)
• Lck and ZAP-70 have roles in the interaction of human MUC1 and beta-catenin in activated Jurkat T cells (PMID:14766232)
• The interplay between Syk and ZAP-70 in thymocytes, certain T cells, and B-chronic lymphocytic leukemia cells will modulate the amplitude of antigen-mediated receptor signaling. (PMID:15059847)
• The interdomain B region of ZAP-70 regulates beta 1 integrin activation by the CD3/T cell receptor complex via control of tyrosine phosphorylation of tyrosine residues 171 and 191 in the linker for activation of T cells (LAT) cytoplasmic domain. (PMID:15100278)
• ZAP-70 is expressed by many lymphoma types, correlates with immunoglobulin heavy-chain variable region gene mutational status and can be detected reliably using immunohistochemical methods. (PMID:15133473)
• Essential for T cell receptor signaling and CD8 cell selection. (PMID:15190462)
• three-dimensional structure of the ZAP-70 kinase domain in complex with staurosporine (PMID:15292186)
• PD-1 modulation of T-cell function involves inhibition of TCR-mediated phosphorylation of ZAP70 and association with CD3zeta (PMID:15358536)
• ZAP-70 is associated with the mutational status of Ig VH genes in B-CLLs; high levels of ZAP-70 correlated with Binet stages B or C indicating an involvement of ZAP-70 in mechanisms promoting growth of B-CLL cells. (PMID:15370248)
• expression of ZAP-70 in CLL allows for more effective IgM signaling in CLL B cells, a feature that could contribute to the relatively aggressive clinical behavior generally associated with CLL cells that express unmutated IgV(H) (PMID:15514014)
• The ZAP-70 expression analyses provided complementary prognostic information identifying three patient subgroups with good, intermediate and poor prognosis. (PMID:15759031)
• ZAP-70 is expressed in a subpopulation of tonsillar and splenic normal B-lymphocytes that express an activated phenotype (PMID:15800671)
• murine leukemia model with many similarities to human ZAP-70+ B cell chronic lymphocytic leukemia when human B cells are transplanted into NOD/SCID mice. (PMID:15856008)
• To analyze the expression of Syk tyrosine kinase during the multi step development of human breast carcinoma (PMID:15861514)
• These findings suggest that a general autoinhibitory mechanism employed by RTKs is also used by some cytoplasmic tyrosine kinases, such as ZAP-70. (PMID:15923611)
• ZAP-70 is required for cell survival and signaling in chronic lymphocytic leukemia, and inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling (PMID:15972449)
• ZAP-70 is consistently expressed and phosphorylated in Blin-ALL cells (PMID:15996927)
• oorellation between expression of ZAP-70 and methylation status of a specific CpG site at the intron 1 - exon 2 boundary of the ZAP-70 gene in chronic lymphocytic leukemia. (PMID:16079094)
• Methylation of a highly conserved intronic region of ZAP-70 may be responsible for regulation of expression in normal and chronic lymphocytic leukemia cells. (PMID:16079107)
• results suggest a novel functional role for ZAP 70 in nuclear receptor-driven transactivation in T lymphocytes. (PMID:16096284)
• The difference in the spatio-temporal localization of LCK and ZAP70 proteins following stimulation may eliminate signal crosstalk, and could explain the differentiation of the specific downstream responses of these pathways (PMID:16219325)
• May be a prognostic marker in chronic lymphocytic leukemia. (review) (PMID:16263570)
• In a variety of cell types, Syk is the tyrosine kinase that plays an important role in the activation of Tpl2. (PMID:16291755)
• The aberrant expression of ZAP-70 in more aggressive forms of chronic lymphocytic leukemia requires the chaperoning action of activated heat-shock protein 90, which may be specifically inhibited by the therapeutic strategies discussed in this review. (PMID:16300468)
• results suggest that biological functions attributed to the association of Zap70 with Vav after T cell activation may equally reflect the association of Zap70 with CrkII, and further support a regulatory role for CrkII in TCR-linked signal transduction (PMID:16339550)
• Dexamethasone induces rapid tyrosine-phosphorylation of ZAP-70 in Jurkat cells (PMID:16406604)
• The ZAP-70-TCR-zeta association mediates the activation of PLC-gamma1 leading to T cell responses even in the absence of kinase activation of ZAP-70. (PMID:16412387)
• There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. (PMID:16418492)
• The ZAP70 protein was found expressed in normal pro/pre B cells but not in a significant proportion of normal B cells with mature phenotype. The presence of ZAP-70 in B-ALLs probably reflects their cellular origin. (PMID:16467082)
• Higher cyclin E expression in samples of ZAP 70-positive patients may reflect a larger proliferating compartment in vivo compared to ZAP 70-negative patients with B-cell chronic leukemia. (PMID:16538501)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zap70	ENSDARG00000015752
mus_musculus	Zap70	ENSMUSG00000026117
rattus_norvegicus	Zap70	ENSRNOG00000016995

Paralogs (32): FGR (ENSG00000000938), MATK (ENSG00000007264), BTK (ENSG00000010671), FYN (ENSG00000010810), STYK1 (ENSG00000060140), TNK2 (ENSG00000061938), TXK (ENSG00000074966), JAK2 (ENSG00000096968), ABL1 (ENSG00000097007), PTK6 (ENSG00000101213), HCK (ENSG00000101336), BMX (ENSG00000102010), CSK (ENSG00000103653), TYK2 (ENSG00000105397), JAK3 (ENSG00000105639), FRK (ENSG00000111816), ITK (ENSG00000113263), PTK2B (ENSG00000120899), SRMS (ENSG00000125508), TEC (ENSG00000135605), BLK (ENSG00000136573), ABL2 (ENSG00000143322), FER (ENSG00000151422), JAK1 (ENSG00000162434), SYK (ENSG00000165025), PTK2 (ENSG00000169398), TNK1 (ENSG00000174292), YES1 (ENSG00000176105), FES (ENSG00000182511), LCK (ENSG00000182866), SRC (ENSG00000197122), LYN (ENSG00000254087)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:99613) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 60 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased CD8-positive, alpha-beta T cell number	7
decreased T cell number	6
abnormal humoral immune response	5
decreased IgG level	5
decreased CD4-positive, alpha-beta T cell number	5
increased central memory CD8-positive, alpha-beta T cell number	4
arrested T cell differentiation	3
abnormal T cell differentiation	3
abnormal positive T cell selection	3
increased B cell number	3
decreased CD8-positive, naive alpha-beta T cell number	3
abnormal T cell physiology	2
increased double-positive T cell number	2
decreased T cell proliferation	2
abnormal splenic cell ratio	2
abnormal lymph node cell ratio	2
decreased CD4-positive, CD25-positive, alpha-beta regulatory T cell number	2
increased central memory CD4-positive, alpha-beta T cell number	2
increased effector memory CD4-positive, alpha-beta T cell number	2
osteoporosis	1
absent CD8-positive, alpha-beta T cells	1
mixed cellular infiltration to dermis	1
impaired hematopoiesis	1
thymus hypoplasia	1
abnormal T cell activation	1

+35 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
Macaca mulatta	P55245	99.3%	Diamond
Bos taurus	Q5ICW4	96.7%	Diamond
Sus scrofa	Q00655	93.0%	Diamond
Gallus gallus	Q00944	91.7%	Diamond
Xenopus laevis	Q91738	88.5%	Diamond
Cyprinus carpio	Q09178	86.8%	Diamond
Xiphophorus maculatus	P13388	61.6%	Diamond
Drosophila melanogaster	Q9VZI2	55.7%	Diamond
Apis mellifera	P0CY46	51.9%	Diamond
Hydra vulgaris	P53356	47.2%	Diamond
Caenorhabditis elegans	G5EBZ8	43.1%	Diamond
Avian leukosis virus	P00534	100.0%	Diamond
Avian erythroblastosis virus (strain ts167)	P11273	100.0%	Diamond
Avian erythroblastosis virus (strain ES4)	P00535	99.5%	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
COX5B	protein-coding	1329
TMEM131	protein-coding	23505
C2orf92	protein-coding	728537
ACTR1B	protein-coding	10120

Protein

Protein identifiers

Tyrosine-protein kinase ZAP-70 — P43403 (reviewed: P43403)

Alternative names: 70 kDa zeta-chain associated protein, Syk-related tyrosine kinase

All UniProt accessions (3): A0ABB0MV86, B4E0E2, P43403

UniProt curated annotations — full annotation on UniProt →

Function. Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Also contributes to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the phosphorylated TCR components CD3E and CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR).

Subunit / interactions. Interacts with CD247/CD3Z; this interaction docks ZAP70 at the stimulated TCR. Interacts with NFAM1. Interacts with adapter protein SLA; this interaction negatively regulates T-cell receptor signaling. Interacts with FCRL3. Interacts with VAV1. Interacts with CBL; this interaction promotes ubiquitination, internalization and subsequent degradation of CD247/CD3Z. Identified in a complex with CBL and UBE2L3. Interacts with SHB. Interacts with adapter protein SLA2; this interaction negatively regulates T-cell receptor signaling. Interacts with CBLB. Interacts (via SH2 domains) with RHOH; this interaction regulates ZAP70 subcellular localization. Interacts with DEF6. Interacts (ubiquitinated form) with OTUD7B and UBASH3B.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in T- and natural killer cells. Also present in early thymocytes and pro/pre B-cells.

Post-translational modifications. Phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation. Phosphorylation of Tyr-315 and Tyr-319 are essential for ZAP70 positive function on T-lymphocyte activation whereas Tyr-292 has a negative regulatory role. Within the C-terminal kinase domain, Tyr-492 and Tyr-493 are phosphorylated after TCR induction, Tyr-492 playing a negative regulatory role and Tyr-493 a positive. Tyr-493 is dephosphorylated by PTN22. Ubiquitinated in response to T cell activation. Deubiquitinated by OTUD7B.

Disease relevance. Immunodeficiency 48 (IMD48) [MIM:269840] A form of severe immunodeficiency characterized by a selective absence of CD8+ T-cells. The disease is caused by variants affecting the gene represented in this entry. Autoimmune disease, multisystem, infantile-onset, 2 (ADMIO2) [MIM:617006] An autosomal recessive, autoimmune disorder characterized by systemic manifestations including blistering skin disease, uncontrollable bullous pemphigoid, inflammatory colitis, autoimmune hypothyroidism, proteinuria and nephrotic syndrome. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by phosphorylation at Tyr-493 in the activation loop. Inhibited by staurosporine.

Domain organisation. Composed of 2 N-terminal SH2 domains and a C-terminal kinase domain. The tandem SH2 domains bind to the doubly phosphorylated tyrosine-based activation motif (ITAM) of CD247/CD3Z and the non-canonical phosphorylated tyrosine-based activation motif (TAM) of RHOH. The interdomain B located between the second SH2 and the kinase domain contains 3 tyrosines (Tyr-292, Tyr-315, Tyr-319) that are phosphorylated following TCR activation. These sites have been implicated in binding to other signaling molecules including CBL or VAV1. Thus, ZAP70 can also function as a scaffold by recruiting additional factors to the stimulated TCR complex.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P43403-1	1	yes
P43403-2	2, TZK
P43403-3	3

RefSeq proteins (3): NP_001070, NP_001365523, NP_997402 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR000980	SH2	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR012234	Tyr_kinase_non-rcpt_SYK/ZAP70	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR023420	Kinase_SYK/ZAP-70_inter-SH2_sf	Homologous_superfamily
IPR035838	SYK/ZAP-70_N_SH2	Domain
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR050198	Non-receptor_tyrosine_kinases	Family

Pfam: PF00017, PF07714

Enzyme classification (BRENDA)

• EC 2.7.10.2 — non-specific protein-tyrosine kinase (BRENDA: 41 organisms, 396 substrates, 479 inhibitors, 43 Km, 32 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.014–17.64	12
[KDSRC KINASE]-L-TYROSINE	0.0057–0.24	12
POLY(GLU4-TYR)	0.018–0.659	10
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO	0.057	1
S1 PEPTIDE	0.037	1
EEEEY	—	0

Catalyzed reactions (Rhea)

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (113 total): mutagenesis site 26, helix 25, strand 21, sequence variant 13, modified residue 8, turn 6, domain 3, splice variant 3, region of interest 3, binding site 2, chain 1, cross-link 1, active site 1

Structure

Experimental structures (PDB)

15 structures by resolution:

PDB	Title	Method	Resolution (Å)
7SIY	cCBL TKB domain in complex with pZAP70 peptide	X-RAY DIFFRACTION	1.48
2OQ1	Tandem SH2 domains of ZAP-70 with 19-mer zeta1 peptide	X-RAY DIFFRACTION	1.9
2Y1N	Structure of c-Cbl-ZAP-70 peptide complex	X-RAY DIFFRACTION	2
4XZ0	ZAP-70-tSH2:compound-A complex	X-RAY DIFFRACTION	2
2CBL	N-TERMINAL DOMAIN OF CBL IN COMPLEX WITH ITS BINDING SITE ON ZAP-70	X-RAY DIFFRACTION	2.1
3ZNI	Structure of phosphoTyr363-Cbl-b - UbcH5B-Ub - ZAP-70 peptide complex	X-RAY DIFFRACTION	2.21
1U59	Crystal Structure of the ZAP-70 Kinase Domain in Complex with Staurosporine	X-RAY DIFFRACTION	2.3
5O76	Structure of phosphoY371 c-CBL in complex with ZAP70-peptide and UbV.pCBL ubiquitin …	X-RAY DIFFRACTION	2.47
1M61	Crystal structure of the apo SH2 domains of ZAP-70	X-RAY DIFFRACTION	2.5
2OZO	Autoinhibited intact human ZAP-70	X-RAY DIFFRACTION	2.6
4A4C	Structure of phosphoTyr371-c-Cbl-UbcH5B-ZAP-70 complex	X-RAY DIFFRACTION	2.7
4A4B	Structure of modified phosphoTyr371-c-Cbl-UbcH5B-ZAP-70 complex	X-RAY DIFFRACTION	2.79
4XZ1	ZAP-70-tSH2:Compound-B adduct	X-RAY DIFFRACTION	2.8
1FBV	STRUCTURE OF A CBL-UBCH7 COMPLEX: RING DOMAIN FUNCTION IN UBIQUITIN-PROTEIN LIGASES	X-RAY DIFFRACTION	2.9
4K2R	Structural basis for activation of ZAP-70 by phosphorylation of the SH2-kinase linker	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43403-F1	85.91	0.66

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, Tyr protein kinases, Predicted intracellular proteins, Plasma proteins, RAS pathway related proteins, Disease related genes, Potential drug targets, Human disease related genes, Primary immunodeficiency

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH enhanced

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
461	proton acceptor

Ligand- & substrate-binding residues (2)

Position	Role
345–352	ATP
369	ATP

Post-translational modifications (9)

Type	Positions
Phosphotyrosine	248, 292, 315, 319, 492, 493
Phosphoserine	289
N6-acetyllysine	603
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in ubiquitin)	544

Mutagenesis-validated functional residues (26)

Position	Phenotype
37	decreases interaction with phosphorylated cd247; when associated with k-190.
131	increased constitutive kinase activity.
133	increased constitutive kinase activity.
141	increased constitutive kinase activity.
144	increased kinase activity after activation by lck.
145	increased kinase activity after activation by lck.
147	increased kinase activity after activation by lck.
190	decreases interaction with phosphorylated cd247; when associated with k-37.
292	induces constitutive tcr stimulation-independent nfat induction.
304	no effect on ubiquitination.
314	increased constitutive kinase activity.
315–319	increases strongly constitutive kinase activity on lat phosphorylation.
315	increased constitutive kinase activity; when associated with f-319.
315	increased constitutive kinase activity; when associated with f-319. about 75% loss of cd247/cd3z-binding in stimulated tcr and complete …
319	increased constitutive kinase activity; when associated with f-315.
319	increased constitutive kinase activity; when associated with f-315. about 80% loss of tcr-induced nfat activation.
327	increases constitutive kinase activity on lat phosphorylation, strongly increases subcellular localization of cd69 at the cell surface and …
362	increases constitutive kinase activity on lat phosphorylation, strongly increases subcellular localization of cd69 at the cell surface and …
461	abolishes kinase activity.
479	abolishes kinase activity.
492	increases kinase activity.
493	impairs kinase activity.
538	no effect on ubiquitination.
544	strongly decreased ubiquitination.
597	increased kinase activity after activation by lck.

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 15; 5 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

15 pathways:

ID	Pathway	Evidence
R-HSA-9725371	Nuclear events stimulated by ALK signaling in cancer ⚕	curated
R-HSA-202433	Generation of second messenger molecules	curated
R-HSA-9013407	RHOH GTPase cycle	curated
R-HSA-202430	Translocation of ZAP-70 to Immunological synapse	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers ⚕	—
R-HSA-9725370	Signaling by ALK fusions and activated point mutants ⚕	—
R-HSA-9700206	Signaling by ALK in cancer ⚕	—
R-HSA-1280218	Adaptive Immune System	—
R-HSA-168256	Immune System	—
R-HSA-9012999	RHO GTPase cycle	—
R-HSA-162582	Signal Transduction	—
R-HSA-194315	Signaling by Rho GTPases	—
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3	—
R-HSA-202403	TCR signaling	—

MSigDB gene sets: 405 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_B_CELL_ACTIVATION, BIOCARTA_TCRA_PATHWAY, GOBP_THYMIC_T_CELL_SELECTION, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GNF2_ZAP70

GO Biological Process (16): adaptive immune response (GO:0002250), protein phosphorylation (GO:0006468), immune response (GO:0006955), peptidyl-tyrosine phosphorylation (GO:0018108), T cell differentiation (GO:0030217), intracellular signal transduction (GO:0035556), T cell activation (GO:0042110), B cell activation (GO:0042113), positive thymic T cell selection (GO:0045059), positive regulation of T cell differentiation (GO:0045582), T cell receptor signaling pathway (GO:0050852), T cell aggregation (GO:0070489), T cell migration (GO:0072678), immune system process (GO:0002376), leukocyte cell-cell adhesion (GO:0007159), leukocyte migration (GO:0050900)

GO Molecular Function (9): phosphotyrosine residue binding (GO:0001784), protein tyrosine kinase activity (GO:0004713), non-membrane spanning protein tyrosine kinase activity (GO:0004715), ATP binding (GO:0005524), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (8): immunological synapse (GO:0001772), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), T cell receptor complex (GO:0042101), membrane (GO:0016020), membrane raft (GO:0045121)

Reactome top-level categories

11 top-level categories:

Category	Pathways
TCR signaling	2
RHO GTPase cycle	1
Signaling by ALK fusions and activated point mutants	1
Immune System	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Adaptive Immune System	1
Disease	1
Signaling by Rho GTPases	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Signal Transduction	1
Signaling by ALK in cancer	1

GO top-level categories

45 GO namespaces:

Category	Terms
cellular anatomical structure	4
immune system process	2
intracellular anatomical structure	2
lymphocyte activation	2
immune response	1
phosphorylation	1
protein modification process	1
response to stimulus	1
protein phosphorylation	1
lymphocyte differentiation	1
T cell activation	1
signal transduction	1
positive T cell selection	1
thymic T cell selection	1
T cell differentiation	1
regulation of T cell differentiation	1
positive regulation of lymphocyte differentiation	1
positive regulation of T cell activation	1
antigen receptor-mediated signaling pathway	1
lymphocyte aggregation	1
lymphocyte migration	1
biological_process	1
cell-cell adhesion	1
cell migration	1
protein phosphorylated amino acid binding	1
protein kinase activity	1
protein tyrosine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
plasma membrane	1
cytoplasm	1
membrane	1
cell periphery	1
anchoring junction	1
plasma membrane signaling receptor complex	1
membrane microdomain	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 33 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
T cell activation	BP	direct assay
T cell receptor signaling pathway	BP	direct assay
immune response	BP	direct assay
peptidyl-tyrosine phosphorylation	BP	direct assay
positive regulation of T cell differentiation	BP	direct assay
positive thymic T cell selection	BP	direct assay
protein phosphorylation	BP	direct assay
T cell receptor complex	CC	direct assay
cytoplasm	CC	direct assay
plasma membrane	CC	direct assay
non-membrane spanning protein tyrosine kinase activity	MF	direct assay
protein tyrosine kinase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,302 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZAP70	LCP2	Q13094	951
ZAP70	CD247	P20963	900
ZAP70	CD4	P01730	832
ZAP70	CD28	P10747	832
ZAP70	LAT	O43561	825
ZAP70	CD8A	P01732	810
ZAP70	UBASH3A	P57075	808
ZAP70	IL2	P01585	788
ZAP70	PTPN11	Q06124	779
ZAP70	UBASH3B	Q8TF42	774
ZAP70	IGHV4-38-2	P0DP08	771
ZAP70	LCK	P06239	769
ZAP70	VAV1	P15498	762
ZAP70	CD38	P28907	740
ZAP70	PLCG2	P16885	731

IntAct

Human interaction partners of ZAP70 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

21 partners by confidence:

Partner	Interaction type	MIscore	Records
CD247	physical association	0.920	24
LCK	phosphorylation reaction	0.700	3
EGFR	physical association	0.690	3
CBL	direct interaction	0.610	3
PTPN22	direct interaction	0.600	2
THEMIS	physical association	0.590	2
CD3E	association	0.530	3
KIT	direct interaction	0.440	2
MET	direct interaction	0.440	2
DAPK1	direct interaction	0.440	1
ERBB3	direct interaction	0.440	1
LRRK2	direct interaction	0.440	1
HSP90AA1	physical association	0.400	1
SHC1	physical association	0.400	1
ALK	physical association	0.370	1
ANAPC11	physical association	0.370	1
ASB3	physical association	0.370	1
NDUFB8	physical association	0.370	1
NR0B2	physical association	0.370	1
CRK	association	0.350	1
VAV1	association	0.350	1

BioGRID (135 interactions; top human partners by supporting records): CBL (Co-crystal Structure; 11 records), CD247 (Affinity Capture-Western; 10 records), EGFR (Two-hybrid; 5 records), SHC1 (Protein-peptide; 5 records), CBLB (Affinity Capture-Western; 4 records), DBNL (Affinity Capture-Western; 4 records), LAT (Biochemical Activity; 4 records), LCK (Affinity Capture-Western; 4 records), CD3E (Affinity Capture-Western; 3 records), PLCG1 (Affinity Capture-Western; 3 records), TUBA1A (Affinity Capture-Western; 3 records), CD3D (Affinity Capture-Western; 2 records), CD3G (Affinity Capture-Western; 2 records), ERBB3 (Reconstituted Complex; 2 records), FYN (Phenotypic Enhancement; 2 records)

SIGNOR signaling

showing 29 of 64 signaling interactions:

A	Effect	B	Mechanism
ZAP70	“up-regulates activity”	LCP2	phosphorylation
ZAP70	“up-regulates activity”	GAB2	phosphorylation
ZAP70	up-regulates	DBNL	phosphorylation
PTCRA	“up-regulates activity”	ZAP70	binding
ZAP70	“up-regulates activity”	MAPK14	phosphorylation
ZAP70	“up-regulates activity”	ZAP70	phosphorylation
PTPN22	down-regulates	ZAP70	dephosphorylation
ZAP70	“up-regulates activity”	LAT	phosphorylation
ZAP70	“up-regulates activity”	MUC1	phosphorylation
PTPN22	“down-regulates activity”	ZAP70	dephosphorylation
LCK	“up-regulates activity”	ZAP70	phosphorylation
LCK	unknown	ZAP70	phosphorylation
RHOH	“up-regulates activity”	ZAP70	binding
STOML2	“up-regulates activity”	ZAP70	binding
DLG1	“up-regulates activity”	ZAP70	phosphorylation
VAV1	“up-regulates activity”	ZAP70	binding
MAPK14	“down-regulates activity”	ZAP70	phosphorylation
ZAP70	“up-regulates activity”	VAV1	phosphorylation
FYN	“up-regulates activity”	ZAP70	phosphorylation
SRC	“up-regulates activity”	ZAP70	phosphorylation
ZAP70	“up-regulates activity”	SLC39A6	phosphorylation
ZAP70	up-regulates	LCP2	phosphorylation
LCK	“up-regulates activity”	ZAP70	binding
ZAP70	up-regulates	SH2B3	phosphorylation
ZAP70	up-regulates	SHC1	phosphorylation
PTPN6	down-regulates	ZAP70	dephosphorylation
ZAP70	up-regulates	DUSP3	phosphorylation
CD3	“up-regulates activity”	ZAP70	binding
PTPRG	“up-regulates activity”	ZAP70	dephosphorylation

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
CRKL-WAS-WIPF1-ZAP70 complex	4	CRKL, WAS, WIPF1, ZAP70
GRB2-p36/p38-PLCG1-SOS1-ZAP70 complex	4	GRB2, PLCG1, SOS1, ZAP70

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 21 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
Constitutive Signaling by Aberrant PI3K in Cancer	6	38.1×	2e-06
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	6	29.0×	2e-06
PIP3 activates AKT signaling	6	20.0×	1e-05
Diseases of signal transduction by growth factor receptors and second messengers	6	17.0×	3e-05
Signaling by Receptor Tyrosine Kinases	6	15.5×	4e-05
RAF/MAP kinase cascade	5	15.3×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor protein tyrosine kinase signaling pathway	5	41.4×	4e-05
T cell receptor signaling pathway	5	36.1×	4e-05
positive regulation of MAPK cascade	5	19.2×	5e-04
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	5	18.7×	5e-04
intracellular signal transduction	6	10.9×	7e-04
positive regulation of gene expression	5	9.2×	5e-03
negative regulation of apoptotic process	5	8.3×	7e-03

Disease & clinical

Genetic variants

Variant evidence for ZAP70: 596 ClinVar records (37 pathogenic / likely pathogenic); 10 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	13
Uncertain significance	224
Likely benign	268
Benign	20

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 37 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
13253	NM_001079.4(ZAP70):c.1624-11G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	8
38912	NM_001079.4(ZAP70):c.1393C>T (p.Arg465Cys)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
13256	NM_001079.4(ZAP70):c.1510_1522del (p.Lys504fs)	Pathogenic	criteria provided, single submitter	2
418647	NM_001079.4(ZAP70):c.1280del (p.Val427fs)	Pathogenic	criteria provided, single submitter	1
489150	NM_001079.4(ZAP70):c.117C>A (p.Cys39Ter)	Pathogenic	criteria provided, single submitter	1
567226	NM_001079.4(ZAP70):c.1247dup (p.Met416fs)	Pathogenic	criteria provided, single submitter	1
659957	NM_001079.4(ZAP70):c.1529_1532dup (p.Ile511fs)	Pathogenic	criteria provided, single submitter	1
827753	NM_001079.4(ZAP70):c.283C>T (p.Pro95Ser)	Pathogenic	criteria provided, single submitter	1
954252	NM_001079.4(ZAP70):c.261C>G (p.Tyr87Ter)	Pathogenic	criteria provided, single submitter	1
1072344	NM_001079.4(ZAP70):c.475G>T (p.Glu159Ter)	Pathogenic	criteria provided, single submitter	1
1390316	NM_001079.4(ZAP70):c.1518C>A (p.Tyr506Ter)	Pathogenic	criteria provided, single submitter	1
1394530	NM_001079.4(ZAP70):c.703-1G>A	Pathogenic	criteria provided, single submitter	1
1455724	NM_001079.4(ZAP70):c.847C>T (p.Arg283Ter)	Pathogenic	criteria provided, single submitter	1
2088832	NM_001079.4(ZAP70):c.1450A>T (p.Lys484Ter)	Pathogenic	criteria provided, single submitter	1
2501785	NM_001079.4(ZAP70):c.493del (p.His165fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore ZAP70’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; 34 predictions of 1,623):

Position(s)	Effect	Δscore	Sites
2:97724439–97724440	donor_loss	1.0000	5
2:97725090–97725091	acceptor_loss	1.0000	4
2:97733022–97733023	donor_loss	1.0000	5
2:97735457–97735458	donor_loss	1.0000	5
2:97737467	acceptor_gain	1.0000
2:97737471–97737472	acceptor_loss	1.0000	4
2:97737472	acceptor_gain	1.0000
2:97737667	donor_loss	1.0000	2
2:97737755–97737756	acceptor_loss	1.0000	6
2:97737983	acceptor_gain	1.0000

AlphaMissense

2,194 missense substitutions predicted likely pathogenic (of 4,066 scored), across 460 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
M449	9	0.990	1.000
M390	9	0.978	0.999
M414	9	0.936	0.998
M572	9	0.918	0.997
M411	9	0.887	0.988
M359	9	0.874	0.989
D461	8	1.000	1.000
N466	8	1.000	1.000
D479	8	1.000	1.000
D521	8	0.999	0.999
H459	8	0.998	1.000
F480	8	0.998	1.000
H210	8	0.994	0.999
F516	8	0.989	1.000
H58	8	0.986	0.997
F586	8	0.984	0.998
F229	8	0.983	1.000
F349	8	0.978	1.000
D230	8	0.977	0.994
D244	8	0.967	0.994

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
Head and Neck Squamous Cell Carcinoma (TCGA)	favorable	2.33e-05
Liver Hepatocellular Carcinoma (validation)	favorable	0.000127
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	favorable	0.000196

Disease associations

OMIM: gene MIM:176947 | disease phenotypes: MIM:269840, MIM:617006

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
combined immunodeficiency due to ZAP70 deficiency	Definitive	Autosomal recessive	4
autoimmune disease, multisystem, infantile-onset, 2	Strong	Autosomal recessive

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
combined immunodeficiency due to ZAP70 deficiency	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (4 panels, 2 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

4 panels:

Panel	Rating
COVID-19 research	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green
Gastrointestinal epithelial barrier disorders	amber
Infantile enterocolitis & monogenic inflammatory bowel disease	amber

Mondo (4): combined immunodeficiency due to ZAP70 deficiency (MONDO:0010023), severe combined immunodeficiency (MONDO:0015974), autoimmune disease, multisystem, infantile-onset, 2 (MONDO:0014861), combined immunodeficiency (MONDO:0015131)

Orphanet (3): Combined immunodeficiency due to ZAP70 deficiency (Orphanet:911), Severe combined immunodeficiency (Orphanet:183660), Combined T and B cell immunodeficiency (Orphanet:101972)

HPO phenotypes

59 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000100	Nephrotic syndrome
HP:0000155	Oral ulcer
HP:0000964	Eczematoid dermatitis
HP:0000988	Skin rash
HP:0001297	Stroke
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001744	Splenomegaly
HP:0001880	Increased total eosinophil count
HP:0001890	Autoimmune hemolytic anemia
HP:0001973	Autoimmune thrombocytopenia
HP:0002028	Chronic diarrhea
HP:0002090	Pneumonia
HP:0002205	Recurrent respiratory infections
HP:0002240	Hepatomegaly
HP:0002583	Colitis
HP:0002665	Lymphoma
HP:0002716	Lymphadenopathy
HP:0002718	Recurrent bacterial infections
HP:0002728	Recurrent mucocutaneous candidiasis
HP:0002733	Abnormal lymph node morphology
HP:0002788	Recurrent upper respiratory tract infections
HP:0002840	Lymphadenitis
HP:0002960	Autoimmunity
HP:0003139	Panhypogammaglobulinemia
HP:0003593	Infantile onset
HP:0004429	Recurrent viral infections
HP:0004798	Recurrent infection of the gastrointestinal tract
HP:0005390	Recurrent opportunistic infections
HP:0005401	Recurrent Candida infection
HP:0005406	Recurrent bacterial skin infections
HP:0005415	Decreased total CD8+ T cell proportion
HP:0005422	Absence of CD8+ T cells
HP:0005523	Lymphoproliferative disorder
HP:0009098	Recurrent oral thrush
HP:0010280	Stomatitis
HP:0010975	Abnormal total B cell count
HP:0011274	Recurrent mycobacterial infections
HP:0012476	Decreased circulating specific pneumococcal antibody concentration
HP:0012579	Minimal change glomerulonephritis
HP:0020102	Pneumocystis jirovecii pneumonia
HP:0025834	Impaired phytohemagglutinin-induced T lymphocyte transformation
HP:0031266	Podocyte foot process effacement
HP:0031381	Decreased mitogen-induced T-cell proliferation
HP:0031382	Decreased anti-CD3/28-induced T-cell proliferation
HP:0031540	Linear IgG deposits along the epidermal basement membrane zone
HP:0033221	Increased CD4:CD8 ratio
HP:0033399	Persistent fever
HP:0100827	Increased total lymphocyte count
HP:0200117	Recurrent upper and lower respiratory tract infections
HP:0410240	Abnormal circulating IgA concentration
HP:0410241	Abnormal circulating IgE concentration
HP:0410242	Abnormal circulating IgG concentration
HP:0410243	Abnormal circulating IgM concentration
HP:0410293	Absent circulating isohemagglutinin
HP:0410295	Complete or near-complete absence of specific antibody response to tetanus vaccine
HP:6001096	Decreased CD4+ T cell ZAP-70 protein expression

GWAS associations

10 associations:

Study	Trait	p-value
GCST010701_12	Cortical surface area (MOSTest)	2e-16
GCST010700_9	Cortical thickness (MOSTest)	9e-14
GCST006630_69	Diastolic blood pressure	6e-13
GCST010697_12	Cortical surface area (min-P)	6e-12
GCST010699_85	Brain morphology (min-P)	2e-11
GCST010703_48	Brain morphology (MOSTest)	1e-10
GCST010702_54	Subcortical volume (MOSTest)	5e-9
GCST010698_48	Subcortical volume (min-P)	9e-9
GCST008310_6	Cardiac Troponin-T levels	5e-7
GCST008103_114	Bipolar disorder	2e-6

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0005043	cardiac troponin T measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

MeSH disease descriptors

2 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
C536722	ZAP70 deficiency *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2803 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 74,098 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

14 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL288441	BOSUTINIB	4	12,869
CHEMBL2403108	CERITINIB	4	9,002
CHEMBL601719	CRIZOTINIB	4	15,133
CHEMBL1287853	FEDRATINIB	4	3,770
CHEMBL608533	MIDOSTAURIN	4	7,641
CHEMBL502835	NINTEDANIB	4	8,978
CHEMBL576982	QUIZARTINIB	4	4,647
CHEMBL603469	LESTAURTINIB	3
CHEMBL274654	ORANTINIB	3	3,745
CHEMBL276711	SEMAXANIB	3	6,384
CHEMBL215152	DEFOSBARASERTIB	2	381
CHEMBL3979920	MIVAVOTINIB	2	106
CHEMBL475251	R-406	2	787
CHEMBL1908397	KW-2449	1	655

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Syk family

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
mivavotinib	Inhibition	7.13	pIC50
aloisine	Inhibition	5.58	pKi
Syk inhibitor II	Inhibition	4.95	pIC50

Binding affinities (BindingDB)

311 measured of 494 human assays (497 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
6-(3-aminopropyl)-8-(4-morpholin-4-ylanilino)-2H-2,7-naphthyridin-1-one	IC50	1 nM	US-8546370: Compounds and compositions as kinase inhibitors
Staurosporine	KD	1.7 nM
8-[4-(1-methylpiperidin-4-yl)anilino]-6-pyrimidin-5-yl-2H-2,7-naphthyridin-1-one	IC50	2 nM	US-8546370: Compounds and compositions as kinase inhibitors
CHEMBL4582324	IC50	2 nM
6-(4-ethylpiperazin-1-yl)-8-(4-morpholin-4-ylanilino)-2H-2,7-naphthyridin-1-one	IC50	3 nM	US-8546370: Compounds and compositions as kinase inhibitors
CEP-701	KD	3.4 nM
5-((1S,2R)-2-aminocyclohexylamino)-7-(3,5-dimethoxyphenylamino)-[1,2,4]triazolo[1,5-f]pyrimidine-8-carboxamide	IC50	4 nM
CHEMBL4577049	IC50	4 nM
CHEMBL4545269	IC50	4 nM
CHEMBL4443654	IC50	4 nM
CHEMBL4445994	IC50	4 nM
CHEMBL4537527	IC50	4 nM
CERITINIB	IC50	5 nM	US-10053458: Pyrimidine-2,4-diamine derivative and anticancer pharmaceutical composition comprising same as effective ingredient
4-[4-[(5-tert-butyl-2-quinolin-6-ylpyrazol-3-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	IC50	5.5 nM
3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	IC50	5.6 nM	US-8822500: Tyrosine kinase inhibitors
cis-5-(2-Aminocyclohexylamino)-7-(3,5-dimethoxylphenylamino)imidazo[1,2-c]pyrimidine-8-carboxamide	IC50	6 nM
cis-5-(2-Aminocyclohexylamino)-7-(3,5-dimethylphenylamino)imidazo[1,2-c]pyrimidine-8-carboxamide	IC50	6 nM
Staurosporine, 8	IC50	6.5 nM
N,2-dimethyl-2-[4-[(8-oxo-3-pyrimidin-5-yl-7H-2,7-naphthyridin-1-yl)amino]phenyl]propanamide	IC50	8 nM	US-8546370: Compounds and compositions as kinase inhibitors
6-(5-methoxy-3-pyridinyl)-8-[4-[1-(3-oxobutyl)piperidin-4-yl]anilino]-2H-2,7-naphthyridin-1-one	IC50	8 nM	US-8546370: Compounds and compositions as kinase inhibitors
CHEMBL4437906	IC50	8 nM
CHEMBL4465866	KD	8 nM
5-(2-aminoethylamino)-7-(3,5-dimethoxyphenylamino)-[1,2,4]triazolo[4,3-c]pyrimidine-8-carboxamide	IC50	9 nM
5-((1S,2R)-2-aminocyclohexylamino)-7-(3,5-dimethoxyphenylamino)-[1,2,4]triazolo[4,3-c]pyrimidine-8-carboxamide	IC50	9 nM
4-(4-(5-chloro-4-(2-(propylsulfonyl)phenylamino)pyrimidin-2-ylamino)-3-methoxyphenyl)-N-methylpiperazine-1-carboxamide	IC50	10 nM
2-(5-bromo-2-(2,3-dihydro-1H-inden-4-ylamino)pyrimidin-4-ylamino)-N-methylbenzenesulfonamide	IC50	10 nM
{4-[6-((S)-3-Methyl-piperazin-1-yl)-pyridin-3-yl]-pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine	IC50	11 nM
CHEMBL4469360	IC50	13 nM
N-[4-[[(2-hydroxy-1H-indol-3-yl)-phenylmethylidene]amino]phenyl]-N-methyl-2-(4-methylpiperazin-1-yl)acetamide	KI	15 nM	US-10981896: Indolinone derivatives as inhibitors of maternal embryonic leucine zipper kinase
CHEMBL1240703	KD	15 nM
N-(4-(3-(2-(Methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-2-(phenylamino)benzamide	EC50	15 nM
N-(4-methyl-3-(3-(4-(methylamino)-1,3,5-triazin-2-yl)pyridin-2-yloxy)phenyl)-3-(1,1,2,2-tetrafluoroethoxy)benzamide	IC50	16 nM
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide	IC50	17 nM
3-methoxy-2-methyl-4-methylamino-(2S,3S,4S,6R)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8(13),9,11,14(28),15(19),20(27),21,23,25-nonaen-16-one	IC50	18 nM
3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid((S)-1-phenyl-2-pyrrolidin-1-yl-ethyl)-amide	IC50	18 nM
CHEMBL4568087	IC50	20 nM
CHEMBL4483095	IC50	21 nM
8-(4-morpholin-4-ylanilino)-6-(2,2,2-trifluoroethylamino)-2H-2,7-naphthyridin-1-one	IC50	24 nM	US-8546370: Compounds and compositions as kinase inhibitors
4-(4-Fluorophenyl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)-pyridin-2-yloxy)phenyl)phthalazin-1-amine	EC50	24 nM
{4-[6-(3-Methyl-piperazin-1-yl)-pyridin-3-yl]-pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine	IC50	26 nM
N-(2,6-difluorophenyl)-5-(3-(2-(5-ethyl-2-methoxy-4-(4-(4-(methylsulfonyl)piperazin-1-yl)piperidin-1-yl)phenylamino)pyrimidin-4-yl)imidazo[1,2-a]pyridin-2-yl)-2-methoxybenzamide	IC50	27 nM
5-((1S,2R)-2-Aminocyclohexylamino)-7-(3,5-dimethoxyphenylamino)-2-phenylimidazo[1,2-c]pyrimidine-8-carboxamide	IC50	28 nM
NQLPpYNELNLGRREEpYDVLD	IC50	30 nM
cis-5-(2-Aminocyclohexylamino)-7-(3-methoxyphenylamino)imidazo[1,2-c]pyrimidine-8-carboxamide	IC50	30 nM
cis-5-(2-Aminocyclohexylamino)-7-(3,5-difluorophenylamino)imidazo[1,2-c]pyrimidine-8-carboxamide	IC50	30 nM
6-(6-methoxypyrazin-2-yl)-8-[3-methyl-4-(oxan-4-yl)anilino]-2H-2,7-naphthyridin-1-one	IC50	31 nM	US-8546370: Compounds and compositions as kinase inhibitors
[4-(6-[1,4]Diazepan-1-yl-pyridin-3-yl)-pyrimidin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine	IC50	31 nM
6-[[(1R,2S)-2-aminocyclohexyl]amino]-7-fluoro-4-(1-methylpyrazol-4-yl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one	IC50	31 nM	US-11077111: Use of fused heteroaromatic pyrrolidones for treatment and prevention of diseases in animals
(Z)-3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid	IC50	35 nM

ChEMBL bioactivities

290 potent at pChembl≥5 of 340 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL3642578
8.96	IC50	1.1	nM	STAUROSPORINE
8.89	IC50	1.3	nM	STAUROSPORINE
8.70	IC50	2	nM	CHEMBL3642585
8.52	IC50	3	nM	CHEMBL3642579
8.48	IC50	3.29	nM	STAUROSPORINE
8.34	IC50	4.6	nM	CHEMBL5416354
8.28	IC50	5.3	nM	CHEMBL3415583
8.28	IC50	5.2	nM	CHEMBL5415461
8.13	IC50	7.35	nM	STAUROSPORINE
8.10	IC50	8	nM	CHEMBL3642588
8.10	IC50	8	nM	CHEMBL3642590
8.10	IC50	8	nM	CHEMBL112346
8.06	IC50	8.63	nM	STAUROSPORINE
8.05	IC50	9	nM	CHEMBL3642579
8.05	IC50	8.9	nM	CHEMBL5404631
8.03	IC50	9.4	nM	CHEMBL5417597
8.00	IC50	10	nM	CHEMBL573483
8.00	IC50	10	nM	CHEMBL575048
7.98	IC50	10.4	nM	CHEMBL5397244
7.96	IC50	11	nM	CHEMBL325912
7.91	IC50	12.4	nM	STAUROSPORINE
7.91	IC50	12.3	nM	STAUROSPORINE
7.85	IC50	14	nM	CHEMBL3262616
7.85	Kd	14	nM	CHEMBL4786316
7.84	IC50	14.6	nM	CHEMBL5414412
7.80	Kd	16	nM	LESTAURTINIB
7.75	IC50	18	nM	CHEMBL3262622
7.68	Kd	21	nM	R-406
7.62	IC50	24	nM	CHEMBL3642587
7.62	IC50	24	nM	MRL-SYKi
7.58	IC50	26	nM	CHEMBL112518
7.55	EC50	28	nM	CHEMBL4582324
7.52	IC50	30	nM	CHEMBL439120
7.52	IC50	30.5	nM	CHEMBL5434338
7.51	IC50	31	nM	CHEMBL3642596
7.51	IC50	31	nM	CHEMBL112172
7.48	IC50	33	nM	CHEMBL3262357
7.42	IC50	38	nM	CHEMBL411163
7.40	IC50	40	nM	CHEMBL573019
7.39	EC50	41	nM	CHEMBL4445994
7.39	IC50	41	nM	CHEMBL459147
7.38	IC50	42	nM	R-406
7.38	EC50	42	nM	CHEMBL4577049
7.36	IC50	44	nM	CHEMBL3642583
7.36	Kd	44	nM	STAUROSPORINE
7.35	IC50	44.8	nM	CHEMBL4870513
7.34	IC50	46	nM	CHEMBL3642595
7.34	IC50	46	nM	CHEMBL420672
7.33	IC50	47	nM	CHEMBL3262620

PubChem BioAssay actives

312 with measured affinity, of 1514 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1762564: Inhibition of N-terminal GST-fused human recombinant full length ZAP70 (1 to 619 residues) expressed in baculovirus-infected Sf21 cells using FAM-22 peptide as substrate preincubated with enzyme for 10 mins followed by substrate addition for 30 mins in presence of ATP by caliper mobility shift assay	ic50	0.0011	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-[3-methoxy-4-(4-methylpiperazin-1-yl)anilino]imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0046	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-[3-methoxy-4-[4-(oxetan-3-yl)piperazin-1-yl]anilino]imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0052	uM
5-[[(1R,2S)-2-aminocyclohexyl]amino]-3-[(4,6-dimethyl-2-pyridinyl)amino]pyridine-2-carboxamide	1199534: Inhibition of GST-fused Zap70 (unknown origin) expressed in insect SF9 cells using biotin-EQEDEPEGDYFEWLE-CONH2 as substrate preincubated for 10 mins followed by substrate/ATP addition measured after 45 mins by TR-FRET assay	ic50	0.0053	uM
4-[6-[(3S)-3-ethylpiperazin-1-yl]-3-pyridinyl]-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine	220426: Inhibition of Zeta-chain (TCR) associated protein kinase 70 kDa phosphorylation of polyGly-Tyr.	ic50	0.0080	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-[4-(4-hydroxypiperidin-1-yl)-3-methoxyanilino]imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0089	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-(3-ethoxy-4-morpholin-4-ylanilino)imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0094	uM
4-[4-[[5-chloro-4-(2-propylsulfonylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]-N-methylpiperazine-1-carboxamide	440573: Inhibition of human GST-fused ZAP-70 expressed in Sf9 cells	ic50	0.0100	uM
2-[[5-bromo-2-(2,3-dihydro-1H-inden-4-ylamino)pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide	440573: Inhibition of human GST-fused ZAP-70 expressed in Sf9 cells	ic50	0.0100	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-[3-methoxy-4-(4-methyl-1,4-diazepan-1-yl)anilino]imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0104	uM
4-[6-[(3S)-3-methylpiperazin-1-yl]-3-pyridinyl]-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine	220426: Inhibition of Zeta-chain (TCR) associated protein kinase 70 kDa phosphorylation of polyGly-Tyr.	ic50	0.0110	uM
7-[[(1R,2S)-2-aminocyclohexyl]amino]-5-(1H-indol-4-ylamino)-3H-pyrido[4,3-d]pyrimidin-4-one	1140427: Inhibition of ZAP70 (unknown origin)	ic50	0.0140	uM
5-[[4-[4-[(dimethylamino)methyl]pyrazol-1-yl]pyrimidin-2-yl]amino]-N,1-dimethylindazole-3-carboxamide	1681029: Binding affinity to ZAP70 (unknown origin)	kd	0.0140	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-(3-methoxy-4-morpholin-4-ylanilino)imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0146	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	508138: Binding affinity to ZAP70	kd	0.0160	uM
6-[[(3R,4R)-3-aminooxan-4-yl]amino]-8-[(2-methylindazol-4-yl)amino]-2H-2,7-naphthyridin-1-one	1140427: Inhibition of ZAP70 (unknown origin)	ic50	0.0180	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624744: Binding constant for ZAP70 kinase domain	kd	0.0210	uM
4-[6-(3-methylpiperazin-1-yl)-3-pyridinyl]-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine	220426: Inhibition of Zeta-chain (TCR) associated protein kinase 70 kDa phosphorylation of polyGly-Tyr.	ic50	0.0260	uM
1-[1-(tert-butylcarbamoyl)piperidin-4-yl]-N-[4-[(6-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)amino]-3-methylphenyl]indazole-3-carboxamide	1512570: Effect on ZAP70 phosphorylation in human Jurkat cells pre-incubated for 30 mins followed by anti-CD3/CD28 stimulation measured after 10 mins	ec50	0.0280	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2,4-diamino-4-oxobutanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]pyrrolidine-2-carbonyl]amino]-3-(4-phosphonooxyphenyl)propanoyl]amino]-4-oxobutanoyl]amino]-4-carboxybutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-4-carboxybutanoyl]amino]-4-carboxybutanoyl]amino]-3-(4-phosphonooxyphenyl)propanoyl]amino]-3-carboxypropanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]butanedioic acid	221985: Inhibition of binding to human ZAP-70 SH2 domain	ic50	0.0300	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-[3-(hydroxymethyl)-4-morpholin-4-ylanilino]imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0305	uM
4-[6-(1,4-diazepan-1-yl)-3-pyridinyl]-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine	220426: Inhibition of Zeta-chain (TCR) associated protein kinase 70 kDa phosphorylation of polyGly-Tyr.	ic50	0.0310	uM
7-[[(1R,2S)-2-aminocyclohexyl]amino]-5-[(3-methyl-1H-indol-7-yl)amino]-3H-pyrido[4,3-d]pyrimidin-4-one	1140427: Inhibition of ZAP70 (unknown origin)	ic50	0.0330	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-amino-4-oxobutanoyl]amino]-5-amino-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-3-(4-phosphonooxyphenyl)propanoyl]amino]-4-amino-4-oxobutanoyl]amino]-4-carboxybutanoyl]amino]-4-methylpentanoyl]amino]-4-amino-4-oxobutanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-carboxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-1-oxo-3-(4-phosphonooxyphenyl)propan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	220421: Binding affinity against SH2 domain of Zeta-chain (TCR) associated protein kinase 70 kDa	ic50	0.0380	uM
4-[4-[[5-chloro-4-(2-propylsulfonylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]-N,N-dimethylpiperazine-1-carboxamide	440573: Inhibition of human GST-fused ZAP-70 expressed in Sf9 cells	ic50	0.0400	uM
5-[[(1S,2R)-2-aminocyclohexyl]amino]-7-(3,5-dimethoxyanilino)-2-phenylimidazo[1,2-c]pyrimidine-8-carboxamide	389369: Inhibition of human ZAP70 expressed in Sf9 cells	ic50	0.0410	uM
N-[3-chloro-4-[(6-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)amino]phenyl]-1-[1-(3-cyano-3-methylbutanoyl)piperidin-4-yl]-5-fluoroindazole-3-carboxamide	1512570: Effect on ZAP70 phosphorylation in human Jurkat cells pre-incubated for 30 mins followed by anti-CD3/CD28 stimulation measured after 10 mins	ec50	0.0410	uM
1-[1-(tert-butylcarbamoyl)piperidin-4-yl]-N-[3-methyl-4-(pyrazolo[1,5-a]pyridine-3-carbonylamino)phenyl]indazole-3-carboxamide	1512570: Effect on ZAP70 phosphorylation in human Jurkat cells pre-incubated for 30 mins followed by anti-CD3/CD28 stimulation measured after 10 mins	ec50	0.0420	uM
5-[[3-[(2-chloroacetyl)amino]phenyl]methylamino]-7-(3,5-dimethoxyanilino)imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0448	uM
4-[6-(4-methylpiperazin-1-yl)-3-pyridinyl]-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine	220426: Inhibition of Zeta-chain (TCR) associated protein kinase 70 kDa phosphorylation of polyGly-Tyr.	ic50	0.0460	uM
(E)-3-[4-[[[8-carbamoyl-7-(3,5-dimethoxyanilino)imidazo[1,2-c]pyrimidin-5-yl]amino]methyl]phenyl]prop-2-enoic acid	1798683: Intracellular ZAP-70 Kinase Inhibition Assay from Article 10.1016/j.bmc.2008.10.070: “Structure-activity relationship studies of 5-benzylaminoimidazo[1,2-c]pyrimidine-8-carboxamide derivatives as potent, highly selective ZAP-70 kinase inhibitors.”	ic50	0.0470	uM
7-[[(3R,4R)-3-aminooxan-4-yl]amino]-5-[(3-methyl-1H-indol-7-yl)amino]-3H-pyrido[4,3-d]pyrimidin-4-one	1140427: Inhibition of ZAP70 (unknown origin)	ic50	0.0470	uM
7-(3,5-dimethoxyanilino)-5-[[4-fluoro-3-(prop-2-enoylamino)phenyl]methylamino]imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0475	uM
1-[1-(tert-butylcarbamoyl)piperidin-4-yl]-N-[3-chloro-4-(pyrazolo[1,5-a]pyridine-3-carbonylamino)phenyl]indazole-3-carboxamide	1512570: Effect on ZAP70 phosphorylation in human Jurkat cells pre-incubated for 30 mins followed by anti-CD3/CD28 stimulation measured after 10 mins	ec50	0.0490	uM
2-[[5-chloro-2-[4-[3-(dimethylamino)-2,2-dimethylpropoxy]-2-methoxyanilino]pyrimidin-4-yl]amino]-N-propan-2-ylbenzenesulfonamide	440573: Inhibition of human GST-fused ZAP-70 expressed in Sf9 cells	ic50	0.0500	uM
4-(6-piperazin-1-yl-3-pyridinyl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine	220426: Inhibition of Zeta-chain (TCR) associated protein kinase 70 kDa phosphorylation of polyGly-Tyr.	ic50	0.0540	uM
1-[1-(tert-butylcarbamoyl)piperidin-4-yl]-N-[3-chloro-4-[(6-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)amino]phenyl]-5-fluoroindazole-3-carboxamide	1512570: Effect on ZAP70 phosphorylation in human Jurkat cells pre-incubated for 30 mins followed by anti-CD3/CD28 stimulation measured after 10 mins	ec50	0.0560	uM
7-(3,5-dimethoxyanilino)-5-[[2-(prop-2-enoylamino)-4-pyridinyl]methylamino]imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0583	uM
2-[[(1R,2S)-2-aminocyclohexyl]amino]-4-[3-(triazol-2-yl)anilino]pyrimidine-5-carboxamide	1140427: Inhibition of ZAP70 (unknown origin)	ic50	0.0600	uM
3-[[(1R,2S)-2-aminocyclohexyl]amino]-5-(1H-indol-7-ylamino)-1,2,4-triazine-6-carboxamide	1199675: Competitive binding affinity to human ZAP70	kd	0.0650	uM
2-[[5-bromo-2-[3-(dimethylamino)-2-methylanilino]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide	440573: Inhibition of human GST-fused ZAP-70 expressed in Sf9 cells	ic50	0.0700	uM
5-[[4-[4-[(dimethylamino)methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-N,1-dimethylindazole-3-carboxamide	1681029: Binding affinity to ZAP70 (unknown origin)	kd	0.0730	uM
7-[[(1R,2S)-2-aminocyclohexyl]amino]-5-[3-(triazol-2-yl)anilino]-3H-pyrido[4,3-d]pyrimidin-4-one	1140427: Inhibition of ZAP70 (unknown origin)	ic50	0.0740	uM
5-[[4-chloro-3-(prop-2-enoylamino)phenyl]methylamino]-7-(4-morpholin-4-ylanilino)imidazo[1,2-c]pyrimidine-8-carboxamide	2012593: Inhibition of ZAP-70 (unknown origin) using ULight-TK peptide as substrate incubated for 120 mins in presence of ATP by Lance Ultra Kinase assay	ic50	0.0748	uM
6-[[(1R,2S)-2-aminocyclohexyl]amino]-7-fluoro-4-(1-methylpyrazol-4-yl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one	1330028: Inhibition of human full length N-terminal GST-tagged ZAP-70 (1 to 619 residues) expressed in baculovirus expression system using ULight peptide as substrate after 1 hr in presence of ATP by TR-FRET assay	ic50	0.0750	uM
2-[[5-bromo-2-[2-methoxy-4-(2-methylimidazol-1-yl)anilino]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide	440573: Inhibition of human GST-fused ZAP-70 expressed in Sf9 cells	ic50	0.0800	uM
6-[[(1R,2S)-2-aminocyclohexyl]amino]-8-[(3-methyl-1H-indol-7-yl)amino]-2H-2,7-naphthyridin-1-one	1140427: Inhibition of ZAP70 (unknown origin)	ic50	0.0810	uM
ethyl (E)-3-[4-[[[8-carbamoyl-7-(3,5-dimethoxyanilino)imidazo[1,2-c]pyrimidin-5-yl]amino]methyl]phenyl]prop-2-enoate	1798683: Intracellular ZAP-70 Kinase Inhibition Assay from Article 10.1016/j.bmc.2008.10.070: “Structure-activity relationship studies of 5-benzylaminoimidazo[1,2-c]pyrimidine-8-carboxamide derivatives as potent, highly selective ZAP-70 kinase inhibitors.”	ic50	0.0880	uM
1-[1-(3-cyano-3-methylbutanoyl)piperidin-4-yl]-N-[3-methyl-4-(pyrazolo[1,5-a]pyridine-3-carbonylamino)phenyl]indazole-3-carboxamide	1512570: Effect on ZAP70 phosphorylation in human Jurkat cells pre-incubated for 30 mins followed by anti-CD3/CD28 stimulation measured after 10 mins	ec50	0.0880	uM
1-[4-[[5-chloro-4-(2-propylsulfonylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]piperidine-4-carboxamide	440573: Inhibition of human GST-fused ZAP-70 expressed in Sf9 cells	ic50	0.0900	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases mutagenesis	4
(+)-JQ1 compound	decreases expression	3
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
Nickel	increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
GSK-J4	increases expression	1
perfluorooctanoic acid	decreases expression	1
aflatoxin B2	decreases methylation	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
entinostat	increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
bisperoxovanadium	affects reaction, increases expression	1
ON 01910	decreases phosphorylation	1
Dasatinib	increases response to substance	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Allergens	affects cotreatment, increases expression	1
Vehicle Emissions	affects cotreatment, increases expression	1
Camptothecin	decreases response to substance	1
Polycyclic Aromatic Hydrocarbons	increases activity	1
Valproic Acid	increases methylation	1
Vanadium	decreases expression	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	decreases expression	1
Copper Sulfate	increases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

451 unique, capped per target: 448 binding, 2 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1006346	Binding	Inhibition of Tel-fused ZAP70 kinase-mediated mouse BaF3 cell proliferation	Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. — *Proc Natl Acad Sci U S A*
CHEMBL4424915	ADMET	Inhibition of human full-length C-terminal His6-tagged ZAP70 expressed in baculovirus infected Sf21 insect cells using Poly (Glu4-Tyr) (4:1) as substrate	Optimization of an azetidine series as inhibitors of colony stimulating factor-1 receptor (CSF-1R) Type II to lead to the clinical candidate JTE-952. — *Bioorg Med Chem Lett*
CHEMBL823525	Functional	Antagonistic activity at 100 uMolar concentration to the SH2 domain of ZAP-70 protein.	Solid phase synthesis of a biased mini tetrapeptoid-library for the discovery of monodentate ITAM mimics as ZAP-70 inhibitors. — *Bioorg Med Chem Lett*

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_6430	P116.cl39	Cancer cell line	Male
CVCL_B2LM	Abcam HeLa ZAP70 KO	Cancer cell line	Female
CVCL_B7VC	Abcam Jurkat ZAP70 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

48 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
NCT02737384	Phase 2	TERMINATED	Hematopoietic Stem Cells Transplantation in Children With Combined Immunodeficiency (CID)
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
NCT03655223	Not specified	ACTIVE_NOT_RECRUITING	Early Check: Expanded Screening in Newborns
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
NCT02915406	Not specified	NO_LONGER_AVAILABLE	cliniMACs HUD for T Cell Depletion
NCT04902807	Not specified	COMPLETED	Conception of a Diagnosis, Prognosis and Therapeutic Decision Tool for Patients With Autoimmunity and Inflammation

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ZAP70 across ~30M SureChEMBL compounds — explore on Sugi Predict.