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NFATC1

gene
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Also known as NF-ATCNFATcNFAT2

Summary

NFATC1 (nuclear factor of activated T cells 1, HGNC:7775) is a protein-coding gene on chromosome 18q23, encoding Nuclear factor of activated T-cells, cytoplasmic 1 (O95644). Plays a role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2 or IL-4 gene transcription.

The product of this gene is a component of the nuclear factor of activated T cells DNA-binding transcription complex. This complex consists of at least two components: a preexisting cytosolic component that translocates to the nucleus upon T cell receptor (TCR) stimulation, and an inducible nuclear component. Proteins belonging to this family of transcription factors play a central role in inducible gene transcription during immune response. The product of this gene is an inducible nuclear component. It functions as a major molecular target for the immunosuppressive drugs such as cyclosporin A. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. Different isoforms of this protein may regulate inducible expression of different cytokine genes.

Source: NCBI Gene 4772 — RefSeq curated summary.

At a glance

  • Gene–disease (curated): inborn error of immunity (Moderate, GenCC) — +1 more curated relationship
  • GWAS associations: 59 (top 1% of genes corpus-wide)
  • Clinical variants (ClinVar): 399 total — 2 pathogenic (top 8% of genes corpus-wide)
  • GTEx eGene: eQTL in 23 tissues, sQTL in 7 (q < 0.05)
  • Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.46 (moderately constrained)
  • Transcription factor: yes — 131 downstream targets (CollecTRI)
  • MANE Select transcript: NM_001278669
  • Interaction hub: 2,546 STRING partners (top 4% of genes corpus-wide)
  • Notable: 399 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:7775
Approved symbolNFATC1
Namenuclear factor of activated T cells 1
Location18q23
Locus typegene with protein product
StatusApproved
AliasesNF-ATC, NFATc, NFAT2
Ensembl geneENSG00000131196
Ensembl biotypeprotein_coding
OMIM600489
Entrez4772

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 12 protein_coding, 4 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

MANE Select: ENST00000427363

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 11, TSL 2: 4, TSL 3: 3

ENST00000427363, ENST00000253506, ENST00000318065, ENST00000329101, ENST00000397790, ENST00000542384, ENST00000545796, ENST00000586434, ENST00000586695, ENST00000587635, ENST00000590172, ENST00000590224, ENST00000590313, ENST00000590861, ENST00000591065, ENST00000591089, ENST00000591814, ENST00000592223, ENST00001131627

RefSeq mRNA: 10 — MANE Select: NM_001278669 NM_001278669, NM_001278670, NM_001278672, NM_001278673, NM_001278675, NM_006162, NM_172387, NM_172388, NM_172389, NM_172390

CCDS: CCDS12015, CCDS12016, CCDS32850, CCDS59326, CCDS59327, CCDS62467, CCDS62468, CCDS62469, CCDS62470, CCDS62471

Canonical transcript exons

ENST00000427363 — 10 exons

ExonStartEnd
ENSE000022448197941040379411501
ENSE000035010177948624879486937
ENSE000035284907945167679451816
ENSE000035406547943357979433738
ENSE000035559627946131179461366
ENSE000035915557944878279448984
ENSE000036717047946745079467582
ENSE000036893587945095479451126
ENSE000039068267952752879529323
ENSE000039075377939593079396351

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 92.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.8498 / max 594.9656, expressed in 1668 samples.

Highest expression (Bgee): oocyte, hindlimb stylopod muscle, secondary oocyte, skeletal muscle tissue of rectus abdominis, triceps brachii.

Genetic regulation across tissues (GTEx eQTL / sQTL)

NFATC1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 23 tissues and its splicing (sQTL) in 7 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 30 significant tissue × QTL associations:

TissueQTLq-valueSlopeLead variant
Muscle Skeletaleqtl7.5e-52-0.3618:79400235:A:C
Heart Left Ventricleeqtl5.5e-11-0.2718:79400235:A:C
Stomacheqtl3.1e-09+0.2618:79400367:C:CGCCCCG
Whole Bloodeqtl9.4e-09-0.1318:79400235:A:C
Adrenal Glandeqtl2.2e-07+1.2118:79401324:G:A
Pancreaseqtl6.0e-07-0.3418:79400235:A:C
Adipose Subcutaneouseqtl6.2e-07-0.2018:79400235:A:C
Muscle Skeletalsqtl1.5e-06+0.3018:79400235:A:C
Cells EBV-transformed lymphocytessqtl3.5e-06-0.7018:79461095:T:G
Livereqtl7.0e-06-0.5018:79397846:T:C
Testiseqtl5.1e-05-0.2718:79404056:G:A
Cells Cultured fibroblastseqtl1.7e-04+0.1718:79461539:A:G
Skin Not Sun Exposed Suprapubiceqtl2.5e-04+0.1518:79400367:C:CGCCCCG
Testissqtl2.5e-04-0.4218:79504442:C:T
Brain Caudate basal gangliaeqtl7.6e-04+0.1418:79545852:A:G
Thyroideqtl8.8e-04-0.3518:79479775:G:A
Breast Mammary Tissueeqtl2.3e-03-0.1918:79400235:A:C
Skin Sun Exposed Lower legeqtl2.4e-03+0.1518:79400367:C:CGCCCCG
Spleensqtl3.3e-03+0.6218:79461094:C:T
Brain Putamen basal gangliasqtl3.3e-03+0.5118:78398154:C:A

FANTOM5 promoters

3 alternative TSS:

Promoter IDTPM avgSamples expressed
1709029.35891230
1709047.20271556
1709030.2882126

Top tissues by expression

showing 100 of 280 tissues by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
oocyteCL:000002392.69gold quality
hindlimb stylopod muscleUBERON:000425292.40gold quality
secondary oocyteCL:000065592.39gold quality
skeletal muscle tissue of rectus abdominisUBERON:000451192.08gold quality
triceps brachiiUBERON:000150991.62gold quality
gastrocnemiusUBERON:000138890.59gold quality
skeletal muscle tissue of biceps brachiiUBERON:000450290.51gold quality
muscle of legUBERON:000138390.45gold quality
sural nerveUBERON:001548890.11gold quality
muscle organUBERON:000163090.08gold quality
gluteal muscleUBERON:000200089.73gold quality
skeletal muscle tissueUBERON:000113489.56gold quality
vastus lateralisUBERON:000137989.30gold quality
periodontal ligamentUBERON:000826689.15gold quality
biceps brachiiUBERON:000150789.08gold quality
tendon of biceps brachiiUBERON:000818889.02gold quality
quadriceps femorisUBERON:000137788.81gold quality
deltoidUBERON:000147687.63gold quality
lymph nodeUBERON:000002987.26gold quality
muscle tissueUBERON:000238587.13gold quality
hair follicleUBERON:000207387.10gold quality
tibial nerveUBERON:000132386.76gold quality
spermCL:000001986.51gold quality
spleenUBERON:000210686.46gold quality
tibiaUBERON:000097986.15gold quality
granulocyteCL:000009485.82gold quality
male germ cellCL:000001585.32gold quality
synovial jointUBERON:000221785.32gold quality
tibialis anteriorUBERON:000138585.15silver quality
parietal pleuraUBERON:000240084.81gold quality
apex of heartUBERON:000209884.68gold quality
gall bladderUBERON:000211084.48gold quality
pleuraUBERON:000097784.47gold quality
bloodUBERON:000017884.46gold quality
layer of synovial tissueUBERON:000761684.40gold quality
ascending aortaUBERON:000149684.19gold quality
tibial arteryUBERON:000761084.19gold quality
popliteal arteryUBERON:000225084.15gold quality
aortaUBERON:000094784.06gold quality
thoracic aortaUBERON:000151584.03gold quality
parotid glandUBERON:000183183.95gold quality
descending thoracic aortaUBERON:000234583.94gold quality
leukocyteCL:000073883.83gold quality
right lungUBERON:000216783.78gold quality
right atrium auricular regionUBERON:000663183.77gold quality
monocyteCL:000057683.59gold quality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099183.57gold quality
visceral pleuraUBERON:000240183.57gold quality
mononuclear cellCL:000084283.41gold quality
omental fat padUBERON:001041483.21gold quality
peritoneumUBERON:000235883.14gold quality
male germ line stem cell (sensu Vertebrata) in testisCL:0000089 ∩ UBERON:000047383.05gold quality
tendonUBERON:000004383.04gold quality
adipose tissue of abdominal regionUBERON:000780882.90gold quality
diaphragmUBERON:000110382.76silver quality
cardiac atriumUBERON:000208182.71gold quality
lower esophagus muscularis layerUBERON:003583382.64gold quality
lower esophagusUBERON:001347382.55gold quality
heart left ventricleUBERON:000208481.94gold quality
upper lobe of left lungUBERON:000895281.91gold quality
esophagogastric junction muscularis propriaUBERON:003584181.88gold quality
left coronary arteryUBERON:000162681.84gold quality
vermiform appendixUBERON:000115481.82gold quality
left uterine tubeUBERON:000130381.77gold quality
skin of legUBERON:000151181.70gold quality
cardiac ventricleUBERON:000208281.63gold quality
subcutaneous adipose tissueUBERON:000219081.59gold quality
skin of abdomenUBERON:000141681.55gold quality
upper lobe of lungUBERON:000894881.35gold quality
muscle layer of sigmoid colonUBERON:003580581.22gold quality
coronary arteryUBERON:000162181.07gold quality
heartUBERON:000094881.06gold quality
olfactory segment of nasal mucosaUBERON:000538680.98gold quality
adipose tissueUBERON:000101380.95gold quality
connective tissueUBERON:000238480.92gold quality
zone of skinUBERON:000001480.88gold quality
calcaneal tendonUBERON:000370180.78gold quality
small intestine Peyer’s patchUBERON:000345480.67gold quality
mucosa of stomachUBERON:000119980.63gold quality
metanephric glomerulusUBERON:000473680.56gold quality
right coronary arteryUBERON:000162580.43gold quality
cartilage tissueUBERON:000241880.39gold quality
renal glomerulusUBERON:000007480.01gold quality
superficial temporal arteryUBERON:000161479.90gold quality
bronchial epithelial cellCL:000232879.05gold quality
body of uterusUBERON:000985378.90gold quality
tonsilUBERON:000237278.87gold quality
caecumUBERON:000115378.78gold quality
small intestineUBERON:000210878.71gold quality
left testisUBERON:000453378.56gold quality
trabecular bone tissueUBERON:000248378.42gold quality
epithelium of bronchusUBERON:000203178.27gold quality
right testisUBERON:000453478.19gold quality
skin of hipUBERON:000155478.12gold quality
bronchusUBERON:000218577.93gold quality
testisUBERON:000047377.83gold quality
sigmoid colonUBERON:000115977.64gold quality
lungUBERON:000204877.47gold quality
left lobe of thyroid glandUBERON:000112077.28gold quality
cauda epididymisUBERON:000436077.26gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

ExperimentMarker?Max mean expression
E-MTAB-7008yes188.32
E-CURD-112yes14.85
E-GEOD-135922yes9.71
E-ANND-3yes6.82

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cellAxisnTPMProtein (IHC)
Choroid plexustissue57.4
Skeletal muscletissue26.1not detected
Lymph nodetissue19.8high
Tonsiltissue12.7high
Spleentissue12.1low
Appendixtissue11.0high
Spinal cordtissue10.3
Olfactory bulbtissue9.7
Gallbladdertissue9.4not detected
Adipose tissuetissue8.7not detected
Tonguetissue8.7
Periaqueductal graytissue8.6
Locus coeruleustissue8.4
Hippocampustissue7.9not detected
Thymustissue7.8
Hypothalamustissue7.5
Substantia nigratissue7.4
Heart muscletissue6.8not detected
Pancreastissue6.6not detected
Nucleus accumbenstissue6.5
Medulla oblongatatissue6.2
Lungtissue6.0not detected
Corpus callosumtissue6.0
Septumtissue6.0
Urinary bladdertissue5.9not detected
Ponstissue5.6
Vaginatissue5.6not detected
Midbraintissue5.4
Basal gangliatissue5.3not detected
Thalamustissue5.3
Putamentissue5.2
Superior colliculitissue5.1
Stomach 1tissue5.0not detected
Hippocampal formationtissue4.8
Ventral forebraintissue4.7
Testistissue4.5not detected
Amygdalatissue4.3
Skin 1tissue4.2not detected
Ovarytissue3.8not detected
Parathyroid glandtissue3.8not detected
Placentatissue3.8not detected
Cerebral cortextissue3.7not detected
Bone marrowtissue3.7medium
Insular cortextissue3.7
Breasttissue3.6not detected
Endometrium 1tissue3.6not detected
Fallopian tubetissue3.4not detected
Pituitary glandtissue3.3
Motor cortextissue3.3
Entorhinal cortextissue3.3
Prefrontal cortextissue3.2
Postcentral gyrustissue3.1
Retrosplenial cortextissue3.1
Smooth muscletissue3.0not detected
Retrosplenial and cingulate cortextissue3.0
Temporal cortextissue3.0
Duodenumtissue2.9not detected
Caudate putamentissue2.9
Esophagustissue2.8not detected
Cervixtissue2.7not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Nucleus gracilis (17.1), Area postrema (16.4), Cervical spinal cord, central gray (15.3), Nucleus tractus solitarii (14.8), Periaquaductal grey, lateral (14.8).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

showing 30 of 131 targets:

TargetRegulation
ACHE
ACP5
ADAM2
AKT1
AQP2
ATP6V0D2
ATP6V1B2
B3GAT3Repression
BCL2
BGLAPRepression
BMP7Activation
CALCR
CCNA2Activation
CCND1Unknown
CCR9
CD3GActivation
CD40
CD5
CDH1
CDKN1B
CIITA
CKM
COL1A1Activation
CORT
CSF2Activation
CTSKActivation
CX3CR1
CYP2E1Activation
DCSTAMP
DIO2

Upstream regulators (CollecTRI, top): CREM, FOS, FOXP3, HEY1, KLF15, LMO2, MAFB, NFATC1, NFATC2, NFKB, PPARG, PRDM2, RARA, RBPJ, RELA, SP1, STAT6

miRNA regulators (miRDB)

Targeting NFATC1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

14 miRNAs:

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-4262100.0073.263931
HSA-MIR-1468-3P99.9672.743797
HSA-MIR-10527-5P99.9172.283754
HSA-MIR-548E-5P99.8972.734486
HSA-MIR-64699.6867.841645
HSA-MIR-432899.5771.064094
HSA-MIR-4687-3P99.4866.41968
HSA-MIR-608199.4866.071446
HSA-MIR-499A-3P99.1869.201392
HSA-MIR-499B-3P99.1869.271391
HSA-MIR-6830-5P99.0168.731884
HSA-MIR-3124-3P98.8768.952123
HSA-MIR-3127-5P97.5265.24786
HSA-MIR-6894-3P96.7365.64798

Functional genomics

gnomAD constraint: pLI 0.998, LOEUF 0.461, missense Z -0.497 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000427363 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 / expo/eConstrained
18:79,396,225–79,433,657691 / 613.11.13no
18:79,433,658–79,467,486242 / 329.20.74no
18:79,467,487–79,527,574424 / 395.41.07no

Literature-anchored findings (GeneRIF, showing 40)

  • selective expression in basophils suggests involvement in IgE-mediated IL-4 production in these cells (PMID:11897999)
  • C-terminal one third of DNA binding domain confers different binding specificity of NFATc and NFATp to an NFAT site in the TNF-alpha promoters (PMID:11911478)
  • role of PKCzeta in T cells through the control of NFAT function by modulating the activity of its transactivation domain (PMID:12021260)
  • opposition of calcineurin-mediated nuclear accumulation and transcriptional activity by glycogen synthase kinase 3 (PMID:12351631)
  • selection of RNA inhibitors to study NFATc function (PMID:12408978)
  • mediates vascular endothelial growth factor-induced proliferation of human pulmonary valve endothelial cells (PMID:12427739)
  • NFATc1 with AP-3 site binding specificity has a role in mediating gene expression of prostate-specific-membrane-antigen (PMID:12850144)
  • NFAT2 has a role in regulating IL13 gene transcription in mast cells (PMID:15229217)
  • RANKL-induced cathepsin K gene expression is cooperatively regulated by the combination of the transcription factors and p38 MAP kinase in a gradual manner. (PMID:15304486)
  • Interleukin (IL)-15 and IL-2 reciprocally regulate expression of the chemokine receptor CX3CR1 through selective NFAT1- and NFAT2-dependent mechanisms (PMID:15347678)
  • association of nuclear factor-kappaB and NFAT with its enhancer region is dependent on activation of the HIV-1 clade E long terminal repeat, which is inhibited by T-cell activation (PMID:15466412)
  • PC1 signaling elevates intracellular Ca(2+), activates Galpha(q) and PLC, which then activates calcineurin and NFAT (PMID:15466861)
  • Expression of NFATc1 and NFATc2 wild type protein or the active catalytic subunit of calcineurin transactivates COX-2 promoter activity, whereas a dominant negative mutant of NFAT inhibited COX-2 induction in colon carcinoma cell lines. (PMID:15632146)
  • analysis of a positive feedback circuit of TRANCE-induced activation of NFATc1, involving NFATc1-mediated OSCAR expression and its subsequent activation of NFATc1, necessary for efficient differentiation of osteoclasts (PMID:16109714)
  • the MCP-1-induced TRAP(+)/CTR(+) multinuclear cells represent an arrested stage in osteoclast differentiation, after NFATc1 induction and cellular fusion but prior to the development of bone resorption activity (PMID:16280328)
  • the beta3 integrin gene is the direct target of NFAT1 in osteoclast formation (PMID:16340127)
  • Unstimulated adult skeletal muscle fibers exhibit a previously unanticipated nucleocytoplasmic shuttling of NFATc1 without appreciable nuclear accumulation. (PMID:16436503)
  • These results establish the beta3 gene as a direct target of NFATc1 in RANKL-dependent osteoclast formation. (PMID:16513293)
  • Tacrolimus or cyclosporine A act on human osteoclast precursors in rheumatoid arthritis patients by targeting the calcineurin-dependent NFAT pathway and activation pathway for c-Jun or MITF. (PMID:16586042)
  • Together, these results demonstrate that ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway is an important mechanism of oncogenic c-myc activation in pancreatic cancer. (PMID:16874304)
  • NFAT1, a transcription factor connected with breast cancer metastasis, is activated by Wnt-5a through a Ca2+ signaling pathway in human breast epithelial cells which was simultaneously counteracted by a Wnt-5a-induced Yes/Cdc42 signaling pathway. (PMID:16880514)
  • Expression of NFATc1/alphaA, the most prominent of six NFATc1 isoforms in peripheral T cells, is strongly induced following T-cell receptor and co-receptor stimulation and maintained by positive autoregulation, as discussed in this review. (PMID:16931157)
  • In Wiskott-Aldrich CD8+ T cells, a block in cytokine production correlates with reduced nuclear levels of both NFAT-1 and NFAT-2. (PMID:17082665)
  • AMPK mediates IL-2 production by regulating NF-AT and AP-1activation during T cell stimulation. (PMID:17097050)
  • role in congenital heart disease (PMID:17110989)
  • Endothelin 1 (ET-1) activates calcineurin and causes nuclear translocation of NFATc1, implicating the pathway in the ET-1-mediated stimulation of osteoblasts. (PMID:17237284)
  • The expression pattern of NFAT and its family member- and lineage-specific regulation during myeloid differentiation will prompt further studies on the role of NFAT in myeloid cells, particularly in megakaryocytes. (PMID:17577925)
  • Our results provide evidence that NFAT2 is constitutively expressed in human neutrophils, and after IgE-dependent activation operates as a transcription factor in the modulation of genes, such as COX2, during allergic inflammation. (PMID:17606988)
  • DSCR1 gene is a direct transcriptional target of NFATc1 proteins within the endocardium during a critical window of heart valve formation. (PMID:17693409)
  • the concerted action of the transcription factors Egr1 and NFAT2 can play a crucial role in regulation of the T cell differentiation in vitro due to the cooperative regulation of Id3 and Rag2 gene expression. (PMID:17922653)
  • The promoter/enhancer activity of the NFAT-binding site in the TNF-alpha gene was up-regulated by NFATc2 but not by NFATc1, whereas both NFATs associated similarly with this region. (PMID:18097033)
  • histone modifications precede the DNA methylation in NFATC1 promoter silencing (PMID:18156209)
  • These data provide evidence that NFATc1, in concert with PU.1, are involved in regulation of beta(3) integrin expression during osteoclast differentiation. (PMID:18288635)
  • Report nucleo-translocation/activation of NFAT2 in lamina propria mononuclear cells in ulcerative colitis. (PMID:18350607)
  • The crystal structure of NFATC1 bound to the HIV-1 LTR tandem kappaB enhancer element is described. (PMID:18462673)
  • the cyclin A-CDK2 complex may be a potential effector of NFATs, specifically NFATc1, in mediating SMC multiplication leading to neointima formation. (PMID:18667424)
  • these data suggest that the proinflammatory, antiapoptotic, and procarcinogenic functions of UV-activated COX-2 may be mediated, in part, by upstream NFAT signaling. (PMID:18708588)
  • cyclic AMP signals enhance histone H3 acetylation at the IL-5 promoter and the concerted binding of GATA-3 and NFATc to the promoter. (PMID:18772129)
  • The presence of NFATc1 and Osx in our material lends further support to the hypothesis that during the process of aortic valve calcification there is expression of osteoblastic phenotypes by valvular cells (PMID:19019468)
  • These findings may provide a better understanding of the NFATc1 regulation of ADAMTS9 expression induced by inflammatory cytokines such as IL-1 beta. (PMID:19052845)

Cross-species orthologs

3 orthologs

OrganismSymbolGene ID
danio_rerionfatc1ENSDARG00000036168
mus_musculusNfatc1ENSMUSG00000033016
rattus_norvegicusNfatc1ENSRNOG00000017146

Paralogs (4): NFATC3 (ENSG00000072736), NFATC4 (ENSG00000100968), NFATC2 (ENSG00000101096), NFAT5 (ENSG00000102908)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:102469) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 78 distinct phenotype terms.

Mouse phenotype (MP)Records
edema2
abnormal B cell physiology2
increased IgM level2
abnormal semilunar valve morphology2
decreased susceptibility to experimental autoimmune encephalomyelitis2
abnormal cardiac outflow tract development2
decreased IgG3 level2
lethality throughout fetal growth and development, complete penetrance2
osteopetrosis1
abnormal heart morphology1
abnormal interventricular septum morphology1
decreased atrioventricular cushion size1
gastrointestinal hemorrhage1
abnormal lymphocyte cell number1
abnormal locomotor behavior1
abnormal cardiovascular system physiology1
anemia1
cardiac hypertrophy1
abnormal immune system physiology1
decreased IgM level1
abnormal blood circulation1
abnormal T cell physiology1
decreased immunoglobulin level1
increased immunoglobulin level1
abnormal immunoglobulin level1

+53 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.

OrganismUniProtIdentityMethod
Sus scrofaO7763885.7%Diamond
Bos taurusP9820185.2%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).

SymbolTypeEntrez
KCNG2protein-coding26251
CTDP1-DTncRNA284241
CTDP1protein-coding9150
ATP9Bprotein-coding374868
SALL3protein-coding27164

Protein

Protein identifiers

Nuclear factor of activated T-cells, cytoplasmic 1 — O95644 (reviewed: O95644)

Alternative names: NFAT transcription complex cytosolic component

All UniProt accessions (4): F5H4S8, K7EQ04, K7ER53, O95644

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2 or IL-4 gene transcription. Also controls gene expression in embryonic cardiac cells. Could regulate not only the activation and proliferation but also the differentiation and programmed death of T-lymphocytes as well as lymphoid and non-lymphoid cells. Required for osteoclastogenesis and regulates many genes important for osteoclast differentiation and function.

Subunit / interactions. Member of the multicomponent NFATC transcription complex that consists of at least two components, a pre-existing cytoplasmic component NFATC2 and an inducible nuclear component NFATC1. Other members such as NFATC4, NFATC3 or members of the activating protein-1 family, MAF, GATA4 and Cbp/p300 can also bind the complex. NFATC proteins bind to DNA as monomers. Interacts with HOMER2 and HOMER3; this interaction may compete with calcineurin/PPP3CA-binding and hence prevent NFATC1 dephosphorylation and activation. Interacts with TLE6/GRG6.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in thymus, peripheral leukocytes as T-cells and spleen. Isoforms A are preferentially expressed in effector T-cells (thymus and peripheral leukocytes) whereas isoforms B and isoforms C are preferentially expressed in naive T-cells (spleen). Isoforms B are expressed in naive T-cells after first antigen exposure and isoforms A are expressed in effector T-cells after second antigen exposure. Isoforms IA are widely expressed but not detected in liver nor pancreas, neural expression is strongest in corpus callosum. Isoforms IB are expressed mostly in muscle, cerebellum, placenta and thymus, neural expression in fetal and adult brain, strongest in corpus callosum.

Post-translational modifications. Phosphorylated by NFATC-kinase and GSK3B; phosphorylation induces NFATC1 nuclear exit and dephosphorylation by calcineurin promotes nuclear import. Phosphorylation by PKA and DYRK2 negatively modulates nuclear accumulation, and promotes subsequent phosphorylation by GSK3B or casein kinase 1.

Domain organisation. Rel Similarity Domain (RSD) allows DNA-binding and cooperative interactions with AP1 factors. The N-terminal transactivation domain (TAD-A) binds to and is activated by Cbp/p300. The dephosphorylated form contains two unmasked nuclear localization signals (NLS), which allow translocation of the protein to the nucleus. Isoforms C have a C-terminal part with an additional transactivation domain, TAD-B, which acts as a transcriptional activator. Isoforms B have a shorter C-terminal part without complete TAD-B which acts as a transcriptional repressor.

Induction. Only isoforms A are inducibly expressed in T lymphocytes upon activation of the T-cell receptor (TCR) complex. Induced after co-addition of phorbol 12-myristate 13-acetate (PMA) and ionomycin. Also induced after co-addition of 12-O-tetradecanoylphorbol-13-acetate (TPA) and ionomycin. Weakly induced with PMA, ionomycin and cyclosporin A.

Miscellaneous. Produced by alternative initiation at Met-37 of isoform A-alpha.

Isoforms (10)

UniProt IDNamesCanonical?
O95644-1C-alphayes
O95644-2A-alpha, IA-VIII
O95644-3A-beta, IB-VIII
O95644-4B-alpha, IA-IXS
O95644-5B-beta, IB-IXS
O95644-6C-beta, IB-IXL
O95644-8A-alpha'
O95644-10IA-deltaIX
O95644-11IB-deltaIX
O95644-1710

RefSeq proteins (10): NP_001265598, NP_001265599, NP_001265601, NP_001265602, NP_001265604, NP_006153, NP_765975, NP_765976, NP_765977, NP_765978 (=MANE)

Domains & families (InterPro)

IDNameType
IPR002909IPT_domDomain
IPR008366NFATFamily
IPR008967p53-like_TF_DNA-bd_sfHomologous_superfamily
IPR011539RHD_DNA_bind_domDomain
IPR013783Ig-like_foldHomologous_superfamily
IPR014756Ig_E-setHomologous_superfamily
IPR032397RHD_dimerDomain
IPR037059RHD_DNA_bind_dom_sfHomologous_superfamily

Pfam: PF00554, PF16179

UniProt features (57 total): strand 13, region of interest 7, splice variant 7, modified residue 5, short sequence motif 4, compositionally biased region 4, repeat 3, sequence variant 3, mutagenesis site 3, sequence conflict 2, helix 2, chain 1, domain 1, DNA-binding region 1, turn 1

Structure

Experimental structures (PDB)

3 structures by resolution:

PDBTitleMethodResolution (Å)
5SVEStructure of Calcineurin in complex with NFATc1 LxVP peptideX-RAY DIFFRACTION2.6
1A66SOLUTION NMR STRUCTURE OF THE CORE NFATC1/DNA COMPLEX, 18 STRUCTURESSOLUTION NMR
1NFAHUMAN TRANSCRIPTION FACTOR NFATC DNA BINDING DOMAIN, NMR, 10 STRUCTURESSOLUTION NMR

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-O95644-F157.660.24

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Immunoglobulin fold

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear bodies; nucleoplasm

Antibody reliability (HPA): IH enhanced · IF supported

Functional residue map

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

Post-translational modifications (5)

TypePositions
Phosphoserine233, 237, 245, 269, 294

Mutagenesis-validated functional residues (3)

PositionPhenotype
169no effect on subcellular localization.
172partial nuclear translocation.
187no effect on subcellular localization.

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 16; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

16 pathways:

IDPathwayEvidence
R-HSA-5607763CLEC7A (Dectin-1) induces NFAT activationcurated
R-HSA-4086398Ca2+ pathwaycurated
R-HSA-2871809FCERI mediated Ca+2 mobilizationcurated
R-HSA-1280218Adaptive Immune System—
R-HSA-3858494Beta-catenin independent WNT signaling—
R-HSA-5621481C-type lectin receptors (CLRs)—
R-HSA-5607764CLEC7A (Dectin-1) signaling—
R-HSA-2025928Calcineurin activates NFATelectronic
R-HSA-9942503Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)electronic
R-HSA-1168372Downstream signaling events of B Cell Receptor (BCR)—
R-HSA-2454202Fc epsilon receptor (FCERI) signaling—
R-HSA-168256Immune System—
R-HSA-168249Innate Immune System—
R-HSA-162582Signal Transduction—
R-HSA-195721Signaling by WNT—
R-HSA-983705Signaling by the B Cell Receptor (BCR)—

MSigDB gene sets: 361 (showing top): PID_BCR_5PATHWAY, MODULE_97, MULLIGHAN_NPM1_SIGNATURE_3_UP, BIOCARTA_FMLP_PATHWAY, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, PEREZ_TP63_TARGETS, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, PID_NFAT_3PATHWAY, MODULE_182, GOBP_VASCULAR_ASSOCIATED_SMOOTH_MUSCLE_CELL_DIFFERENTIATION

GO Biological Process (11): aortic valve morphogenesis (GO:0003180), pulmonary valve morphogenesis (GO:0003184), DNA-templated transcription (GO:0006351), negative regulation of Wnt signaling pathway (GO:0030178), calcineurin-NFAT signaling cascade (GO:0033173), intracellular signal transduction (GO:0035556), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of inflammatory response (GO:0050728), negative regulation of vascular associated smooth muscle cell differentiation (GO:1905064), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (11): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), FK506 binding (GO:0005528), protein phosphatase 2B binding (GO:0030346), mitogen-activated protein kinase p38 binding (GO:0048273), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear body (GO:0016604)

Reactome top-level categories

12 top-level categories:

CategoryPathways
Immune System2
Innate Immune System2
Downstream signaling events of B Cell Receptor (BCR)1
Fc epsilon receptor (FCERI) signaling1
Beta-catenin independent WNT signaling1
CLEC7A (Dectin-1) signaling1
Differentiation of T cells1
Signaling by the B Cell Receptor (BCR)1
Signal Transduction1
Signaling by WNT1
C-type lectin receptors (CLRs)1
Adaptive Immune System1

GO top-level categories

51 GO namespaces:

CategoryTerms
cellular anatomical structure4
RNA polymerase II transcription regulatory region sequence-specific DNA binding3
heart valve morphogenesis2
intracellular anatomical structure2
DNA-templated transcription2
regulation of DNA-templated transcription2
regulation of transcription by RNA polymerase II2
aortic valve development1
pulmonary valve development1
gene expression1
RNA biosynthetic process1
negative regulation of signal transduction1
Wnt signaling pathway1
regulation of Wnt signaling pathway1
calcineurin-mediated signaling1
signal transduction1
positive regulation of RNA biosynthetic process1
transcription by RNA polymerase II1
positive regulation of DNA-templated transcription1
inflammatory response1
negative regulation of defense response1
negative regulation of response to external stimulus1
regulation of inflammatory response1
vascular associated smooth muscle cell differentiation1
negative regulation of smooth muscle cell differentiation1
regulation of vascular associated smooth muscle cell differentiation1
regulation of gene expression1
regulation of RNA biosynthetic process1
cis-regulatory region sequence-specific DNA binding1
chromatin1
DNA-binding transcription factor activity1
DNA-binding transcription factor activity, RNA polymerase II-specific1
DNA-binding transcription activator activity1
positive regulation of transcription by RNA polymerase II1
transcription cis-regulatory region binding1
transcription regulator activity1
macrolide binding1
protein phosphatase binding1
mitogen-activated protein kinase binding1
DNA-binding transcription factor binding1
double-stranded DNA binding1
sequence-specific DNA binding1
nucleic acid binding1
binding1
chromosome1
intracellular membrane-bounded organelle1
nuclear lumen1
protein-containing complex1
cytoplasm1
nucleoplasm1
intracellular membraneless organelle1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 29 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO termNSEvidence
calcineurin-NFAT signaling cascadeBPdirect assay
intracellular signal transductionBPdirect assay
negative regulation of inflammatory responseBPdirect assay
negative regulation of vascular associated smooth muscle cell differentiationBPdirect assay
positive regulation of DNA-templated transcriptionBPdirect assay
positive regulation of transcription by RNA polymerase IIBPdirect assay
chromatinCCdirect assay
nuclear bodyCCdirect assay
nucleoplasmCCdirect assay
nucleusCCdirect assay
protein phosphatase 2B bindingMFphysical interaction
sequence-specific double-stranded DNA bindingMFdirect assay

Protein interactions and networks

STRING

showing 15 of 2,546 interactions by confidence (×1000):

Protein AProtein BPartner UniProtScore
NFATC1TNFSF11O14788941
NFATC1ACP5P13686936
NFATC1DCSTAMPQ9H295893
NFATC1CTSKP43235889
NFATC1FOSP01100861
NFATC1TNFRSF11BO00300799
NFATC1RCAN1P53805780
NFATC1OSCARQ8IYS5776
NFATC1CALML6Q8TD86775
NFATC1CALML5Q9NZT1775
NFATC1CALML4Q96GE6775
NFATC1CALML3P27482774
NFATC1CALM1P02593773
NFATC1CALCRP30988766
NFATC1PPP3R1P06705761

IntAct

Human interaction partners of NFATC1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

27 partners by confidence:

PartnerInteraction typeMIscoreRecords
PPP3CAphysical association0.7204
JUNphysical association0.6103
ATF1physical association0.5802
CREB1physical association0.5802
PPP3CCassociation0.5302
OGTphysical association0.5002
ATF2physical association0.5001
ATF3physical association0.5001
HOXC13physical association0.5001
SMARCA4proximity0.4804
TP53proximity0.4801
JAK3phosphorylation reaction0.4401
YWHAZphysical association0.4001
IFNL1physical association0.3701
XCL2physical association0.3701
IL2association0.3501
NKX2-3association0.3501
OBSL1association0.3501
SMARCA5association0.3501
FBXW7proximity0.2704
SMAD4proximity0.2704
SPOPproximity0.2704
AKT1proximity0.2701
BRAFproximity0.2701
EGFRproximity0.2701
PTENproximity0.2701
PTPN11proximity0.2701

BioGRID (211 interactions; top human partners by supporting records): EP300 (Affinity Capture-Western; 8 records), JUN (Affinity Capture-MS; 4 records), PPP3CC (Affinity Capture-MS; 4 records), CREB1 (Affinity Capture-MS; 3 records), ARMC8 (Affinity Capture-MS; 2 records), CHEK1 (Affinity Capture-Western; 2 records), CREBBP (Affinity Capture-MS; 2 records), DNAAF2 (Affinity Capture-MS; 2 records), FOS (Affinity Capture-MS; 2 records), FOXP3 (Affinity Capture-Luminescence; 2 records), GSK3B (Affinity Capture-Western; 2 records), HDAC2 (Affinity Capture-MS; 2 records), HDAC5 (Biochemical Activity; 2 records), HMGCS2 (Affinity Capture-MS; 2 records), IKZF1 (Affinity Capture-Western; 2 records)

SIGNOR signaling

showing 31 of 49 signaling interactions:

AEffectBMechanism
PPP3CAup-regulatesNFATC1dephosphorylation
PPP3CCup-regulatesNFATC1relocalization
PRKCA“down-regulates activity”NFATC1phosphorylation
NFATC1“up-regulates quantity by expression”IL6“transcriptional regulation”
Calcineurinup-regulatesNFATC1dephosphorylation
AP1“up-regulates activity”NFATC1binding
PPP3CA“up-regulates activity”NFATC1dephosphorylation
NFATC1“up-regulates quantity by expression”PLAUR“transcriptional regulation”
CDC42“up-regulates activity”NFATC1
NFATC1“up-regulates quantity by expression”IL4“transcriptional regulation”
NFATC1up-regulatesMyotube_hypertrophy“transcriptional regulation”
NFATC1“up-regulates quantity by expression”GPC6“transcriptional regulation”
NFATC1“up-regulates quantity by expression”PTGS2“transcriptional regulation”
PP2Bup-regulatesNFATC1relocalization
NFATC1up-regulatesDifferentiation
NFATC1“up-regulates quantity by expression”IL2“transcriptional regulation”
JAK3“up-regulates activity”NFATC1phosphorylation
PIM1“up-regulates activity”NFATC1phosphorylation
IKBKE“up-regulates activity”NFATC1phosphorylation
DYRK1A“up-regulates activity”NFATC1phosphorylation
GSK3B“down-regulates activity”NFATC1phosphorylation
MAPK8“down-regulates activity”NFATC1phosphorylation
MAPK10down-regulatesNFATC1phosphorylation
MAPK14down-regulatesNFATC1phosphorylation
MAPK3down-regulatesNFATC1phosphorylation
PPP3CBup-regulatesNFATC1relocalization
PRKACAdown-regulatesNFATC1phosphorylation
NFATC1“up-regulates quantity by expression”MYH7“transcriptional regulation”
NFATC1“up-regulates activity”T_cell_activation
PIM2“up-regulates activity”NFATC1phosphorylation
PIM3“up-regulates activity”NFATC1phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 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:

PathwayPartnersFoldFDR
Signaling by Interleukins718.0×3e-05
RAF/MAP kinase cascade614.7×4e-04
PIP3 activates AKT signaling513.4×1e-03
Cytokine Signaling in Immune system711.4×4e-04
Signaling by Receptor Tyrosine Kinases510.3×3e-03

GO biological processes:

GO termPartnersFoldFDR
positive regulation of miRNA transcription553.8×1e-05
transforming growth factor beta receptor signaling pathway529.4×1e-04
positive regulation of ERK1 and ERK2 cascade515.8×6e-04
negative regulation of apoptotic process911.6×1e-05
positive regulation of gene expression710.0×4e-04
negative regulation of cell population proliferation57.8×5e-03

Disease & clinical

Genetic variants

Variant evidence for NFATC1: 399 ClinVar records (2 pathogenic / likely pathogenic); 59 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

ClassificationCount (floor)
Pathogenic2
Likely pathogenic0
Uncertain significance223
Likely benign112
Benign37

Top pathogenic / likely-pathogenic (2)

Showing all 2 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant IDHGVSClassificationReviewSubmitters
1807794GRCh37/hg19 18q22.1-23(chr18:66530142-78014123)x1Pathogeniccriteria provided, single submitter1
2500799GRCh37/hg19 18q22.1-23(chr18:66459747-78012829)x1Pathogenicno assertion criteria provided1

Per-variant reference — Sugi Variant

Explore NFATC1’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; 39 predictions of 2,468):

Position(s)EffectΔscoreSites
18:79433739–79433740donor_loss1.00005
18:79448776acceptor_gain1.0000
18:79448780–79448781acceptor_loss1.00005
18:79448985–79448986donor_loss1.00004
18:79450947–79450948acceptor_gain1.00002
18:79461309–79461310acceptor_loss1.00005
18:79396349donor_gain0.9900
18:79396352–79396353donor_loss0.99005
18:79410401–79410402acceptor_loss0.99006
18:79411502–79411503donor_loss0.99005

AlphaMissense

1,691 missense substitutions predicted likely pathogenic (of 6,075 scored), across 391 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:

ResidueLikely-pathogenic substitutionsMean am_pathogenicityMax am_pathogenicity
M52790.9530.998
N54180.9991.000
D54380.9991.000
H43880.9981.000
S44780.9971.000
H48980.9971.000
F49180.9961.000
N55780.9961.000
H49580.9931.000
D55280.9890.998
F62980.9881.000
D53280.9870.999
H44180.9850.999
F56480.9830.999
D48280.9810.998
F47780.9791.000
H45880.9570.998
F62180.9480.999
H43780.9390.998
S17680.9380.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

CancerPrognosticp-value
Breast Invasive Carcinoma (validation)favorable4.79e-05
Rectum Adenocarcinoma (validation)favorable5.38e-05

Disease associations

OMIM: gene MIM:600489 | disease phenotypes:

GenCC curated gene-disease

2 curated gene-disease records:

DiseaseClassificationInheritanceRecords
inborn error of immunityModerateAutosomal recessive
congenital heart diseaseLimitedAutosomal dominant

ClinGen Gene-Disease Validity

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

1 validity classifications:

DiseaseClassificationInheritance
congenital heart diseaseLimitedAD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 0 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

PanelRating
Primary immunodeficiency or monogenic inflammatory bowel diseaseamber

Mondo (2): congenital heart disease (MONDO:0005453), inborn error of immunity (MONDO:0003778)

GWAS associations

showing 30 of 59 associations:

StudyTraitp-value
GCST008058_79Estimated glomerular filtration rate7e-81
GCST008059_14Estimated glomerular filtration rate4e-60
GCST007876_121Estimated glomerular filtration rate8e-45
GCST008747_44Estimated glomerular filtration rate8e-43
GCST008745_70Estimated glomerular filtration rate in non-diabetics2e-36
GCST008747_118Estimated glomerular filtration rate2e-29
GCST007344_16Estimated glomerular filtration rate2e-28
GCST005985_7Creatinine levels1e-25
GCST005984_43Glomerular filtration rate9e-25
GCST90002395_480Mean platelet volume1e-18
GCST008060_27Estimated glomerular filtration rate1e-17
GCST008062_127Blood urea nitrogen levels2e-17
GCST90002395_477Mean platelet volume5e-17
GCST90000025_423Appendicular lean mass1e-16
GCST007916_5Hyperuricemia2e-16
GCST007917_1Estimated glomerular filtration rate2e-16
GCST007919_7Creatinine levels2e-16
GCST007920_9Chronic kidney disease2e-16
GCST90013406_101Liver enzyme levels (alkaline phosphatase)4e-15
GCST004599_80Mean platelet volume8e-15
GCST006979_529Heel bone mineral density2e-14
GCST90002388_619Lymphocyte count2e-13
GCST007448_2Normal facial asymmetry (angle of surface orientation score)4e-13
GCST007877_21Creatinine levels4e-13
GCST90002395_479Mean platelet volume1e-12
GCST008064_45Chronic kidney disease2e-12
GCST90011900_83Serum alkaline phosphatase levels2e-12
GCST006979_528Heel bone mineral density5e-12
GCST006288_568Heel bone mineral density2e-11
GCST006392_3Estimated glomerular filtration rate2e-11

EFO canonical traits (from GWAS)

17 canonical traits:

EFO IDTrait name
EFO:0004763p-tau measurement
EFO:0009270heel bone mineral density
EFO:0009599feeling emotionally hurt measurement
EFO:0009751facial asymmetry measurement
EFO:0009104hyperuricemia
EFO:0009933Thyroid preparation use measurement
EFO:0009936Drugs affecting bone structure and mineralization use measurement
EFO:0004335short-term memory
EFO:0007785femoral neck bone mineral density
EFO:0009819comparative body size at age 10, self-reported
EFO:0005674white matter microstructure measurement
EFO:0007789BMI-adjusted waist circumference
EFO:0004980appendicular lean mass
EFO:0004587lymphocyte count
EFO:0007993lymphocyte percentage of leukocytes
EFO:0007990neutrophil percentage of leukocytes
EFO:0004533alkaline phosphatase measurement

MeSH disease descriptors

2 disease descriptors:

DescriptorNameTree numbers
D006330Heart Defects, CongenitalC14.240.400; C14.280.400; C16.131.240.400
D007153Immunologic Deficiency SyndromesC20.673

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3876 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

4 published findings:

VariantDrug(s)CategoryFindingPMID
rs1017860cyclosporine, methotrexateEfficacyGenotype CC is associated with increased risk of Graft vs Host Disease when treated with cyclosporine and methotrexate in people with Hematopoietic stem cell transplantation as compared to genotypes CT + TT.PMID:25425682
rs8090560cyclosporine, methotrexateEfficacyGenotype GG is associated with increased risk of Graft vs Host Disease when treated with cyclosporine and methotrexate in people with Hematopoietic stem cell transplantation as compared to genotypes AA + AG.PMID:25425682
rs3894049cyclosporine, mycophenolic acid, prednisoneEfficacyGenotype CC is associated with decreased likelihood of transplant rejection when treated with cyclosporine, mycophenolic acid and prednisone in people with Kidney Transplantation as compared to genotype CG.PMID:28244807
rs2280055cyclosporine, mycophenolic acid, prednisoneEfficacyGenotype CC is associated with Decreased glomerular filtration rate when treated with cyclosporine, mycophenolic acid and prednisone in people with Kidney Transplantation as compared to genotypes CT + TT.PMID:28244807

Binding affinities (BindingDB)

17 measured of 17 human assays (17 total across all organisms); most potent 17 below. Values come from heterogeneous assays and are not directly comparable.

LigandMeasureValuePatent
CHEMBL4079572IC501 nM
3-pyridin-4-yl-1H-pyrrolo[2,3-c]pyridineIC501 nMUS-20250099442: COMPOUNDS FOR USE IN TREATING NEUROLOGICAL DISORDERS
CHEMBL4105629IC508 nM
1-propan-2-yl-3-pyridin-4-ylpyrrolo[2,3-c]pyridineIC508 nMUS-20250099442: COMPOUNDS FOR USE IN TREATING NEUROLOGICAL DISORDERS
CHEMBL4091320IC5010 nM
CHEMBL4069163IC5012 nM
CHEMBL4075648IC5061 nM
CHEMBL4098505IC5069 nM
CHEMBL4080488IC5075 nM
CHEMBL4077010IC5089 nM
CHEMBL4095674IC50109 nM
CHEMBL4072138IC50138 nM
CHEMBL4090889IC50242 nM
CHEMBL4066607IC50277 nM
CHEMBL5174163IC504500 nM
CHEMBL5195853IC5011600 nM
CHEMBL5181607IC5018700 nM

ChEMBL bioactivities

12 potent at pChembl≥5 of 17 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
6.51EC50310nMCHEMBL4064316
5.80EC501590nMCHEMBL4105629
5.66EC502210nMCHEMBL4077010
5.53EC502980nMCHEMBL4084955
5.35IC504500nMCHEMBL5174163
5.32EC504800nMCHEMBL4079572
5.31EC504850nMCHEMBL4098505
5.28EC505310nMCHEMBL4075648
5.16EC506900nMCHEMBL4091320
5.16EC506960nMCHEMBL4095674
5.12EC507580nMCHEMBL4069163
5.01EC509800nMCHEMBL4090889

PubChem BioAssay actives

12 with measured affinity, of 86 total; 12 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
1-propan-2-yl-3-pyridin-4-ylpyrrolo[2,3-c]pyridine1478838: Induction of nuclear translocation of human GFP-tagged NFATc1 expressed in virus infected primary human skeletal muscle myoblasts after 3 hrs by DAPI staining based assayec500.3100uM
1-(2-cyclopropylethyl)-3-pyridin-4-ylpyrrolo[2,3-c]pyridine1478838: Induction of nuclear translocation of human GFP-tagged NFATc1 expressed in virus infected primary human skeletal muscle myoblasts after 3 hrs by DAPI staining based assayec501.5900uM
1-methyl-3-pyridin-4-ylpyrrolo[2,3-c]pyridine1478838: Induction of nuclear translocation of human GFP-tagged NFATc1 expressed in virus infected primary human skeletal muscle myoblasts after 3 hrs by DAPI staining based assayec502.2100uM
3-pyridin-4-yl-1H-pyrrolo[2,3-c]pyridine1478838: Induction of nuclear translocation of human GFP-tagged NFATc1 expressed in virus infected primary human skeletal muscle myoblasts after 3 hrs by DAPI staining based assayec502.9800uM
N-[2-[2-chloro-5-[(4-chlorophenyl)sulfamoyl]anilino]-2-oxoethyl]-5-methylthiophene-2-carboxamide1874118: Inhibition of NFATC activity in HEK293T cells preincubated for 2 hrs followed by ionomycin/phorbol 12-myristate 13-acetate stimulation and measured after 4 hrs by luciferase reporter assayic504.5000uM
4-(1H-pyrrolo[2,3-c]pyridin-3-yl)pyrimidin-2-amine1478838: Induction of nuclear translocation of human GFP-tagged NFATc1 expressed in virus infected primary human skeletal muscle myoblasts after 3 hrs by DAPI staining based assayec504.8000uM
3-(2-fluoro-4-pyridinyl)-1H-pyrrolo[2,3-c]pyridine1478838: Induction of nuclear translocation of human GFP-tagged NFATc1 expressed in virus infected primary human skeletal muscle myoblasts after 3 hrs by DAPI staining based assayec504.8500uM
3-(3-chloro-4-pyridinyl)-1H-pyrrolo[2,3-c]pyridine1478838: Induction of nuclear translocation of human GFP-tagged NFATc1 expressed in virus infected primary human skeletal muscle myoblasts after 3 hrs by DAPI staining based assayec505.3100uM
1-(2-methoxyethyl)-3-pyridin-4-ylpyrrolo[2,3-c]pyridine1478838: Induction of nuclear translocation of human GFP-tagged NFATc1 expressed in virus infected primary human skeletal muscle myoblasts after 3 hrs by DAPI staining based assayec506.9000uM
4-[3-(3-pyridin-4-ylpyrrolo[2,3-c]pyridin-1-yl)propyl]morpholine1478838: Induction of nuclear translocation of human GFP-tagged NFATc1 expressed in virus infected primary human skeletal muscle myoblasts after 3 hrs by DAPI staining based assayec506.9600uM
1-[(4-fluorophenyl)methyl]-3-pyridin-4-ylpyrrolo[2,3-c]pyridine1478838: Induction of nuclear translocation of human GFP-tagged NFATc1 expressed in virus infected primary human skeletal muscle myoblasts after 3 hrs by DAPI staining based assayec507.5800uM
4-(7-methoxy-1H-indol-3-yl)pyrimidin-2-amine1478838: Induction of nuclear translocation of human GFP-tagged NFATc1 expressed in virus infected primary human skeletal muscle myoblasts after 3 hrs by DAPI staining based assayec509.8000uM

CTD chemical–gene interactions

72 total (human), top 30 by PubMed support.

ChemicalActions (top 5)PubMed papers
Valproic Acidaffects expression, affects methylation, increases expression, increases methylation6
Benzo(a)pyreneaffects methylation, decreases expression, increases methylation3
Tobacco Smoke Pollutionaffects methylation, decreases expression3
sodium arseniteaffects localization, decreases reaction, increases abundance, affects expression, decreases phosphorylation (+2 more)2
perfluorooctane sulfonic acidaffects expression, decreases expression2
entinostatincreases expression, affects cotreatment2
Calcimycinaffects cotreatment, increases expression, increases reaction, affects localization, decreases expression (+1 more)2
Resveratroldecreases expression, decreases reaction, increases expression, affects cotreatment2
Arsenicaffects methylation, decreases methylation2
Silicon Dioxidedecreases expression, increases expression2
Tetradecanoylphorbol Acetateaffects localization, decreases expression, decreases reaction, affects cotreatment, increases expression (+1 more)2
Cyclosporinedecreases reaction, decreases expression, affects localization, decreases activity, affects cotreatment2
GSK-J4increases expression1
FR900359affects phosphorylation1
GW 506033Xincreases reaction, decreases reaction, increases expression1
triphenyl phosphateaffects expression1
bis(tri-n-butyltin)oxideaffects localization1
bisphenol Adecreases methylation, affects cotreatment, increases methylation1
deoxynivalenolaffects localization1
diphenyleneiodoniumaffects localization, decreases reaction, increases abundance1
alpha-naphthoflavoneaffects localization, decreases reaction1
arseniteaffects localization, decreases reaction, increases abundance1
perfluorooctanoic aciddecreases expression1
ochratoxin Aincreases acetylation, increases expression1
benzo(e)pyreneincreases methylation1
4-hydroxy-2-nonenaldecreases expression1
aflatoxin B2increases methylation1
cupric oxideincreases expression1
acetovanilloneaffects localization, decreases reaction, increases abundance1
perfluoro-n-nonanoic aciddecreases expression1

ChEMBL screening assays

15 unique, capped per target: 15 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL1687116BindingEffect on NFATc1 in HEK293 nuclear extract at 50 uM after 15 mins by EMSA assayIdentification of new GATA4-small molecule inhibitors by structure-based virtual screening. — *Bioorg Med Chem*

Cellosaurus cell lines

11 cell lines: 7 cancer cell line, 3 embryonic stem cell, 1 induced pluripotent stem cell

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

CellosaurusNameCategorySex
CVCL_A4M1SEES3-1V human NFATC1, clone1Embryonic stem cellMale
CVCL_A4M2SEES3-1V human NFATC1, clone2Embryonic stem cellMale
CVCL_A4M3SEES3-1V human NFATC1, clone3Embryonic stem cellMale
CVCL_B1YLAbcam HeLa NFATC1 KOCancer cell lineFemale
CVCL_B8LFAbcam HCT 116 NFATC1 KOCancer cell lineMale
CVCL_B9NLAbcam A-549 NFATC1 KOCancer cell lineMale
CVCL_C1NNNCHi001-AInduced pluripotent stem cellFemale
CVCL_D2GPAbcam MCF-7 NFATC1 KOCancer cell lineFemale
CVCL_E0IXUbigene HeLa NFATC1 KOCancer cell lineFemale
CVCL_TA56HAP1 NFATC1 (-) 1Cancer cell lineMale

Clinical trials (associated diseases)

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

showing 60 of 300 trials:

NCTPhaseStatusTitle
NCT00668824Phase 4UNKNOWNImproved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705Phase 4COMPLETEDNitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982Phase 4COMPLETEDPre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679Phase 4WITHDRAWNTranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811Phase 4UNKNOWNUlinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700Phase 4COMPLETEDFibrinogen Concentrate vs Cryoprecipitate
NCT03408340Phase 4TERMINATEDParavertebral Nerve Blocks in Neonates
NCT03630796Phase 4UNKNOWNEffect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703Phase 4COMPLETEDStress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761Phase 4UNKNOWNThiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389Phase 4RECRUITINGSodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154Phase 4NOT_YET_RECRUITINGPerioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470Phase 3COMPLETEDInfant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494Phase 3COMPLETEDManagement of Patent Ductus in Premature Infants
NCT01134302Phase 3UNKNOWNHybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983Phase 3WITHDRAWNEffects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011Phase 3UNKNOWNApplication of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669Phase 3COMPLETEDPhase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262Phase 3COMPLETEDIntraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137Phase 3COMPLETEDClinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476Phase 3COMPLETEDRole of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194Phase 3COMPLETEDDopamine Versus Norepinephrine Under General Anesthesia
NCT04702373Phase 3UNKNOWNTraining in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590Phase 3COMPLETEDAcute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517Phase 3UNKNOWNComparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674Phase 3RECRUITINGEffect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260Phase 3RECRUITINGSGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375Phase 2COMPLETEDPlatelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220Phase 2COMPLETEDTransfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088Phase 2COMPLETEDN-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785Phase 2COMPLETEDA Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705Phase 2WITHDRAWNParenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945Phase 2TERMINATEDImpact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712Phase 2COMPLETEDSafety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510Phase 2COMPLETEDSpironolactone in Adult Congenital Heart Disease
NCT01189981Phase 2COMPLETEDEffect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433Phase 2COMPLETEDEffects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037Phase 2COMPLETEDBosentan Therapy in Children With Functional Single Ventricle
NCT01668264Phase 2UNKNOWNImaging Assessment of Diastolic Function
NCT01827059Phase 2UNKNOWNBosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE
NCT01841177Phase 2COMPLETEDEvaluating Precision of Therapy - Milrinone
NCT02046135Phase 2TERMINATEDSodium Bicarbonate to Prevent Acute Kidney Injury in Children Undergoing Cardiac Surgery
NCT02133573Phase 2COMPLETEDRandomized Trial of Maternal Progesterone Therapy
NCT02232399Phase 2COMPLETEDIs Levosimendan Superior to Milrinone Regarding Acute Kidney Injury After Cardiac Surgery for Congenital Heart Disease?
NCT02492269Phase 2COMPLETEDStress Response and Neurodevelopmental Outcome After Cardiac Surgery Utilizing CPB in Children: A Prospective, Double Blinded and Randomized Study
NCT02564796Phase 2TERMINATEDErythropoietin to Prevent Unnecessary Transfusions In Patients With Cyanotic CHD - A Prospective Control Trial
NCT02618824Phase 2UNKNOWNRole of Terminal Warm Blood Cardioplegia as Myocardial Protection in the Use of Histidine-Tryptophan-Ketoglutarate Cardioplegia in Complex Congenital Heart Surgery
NCT02769624Phase 2TERMINATEDAcute Effects of Inhaled Treprostinil in Fontan Patients
NCT02877238Phase 2COMPLETEDRemote Preconditioning and Myocardial Protection
NCT03082716Phase 2COMPLETEDCustodiol Versus Blood Cardioplegaia in Paediatric Cardiac Surgery
NCT03425734Phase 2UNKNOWNThe Effect of Dexmedetomidine on Kidney Perfusion in Paediatric Patients
NCT04434001Phase 2TERMINATEDZEPLAST- PED: ZEro_PLASma Trial in Small Infants Undergoing Cardiac Surgery
NCT04807621Phase 2UNKNOWNPlatelets or Fibrinogen as First-line Treatment for Bleeding During Pedatric Heart Surgery
NCT05717049Phase 2COMPLETEDTheophylline Effects in the Fontan Circulation
NCT06080074Phase 2RECRUITINGMulticenter Trial of ECMO in Children With Severe Cardiac Failure Using the Cardiohelp System
NCT07498803Phase 2NOT_YET_RECRUITINGSota-ES - Sotatercept in Patients With Congenital Heart Disease and Eisenmenger´s Syndrome
NCT01698567Phase 1TERMINATEDAntithrombin III in Infants With Cardiopulmonary Bypass (CPB)
NCT02549625Phase 1COMPLETEDPhase I Safety and Feasibility Study of Intracoronary Delivery of Autologous Bone Marrow Derived Mononuclear Cells
NCT03417999Phase 1TERMINATEDPharmacokinetic Study of Intranasal Dexmedetomidine in Pediatric Patients With Congenital Heart Disease
NCT03946462Phase 1WITHDRAWNNitric Oxide During CPB to Reduce AKI in Neonates

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for NFATC1 across ~30M SureChEMBL compounds — explore on Sugi Predict.