NFATC3

Summary

NFATC3 (nuclear factor of activated T cells 3, HGNC:7777) is a protein-coding gene on chromosome 16q22.1, encoding Nuclear factor of activated T-cells, cytoplasmic 3 (Q12968). Acts as a regulator of transcriptional activation.

The product of this gene is a member of the nuclear factors 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. Other members of this family participate to form this complex also. The product of this gene plays a role in the regulation of gene expression in T cells and immature thymocytes. Several transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 4775 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 164 total
• Phenotypes (HPO): 1
• Druggable target: yes
• Transcription factor: yes — 43 downstream targets (CollecTRI)
• MANE Select transcript: NM_173165

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7777
Approved symbol	NFATC3
Name	nuclear factor of activated T cells 3
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	NFAT4, NFATX, n339260
Ensembl gene	ENSG00000072736
Ensembl biotype	protein_coding
OMIM	602698
Entrez	4775

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 8 protein_coding_CDS_not_defined, 7 protein_coding, 4 nonsense_mediated_decay, 3 retained_intron

ENST00000329524, ENST00000346183, ENST00000349223, ENST00000379165, ENST00000535127, ENST00000539828, ENST00000549350, ENST00000553077, ENST00000561714, ENST00000562171, ENST00000562926, ENST00000563288, ENST00000563319, ENST00000563796, ENST00000565750, ENST00000566301, ENST00000566893, ENST00000567152, ENST00000568466, ENST00000569766, ENST00000570212, ENST00000575270

RefSeq mRNA: 3 — MANE Select: NM_173165 NM_004555, NM_173163, NM_173165

CCDS: CCDS10860, CCDS10861, CCDS10862

Canonical transcript exons

ENST00000346183 — 10 exons

Exon	Start	End
ENSE00003470743	68126448	68126610
ENSE00003480086	68121987	68123121
ENSE00003502354	68181475	68181530
ENSE00003503942	68226350	68229259
ENSE00003523645	68166843	68167015
ENSE00003535302	68174374	68174514
ENSE00003555908	68157869	68158068
ENSE00003583006	68190768	68191775
ENSE00003606547	68183240	68183366
ENSE00003841562	68085370	68085784

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 94.68.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.9464 / max 446.2443, expressed in 1808 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154712	8.8030	1578
154710	8.0258	1753
154709	2.9956	1101
154713	1.4051	538
154711	0.6174	305
207924	0.0604	18
154716	0.0309	15
154717	0.0082	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	94.68	gold quality
secondary oocyte	CL:0000655	93.73	gold quality
bone marrow cell	CL:0002092	92.09	gold quality
colonic epithelium	UBERON:0000397	90.74	gold quality
sperm	CL:0000019	90.53	gold quality
thymus	UBERON:0002370	90.52	gold quality
gastrocnemius	UBERON:0001388	89.54	gold quality
granulocyte	CL:0000094	89.37	gold quality
muscle of leg	UBERON:0001383	89.37	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.18	gold quality
adult organism	UBERON:0007023	89.15	gold quality
bone marrow	UBERON:0002371	89.10	gold quality
right testis	UBERON:0004534	88.91	gold quality
left testis	UBERON:0004533	88.90	gold quality
testis	UBERON:0000473	88.78	gold quality
lymph node	UBERON:0000029	88.70	gold quality
blood	UBERON:0000178	88.69	gold quality
deltoid	UBERON:0001476	88.48	gold quality
muscle organ	UBERON:0001630	88.43	gold quality
male germ cell	CL:0000015	88.38	gold quality
trabecular bone tissue	UBERON:0002483	88.22	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.85	gold quality
adrenal tissue	UBERON:0018303	87.84	gold quality
jejunal mucosa	UBERON:0000399	87.75	gold quality
tendon	UBERON:0000043	87.51	gold quality
tibialis anterior	UBERON:0001385	87.39	gold quality
tonsil	UBERON:0002372	87.39	gold quality
leukocyte	CL:0000738	87.23	gold quality
calcaneal tendon	UBERON:0003701	87.14	gold quality
tendon of biceps brachii	UBERON:0008188	87.09	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6505	yes	716.28
E-ANND-3	yes	9.44
E-CURD-11	no	252.07

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

43 targets.

Target	Regulation
ABCA3	Activation
ACHE	Activation
ADRA1D
AP1	Unknown
ATF3	Activation
B3GAT3	Repression
C4B
CD40LG	Repression
CDH1
CR2	Unknown
CTSD	Activation
CXCL13
CXCR5
DDIT4	Unknown
DNAJB6
EDN1	Unknown
FASLG
FASTK
FCER2	Unknown
FOS
GC
GHRH
GPC6	Activation
IFNG	Activation
IL2	Activation
IL5	Activation
IL6	Activation
JUN
KCNB1	Repression
KCNC1	Repression

JASPAR motifs

Motif	Name	Family
MA0625.1	NFATC3	NFAT-related factors
MA0625.2	NFATC3	NFAT-related factors
MA0625.3	NFATC3	NFAT-related factors

JASPAR matrix evidence (PMIDs): PMID:9143705

Upstream regulators (CollecTRI, top): FOXM1, MYC

miRNA regulators (miRDB)

235 targeting NFATC3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345

Literature-anchored findings (GeneRIF, showing 36)

• transactivation activity and role in inducing differentiation of CD4(+)CD8(+) T cells (PMID:11997392)
• NFAT and thyroid transcription factor-1 have roles in regulating transcription of the surfactant protein D gene (PMID:15173172)
• NFATc3 is negatively regulated by class II histone deacetylases through the DnaJ (heat shock protein-40) superfamily member Mrj (PMID:16260608)
• We found that Ca(2+) oscillations were associated with NFAT translocation into the nucleus in undifferentiated hMSCs. As the hMSCs differentiated to adipocytes, the Ca(2+) oscillations disappeared and the translocation of NFAT ceased. (PMID:16445977)
• Calcium signaling and the activation of NFAT in glial cells are required for JC Virus infection of the CNS. (PMID:17035332)
• NFAT and MyoD cooperation regulates myogenin expression and myogenesis (PMID:18676376)
• CHP2 has a role in tumorigenesis and as an activator of the calcineurin/NFAT signaling pathway (PMID:18815128)
• NFATc3 is specifically required for IL2 and cyclooxygenase-2 (COX2) gene expression in T cells and for T-cell proliferation and NFATc3 regulates COX2 in endothelial cells (PMID:21642596)
• The authors report that NFAT4 and NF-kappaB interact at the KB element to co-operatively activate both human polyomavirus JC early and late transcription and viral DNA replication. (PMID:22749879)
• Abeta-activated NFAT4 proteins were associated with astrocytic BACE1 gene expression via direct interaction with the BACE1 promoter region. (PMID:22846573)
• Data indicate that NFATc3 undergoes rapid dephosphorylation and nuclear translocation that are essentially complete within 20 min, although NFATc4 remains phosphorylated and localized to the cytosol. (PMID:22977251)
• The closely related transcription factors NFAT1 and NFAT4 possess distinct nuclear localization dynamics in response to cell stimulation. (PMID:23219532)
• AP-1 and NFAT4 complex promotes miR-23a expression. (PMID:23929433)
• Microvesicles from tumor cells transferred TrpC5 to endothelial cells, inducing the expression of P-glycoprotein by activation of the transcription factor NFATc3 (nuclear factor of activated T cells isoform c3). (PMID:24582564)
• NFATc3 interacted in a SUMO-dependent manner with Trim17, an E3 ubiquitin ligase necessary for neuronal apoptosis (PMID:25215946)
• Suggest nuclear NF-AT3 and NF-AT4 participates in atrial structural remodeling, and that PICP and TGF-beta1 levels may be sensitive serum biomarkers to estimate atrial structural remodeling with atrial fibrillation. (PMID:25422138)
• Results show that two protein isoforms NFAT1 and NFAT4 are both cytosolic and stimulated by the same Ca2+ messenger but require distinct subcellular Ca2+ signals for activity. (PMID:25818645)
• two NFAT isoforms (NFAT4 and NFAT1) have shifted band-pass windows for the same receptor in the GPCR signaling pathway (PMID:26374065)
• Data indicate that RNA interference of NFAT isoforms NFATc1, NFATc2, NFATc3 and NFATc4 regulate gene expression differentially in human retinal microvascular endothelial cells (HRMEC). (PMID:26527057)
• Calcineurin together with its upstream molecule, calpain 2, and its downstream effector, NFAT-c3, might contribute to the development of atrial fibrillation in patients with heart valve disease and diabetes. (PMID:27123462)
• the transcription factor NFATC3 binds to IRF7 and functions synergistically to enhance IRF7-mediated IFN expression in Plasmacytoid dendritic cells. (PMID:27697837)
• NFAT1 is stimulated by subplasmalemmal Ca2+ microdomains, whereas NFAT4 additionally requires Ca2+ mobilization from the inner nuclear envelope by nuclear InsP3 receptors. (PMID:27863227)
• we found that VIP inhibits NFAT nuclear translocation in primary human pulmonary artery smooth muscle cells (PASMC). Early activation of NFATc3 in IPF patients may contribute to disease progression and the increase in VIP expression could be a protective compensatory mechanism (PMID:28125639)
• MicroRNA-214 regulates immunity-related genes in bovine mammary epithelial cells by targeting NFATc3 and TRA (PMID:28627449)
• The NFATc3 first induced the expression of its interaction partner FosB before forming the heterodimeric NFATc3-FosB transcription factor complex, which bound the proximal AP-1 site in the TF gene promoter and activated TF expression. (PMID:28724635)
• Expression of the NFATC3-PLA2G15 chimera correlated with aggressive disease biology in murine patient-derived T-ALL xenografts, and poor prognosis in human T-ALL patients. (PMID:29330284)
• data indicated that NRON alleviates atrial fibrosis via promoting NFATc3 phosphorylation. (PMID:30895498)
• Blocking NFATc3 ameliorates azoxymethane/dextran sulfate sodium induced colitis-associated colorectal cancer in mice via the inhibition of inflammatory responses and epithelial-mesenchymal transition. (PMID:32653643)
• circNFATC3 sponges miR-548I acts as a ceRNA to protect NFATC3 itself and suppressed hepatocellular carcinoma progression. (PMID:32667692)
• NFATc3 inhibits hepatocarcinogenesis and HBV replication via positively regulating RIG-I-mediated interferon transcription. (PMID:33520407)
• Fusobacterium nucleatum Promotes Cisplatin-Resistance and Migration of Oral Squamous Carcinoma Cells by Up-Regulating Wnt5a-Mediated NFATc3 Expression. (PMID:33840648)
• Macrophage NFATc3 prevents foam cell formation and atherosclerosis: evidence and mechanisms. (PMID:34570211)
• Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression. (PMID:35484132)
• lncRNA NEAT1 promotes hypoxia-induced inflammation and fibrosis of alveolar epithelial cells via targeting miR-29a/NFATc3 axis. (PMID:35708150)
• CircNFATC3 promotes the proliferation of gastric cancer through binding to IGF2BP3 and restricting its ubiquitination to enhance CCND1 mRNA stability. (PMID:37340423)
• HNRNPA2B1 stabilizes NFATC3 levels to potentiate its combined actions with FOSL1 to mediate vasculogenic mimicry in GBM cells. (PMID:38862832)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nfatc3a	ENSDARG00000076297
mus_musculus	Nfatc3	ENSMUSG00000031902
rattus_norvegicus	Nfatc3	ENSRNOG00000054264

Paralogs (4): NFATC4 (ENSG00000100968), NFATC2 (ENSG00000101096), NFAT5 (ENSG00000102908), NFATC1 (ENSG00000131196)

Protein

Protein identifiers

Nuclear factor of activated T-cells, cytoplasmic 3 — Q12968 (reviewed: Q12968)

Alternative names: NFATx, T-cell transcription factor NFAT4

All UniProt accessions (9): Q12968, B5B2S0, B5B2S1, F8VPH9, H3BR83, H3BRM3, H3BRS1, H3BU30, I3L3K7

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a regulator of transcriptional activation. Binds to the TNFSF11/RANKL promoter region and promotes TNFSF11 transcription. Binding to the TNFSF11 promoter region is increased by high levels of Ca(2+) which induce NFATC3 expression and may lead to regulation of TNFSF11 expression in osteoblasts. Plays a role in promoting mesenteric arterial wall remodeling in response to the intermittent hypoxia-induced increase in EDN1 and ROCK signaling. As a result NFATC3 colocalizes with F-actin filaments, translocates to the nucleus and promotes transcription of the smooth muscle hypertrophy and differentiation marker ACTA2. Promotes lipopolysaccharide-induced apoptosis and hypertrophy in cardiomyocytes. Following JAK/STAT signaling activation and as part of a complex with NFATC4 and STAT3, binds to the alpha-beta E4 promoter region of CRYAB and activates transcription in cardiomyocytes. In conjunction with NFATC4, involved in embryonic heart development via maintenance of cardiomyocyte survival, proliferation and differentiation. Plays a role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2. Required for thymocyte maturation during DN3 to DN4 transition and during positive selection. Positively regulates macrophage-derived polymicrobial clearance, via binding to the promoter region and promoting transcription of NOS2 resulting in subsequent generation of nitric oxide. Involved in Ca(2+)-mediated transcriptional responses upon Ca(2+) influx via ORAI1 CRAC channels.

Subunit / interactions. NFATC proteins bind to DNA as monomers. 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, or members of the activating protein-1 family, MAF, GATA4 and Cbp/p300 can also bind the complex. Component of a promoter-binding complex composed of STAT3, NFATC3 and NFATC4; complex formation is enhanced by calcineurin. Interacts with TRIM17; this interaction prevents NFATC3 nuclear localization. Interacts with and ubiquitinated by STUB1/CHIP; HSPA1A/HSP70 is required as a co-chaperone.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Predominantly expressed in thymus and is also found in peripheral blood leukocytes and kidney. Predominantly expressed in skeletal muscle. Also found weakly expressed in the thymus, kidney, testis, spleen, prostate, ovary, small intestine, heart, placenta and pancreas. Expressed in thymus and kidney. Expressed in thymus and skeletal muscle.

Post-translational modifications. Ubiquitinated by STUB1/CHIP, leading to proteasomal degradation. Phosphorylated by NFATC-kinase; dephosphorylated by calcineurin.

Domain organisation. Rel Similarity Domain (RSD) allows DNA-binding and cooperative interactions with AP1 factors.

Isoforms (6)

UniProt ID	Names	Canonical?
Q12968-1	1, X1	yes
Q12968-2	2, X2, C
Q12968-3	3, X3
Q12968-4	4, X4
Q12968-5	5, A
Q12968-6	6, B

RefSeq proteins (3): NP_004546, NP_775186, NP_775188* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002909	IPT_dom	Domain
IPR008366	NFAT	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR011539	RHD_DNA_bind_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR032397	RHD_dimer	Domain
IPR037059	RHD_DNA_bind_dom_sf	Homologous_superfamily

Pfam: PF00554, PF16179

UniProt features (47 total): region of interest 7, compositionally biased region 7, sequence conflict 7, modified residue 5, splice variant 5, sequence variant 5, short sequence motif 3, repeat 3, initiator methionine 1, chain 1, helix 1, domain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2XRW	X-RAY DIFFRACTION	1.33
2XS0	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12968-F1	54.99	0.22

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): 2, 344, 372, 1063, 1066

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2025928	Calcineurin activates NFAT
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-5607763	CLEC7A (Dectin-1) induces NFAT activation

MSigDB gene sets: 393 (showing top): BIOCARTA_FMLP_PATHWAY, WANG_CLIM2_TARGETS_UP, REACTOME_INNATE_IMMUNE_SYSTEM, YAGI_AML_WITH_INV_16_TRANSLOCATION, chr16q22, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, RORA1_01, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_THYMIC_T_CELL_SELECTION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (12): regulation of transcription by RNA polymerase II (GO:0006357), inflammatory response (GO:0006954), calcineurin-NFAT signaling cascade (GO:0033173), positive thymic T cell selection (GO:0045059), positive regulation of nitric oxide biosynthetic process (GO:0045429), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of miRNA transcription (GO:1902894), DN4 thymocyte differentiation (GO:1904157), negative regulation of vascular associated smooth muscle cell differentiation (GO:1905064), positive regulation of artery morphogenesis (GO:1905653), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (8): 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 repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Downstream signaling events of B Cell Receptor (BCR)	1
Fc epsilon receptor (FCERI) signaling	1
CLEC7A (Dectin-1) signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
cellular anatomical structure	4
transcription by RNA polymerase II	3
regulation of transcription by RNA polymerase II	3
regulation of DNA-templated transcription	2
negative regulation of DNA-templated transcription	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
defense response	1
calcineurin-mediated signaling	1
positive T cell selection	1
thymic T cell selection	1
nitric oxide biosynthetic process	1
positive regulation of biosynthetic process	1
regulation of nitric oxide biosynthetic process	1
positive regulation of DNA-templated transcription	1
miRNA transcription	1
regulation of miRNA transcription	1
negative regulation of miRNA metabolic process	1
T cell differentiation in thymus	1
vascular associated smooth muscle cell differentiation	1
negative regulation of smooth muscle cell differentiation	1
regulation of vascular associated smooth muscle cell differentiation	1
artery morphogenesis	1
positive regulation of developmental process	1
regulation of artery morphogenesis	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription repressor activity	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1

Protein interactions and networks

STRING

1420 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NFATC3	PPP3R1	P06705	877
NFATC3	SOX10	P56693	757
NFATC3	CALM1	P02593	732
NFATC3	CALML3	P27482	732
NFATC3	CALML5	Q9NZT1	732
NFATC3	CALML6	Q8TD86	723
NFATC3	CALML4	Q96GE6	723
NFATC3	SMAD2	Q15796	683
NFATC3	EGR2	P11161	661
NFATC3	IL2	P01585	599
NFATC3	REL	Q04864	595
NFATC3	PPP3CB	P16298	577
NFATC3	EGR3	Q06889	552
NFATC3	MAPK14	Q16539	549
NFATC3	CD28	P10747	520

IntAct

23 interactions, top by confidence:

A	B	Type	Score
NFATC3	SUFU	psi-mi:“MI:0915”(physical association)	0.560
CDK6	NFATC3	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
NFATC3		psi-mi:“MI:0915”(physical association)	0.400
NFATC3	RAF1	psi-mi:“MI:0915”(physical association)	0.400
XCL2	NFATC3	psi-mi:“MI:0915”(physical association)	0.370
JUN		psi-mi:“MI:0914”(association)	0.350
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
RYBP	PIPSL	psi-mi:“MI:0914”(association)	0.350
NFATC3	FLOT1	psi-mi:“MI:0914”(association)	0.350
PIP	RBM47	psi-mi:“MI:0914”(association)	0.350
NFATC3	CSNK1A1	psi-mi:“MI:0914”(association)	0.350
PPP3R2	MAP2K7	psi-mi:“MI:0914”(association)	0.350
CEP128	CCDC66	psi-mi:“MI:2364”(proximity)	0.270
NFATC3	TRAPPC3	psi-mi:“MI:2364”(proximity)	0.270
HOOK2	SEC16A	psi-mi:“MI:2364”(proximity)	0.270
SFN	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
YWHAB	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAH	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAQ	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAZ	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAG	E2F8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (62): NFATC3 (Affinity Capture-RNA), NFATC3 (Affinity Capture-RNA), NFATC3 (Affinity Capture-RNA), NFATC3 (Affinity Capture-RNA), CSNK1A1 (Affinity Capture-MS), SUFU (Affinity Capture-MS), NFATC3 (Proximity Label-MS), NFATC3 (Affinity Capture-MS), SUFU (Affinity Capture-MS), NFATC3 (Affinity Capture-MS), NFATC3 (Affinity Capture-MS), NFATC3 (Affinity Capture-MS), NFATC3 (Affinity Capture-RNA), NFATC3 (Proximity Label-MS), NFATC3 (Proximity Label-MS)

ESM2 similar proteins: A0A0G2JTY4, A2VD01, A5PMU4, A8E4V2, D2HNW6, E1BEQ5, O54972, O95644, P16236, P59281, P70365, P97305, Q12968, Q13191, Q13469, Q13905, Q15788, Q1LY51, Q2VPU4, Q3LRZ1, Q3TTA7, Q3U182, Q4PJW2, Q4VCS5, Q60591, Q61122, Q66IV1, Q68FF7, Q6DFR2, Q6GQL0, Q6NYU6, Q6ZNC4, Q80TM6, Q80VG1, Q8HWS3, Q8IXK0, Q8IY63, Q8K4S7, Q8N228, Q8VHG2

Diamond homologs: A0A0G2JTY4, D3Z9H7, D3ZGB1, O77638, O88942, O94916, O95644, P97305, P98201, Q12968, Q13469, Q14934, Q60591, Q8K120, Q9WV30

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
MAPK9	down-regulates	NFATC3	relocalization
CSNK1A1	“down-regulates activity”	NFATC3	phosphorylation
MAPK8	down-regulates	NFATC3	phosphorylation
PPP3CA	up-regulates	NFATC3	dephosphorylation
NFATC3	“up-regulates quantity by expression”	IL6	“transcriptional regulation”
Calcineurin	up-regulates	NFATC3	dephosphorylation
NFATC3	“up-regulates quantity by expression”	TFF1	“transcriptional regulation”
NFATC3	“up-regulates quantity by expression”	CTSD	“transcriptional regulation”
NFATC3	“up-regulates quantity by expression”	GPC6	“transcriptional regulation”
NFATC3	“up-regulates quantity by expression”	PTGS2	“transcriptional regulation”
MAPK9	down-regulates	NFATC3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 28 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
Activation of BAD and translocation to mitochondria	6	217.5×	1e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	191.9×	1e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	191.9×	1e-11
Activation of BH3-only proteins	6	141.9×	8e-11
RHO GTPases activate PKNs	6	90.6×	1e-09
Intrinsic Pathway for Apoptosis	6	83.7×	2e-09
FOXO-mediated transcription	5	80.0×	7e-08
SARS-CoV-1-host interactions	6	50.2×	4e-08

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	7	28.2×	1e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	142
Likely benign	8
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2463 predictions. Top by Δscore:

Variant	Effect	Δscore
16:68126444:GTAGC:G	acceptor_loss	1.0000
16:68126445:TAGC:T	acceptor_loss	1.0000
16:68126446:A:AG	acceptor_gain	1.0000
16:68126446:A:T	acceptor_loss	1.0000
16:68126447:G:GG	acceptor_gain	1.0000
16:68126447:GC:G	acceptor_gain	1.0000
16:68126447:GCA:G	acceptor_gain	1.0000
16:68126447:GCAC:G	acceptor_gain	1.0000
16:68126447:GCACA:G	acceptor_gain	1.0000
16:68126609:AGGT:A	donor_loss	1.0000
16:68126610:GG:G	donor_loss	1.0000
16:68126611:GTATG:G	donor_loss	1.0000
16:68126612:T:A	donor_loss	1.0000
16:68147481:AAT:A	acceptor_gain	1.0000
16:68157862:T:A	acceptor_gain	1.0000
16:68157866:TAG:T	acceptor_loss	1.0000
16:68157867:A:AG	acceptor_gain	1.0000
16:68157867:A:C	acceptor_loss	1.0000
16:68157868:G:C	acceptor_loss	1.0000
16:68157868:G:GA	acceptor_gain	1.0000
16:68157868:GCT:G	acceptor_gain	1.0000
16:68157868:GCTC:G	acceptor_gain	1.0000
16:68158018:TACAA:T	donor_gain	1.0000
16:68158019:ACAAA:A	donor_gain	1.0000
16:68158064:GCCAG:G	donor_gain	1.0000
16:68166841:A:AG	acceptor_gain	1.0000
16:68166842:G:GA	acceptor_gain	1.0000
16:68166842:GT:G	acceptor_gain	1.0000
16:68166842:GTA:G	acceptor_gain	1.0000
16:68166842:GTAT:G	acceptor_gain	1.0000

AlphaMissense

6922 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:68122215:T:A	I111N	1.000
16:68122215:T:C	I111T	1.000
16:68122215:T:G	I111S	1.000
16:68122221:T:C	I113T	1.000
16:68126507:T:C	L433P	1.000
16:68126525:C:A	P439H	1.000
16:68126525:C:G	P439R	1.000
16:68126533:C:G	H442D	1.000
16:68126536:C:A	H443N	1.000
16:68126536:C:G	H443D	1.000
16:68126537:A:G	H443R	1.000
16:68126538:T:A	H443Q	1.000
16:68126538:T:G	H443Q	1.000
16:68126539:C:G	R444G	1.000
16:68126540:G:C	R444P	1.000
16:68126543:C:A	A445D	1.000
16:68126545:C:G	H446D	1.000
16:68126548:T:A	Y447N	1.000
16:68126548:T:C	Y447H	1.000
16:68126548:T:G	Y447D	1.000
16:68126549:A:G	Y447C	1.000
16:68126552:A:T	E448V	1.000
16:68126554:A:C	T449P	1.000
16:68126555:C:T	T449I	1.000
16:68126557:G:A	E450K	1.000
16:68126558:A:T	E450V	1.000
16:68126559:A:C	E450D	1.000
16:68126559:A:T	E450D	1.000
16:68126560:G:A	G451S	1.000
16:68126560:G:C	G451R	1.000

dbSNP variants (sampled 300 via entrez): RS1000003648 (16:68164173 G>A), RS1000019222 (16:68115583 C>G), RS1000023194 (16:68211371 A>G), RS1000048003 (16:68205259 G>A,C), RS1000053718 (16:68162578 A>C), RS1000083490 (16:68108695 C>A,G), RS1000089727 (16:68221482 C>G), RS1000097004 (16:68126173 C>T), RS1000111768 (16:68170004 C>G,T), RS1000117298 (16:68151408 G>A), RS1000122705 (16:68188036 C>T), RS1000137180 (16:68172963 G>A), RS1000200676 (16:68145293 G>A,C), RS1000237702 (16:68188283 G>A), RS1000284664 (16:68101797 A>T)

Disease associations

OMIM: gene MIM:602698 | disease phenotypes: MIM:148300

GenCC curated gene-disease

Mondo (1): keratoconus (MONDO:0015486)

Orphanet (2): OBSOLETE: Keratoconus (Orphanet:156071), NON RARE IN EUROPE: Isolated keratoconus (Orphanet:2335)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000563	Keratoconus

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002539_84	Schizophrenia	2.000000e-08
GCST006803_42	Schizophrenia	4.000000e-08
GCST007576_292	Chronotype	2.000000e-08
GCST007876_137	Estimated glomerular filtration rate	2.000000e-10
GCST008972_244	Urate levels	3.000000e-08
GCST010002_113	Refractive error	2.000000e-14
GCST90011900_127	Serum alkaline phosphatase levels	2.000000e-15

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0004531	urate measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007640	Keratoconus	C11.204.627

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725192 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases reaction, affects cotreatment, affects localization, decreases expression, increases expression	2
methacrylaldehyde	decreases expression, increases abundance, affects cotreatment	2
Acrolein	affects cotreatment, decreases expression, increases abundance	2
Arsenic	affects expression, affects binding, decreases expression, increases expression, affects localization (+1 more)	2
Vehicle Emissions	decreases expression, increases abundance	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Cisplatin	affects cotreatment, increases expression	2
Ozone	affects cotreatment, decreases expression, increases abundance	2
Valproic Acid	decreases methylation, increases expression, increases methylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
bisphenol A	decreases methylation	1
beta-lapachone	decreases expression	1
perfluorooctanoic acid	decreases expression	1
coumarin	affects phosphorylation	1
cyclo(Trp-Asp-Pro-Val-Leu)	decreases reaction, increases localization, affects cotreatment	1
perfluorooctane sulfonic acid	decreases expression	1
BQ 788	affects cotreatment, decreases reaction, increases localization	1
perfluoro-n-nonanoic acid	decreases expression	1
monomethylarsonous acid	increases expression	1
fenpyroximate	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
asparanin A	decreases expression	1
picoxystrobin	decreases expression	1
Calcimycin	affects cotreatment, increases expression, increases reaction	1
Arsenic Trioxide	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697658	Binding	Inhibition of NFATC3 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3CB	Abcam HEK293T NFATC3 KO	Transformed cell line	Female
CVCL_E0IZ	Ubigene HeLa NFATC3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

279 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01485211	PHASE4	COMPLETED	Corneal Thickness Changes During Corneal Collagen Cross-linking With Ultraviolet-A Irradiation and Riboflavin
NCT02119039	PHASE4	COMPLETED	Effect of CACICOL20 on Corneal Epithelial Healing After Cross-linking in Patients With Keratoconus
NCT03245853	PHASE4	COMPLETED	Epi-On Corneal Crosslinking for Keratoconus
NCT03429569	PHASE4	UNKNOWN	Cross-Linking ACcéléré Iontophorèse Confocal kératocONE
NCT04427956	PHASE4	COMPLETED	Corneal Crosslinking Treatment Study
NCT07474870	PHASE4	NOT_YET_RECRUITING	Outcomes of CTAK Surgery
NCT00371202	PHASE3	UNKNOWN	Comparison of Penetrating Keratoplasty and Deep Lamellar Keratoplasty With the Big Bubble Technique for Keratoconus
NCT00647699	PHASE3	COMPLETED	Corneal Collagen Cross-linking for Progressive Keratoconus
NCT00815256	PHASE3	UNKNOWN	Safety and Effectiveness of Collagen Cross Linking in Progressive Mild and Moderate Keratoconus
NCT00887900	PHASE3	COMPLETED	Deep Anterior Lamellar Keratoplasty (DALK)
NCT01112072	PHASE3	UNKNOWN	Corneal Collagen Crosslinking and Intacs for Keratoconus and Ectasia
NCT01152541	PHASE3	UNKNOWN	Corneal Collagen Crosslinking for Progressive Keratoconus and Ectasia Using Riboflavin/Dextran and Hypotonic Riboflavin
NCT01190306	PHASE3	TERMINATED	Safety Study of the VEGA UV-A System to Treat Keratoconus
NCT01344187	PHASE3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01459679	PHASE3	TERMINATED	Safety & Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus or Corneal Ectasia After Refractive Surgery
NCT01464268	PHASE3	UNKNOWN	Transepithelial Corneal Collagen Crosslinking for Keratoconus and Corneal Ectasia
NCT01604135	PHASE3	ACTIVE_NOT_RECRUITING	Collagen Crosslinking for Keratoconus - a Randomized Controlled Clinical Trial
NCT01643226	PHASE3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01672814	PHASE3	COMPLETED	Microwave Treatment and Corneal Collagen Crosslinking for Keratoconus
NCT01682993	PHASE3	TERMINATED	Corneal Cross Linking and Topography Guided Excimer Laser Treatment
NCT01972854	PHASE3	TERMINATED	Safety and Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT02613780	PHASE3	UNKNOWN	Refractive Treatment of Early Keratoconus
NCT02638376	PHASE3	UNKNOWN	Evaluating the Safety and Efficacy of the KXL System for Corneal Collagen Cross-Linking in Eyes Having Keratoconus
NCT03080077	PHASE3	UNKNOWN	Safety and Effectiveness of Corneal Crosslinking (CXL): Keratoconus and Post-Refractive Ectasia
NCT03187912	PHASE3	COMPLETED	Accelerated Corneal Cross-linking With Different Riboflavin Solutions
NCT03442751	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Epi-on Corneal Cross-linking in Eyes With Progressive Keratoconus
NCT03858036	PHASE3	UNKNOWN	Corneal Collagen Cross-Linking (CXL) Performed With Epi-ON Versus Epi-OFF in Eyes With Keratoconus and Other Corneal Ectatic Disorders
NCT04897503	PHASE3	UNKNOWN	Corneal Collagen Crosslinking for Keratoconus and Ectasia Using Riboflavin/Dextran or Riboflavin/Methylcellulose
NCT04905108	PHASE3	UNKNOWN	Transepithelial (Epi-on) Corneal Collagen Crosslinking to Treat Keratoconus and Corneal Ectasia
NCT05027295	PHASE3	UNKNOWN	Accelerated Corneal Collagen Crosslinking for Keratoconus and Ectasia Using Pulse or Continuous UV-A Light
NCT06100939	PHASE3	ACTIVE_NOT_RECRUITING	Epithelium-On Corneal Cross-linking in Subjects 8 to 45 Years of Age With Keratoconus
NCT06100952	PHASE3	ACTIVE_NOT_RECRUITING	Epithelium-On Corneal Cross-linking in Subjects 8 to 45 Years of Age with Keratoconus
NCT06450470	PHASE3	RECRUITING	Use of a Freeze-dried Amniotic Membrane Post Crosslinking in Subjects With Progressive Keratoconus
NCT06601101	PHASE3	RECRUITING	Effects of Topical Insulin on Corneal Epithelium Healing After Corneal Crosslinking in Patients With Keratoconus
NCT07124910	PHASE3	RECRUITING	Comparison of Epi-ON Corneal Collagen Crosslinking Performed Using an 18-Minute UVA Exposure vs. a 24-Minute UVA Exposure on Eyes With Ectatic Corneal Diseases
NCT07135167	PHASE3	RECRUITING	Compassionate Use Study of Epi-ON Corneal Collagen Crosslinking Performed Using UVA Exposure on Eyes With Ectatic Corneal Diseases for Subjects With Down Syndrome
NCT00409955	PHASE2	COMPLETED	Lamellar Transplant With Lyophilized Corneas
NCT00925327	PHASE2	UNKNOWN	Safety and Effectiveness of the UV-X System for Corneal Collagen Cross-Linking for Compassionate Treatment in Pediatric Patients With Progressive Keratoconus
NCT01143389	PHASE2	COMPLETED	Corneal Crosslinking in Patients With Keratoconus and Post-Refractive Ectasia
NCT01181219	PHASE2	COMPLETED	Transepithelial Corneal Collagen Cross-linking (CXL) in Treatment of Keratoconus