NFATC4

Summary

NFATC4 (nuclear factor of activated T cells 4, HGNC:7778) is a protein-coding gene on chromosome 14q12, encoding Nuclear factor of activated T-cells, cytoplasmic 4 (Q14934). Ca(2+)-regulated transcription factor that is involved in several processes, including the development and function of the immune, cardiovascular, musculoskeletal, and nervous systems.

This gene encodes a member of the nuclear factor of activated T cells (NFAT) protein family. The encoded protein is part of a 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 stimulation and an inducible nuclear component. NFAT proteins are activated by the calmodulin-dependent phosphatase, calcineurin. The encoded protein plays a role in the inducible expression of cytokine genes in T cells, especially in the induction of interleukin-2 and interleukin-4. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 4776 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 132 total
• Transcription factor: yes — 45 downstream targets (CollecTRI)
• MANE Select transcript: NM_004554

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7778
Approved symbol	NFATC4
Name	nuclear factor of activated T cells 4
Location	14q12
Locus type	gene with protein product
Status	Approved
Aliases	NFAT3
Ensembl gene	ENSG00000100968
Ensembl biotype	protein_coding
OMIM	602699
Entrez	4776

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 27 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000250373, ENST00000413692, ENST00000422617, ENST00000424781, ENST00000440487, ENST00000539237, ENST00000553469, ENST00000553708, ENST00000553879, ENST00000554050, ENST00000554344, ENST00000554473, ENST00000554591, ENST00000554655, ENST00000554661, ENST00000554779, ENST00000554903, ENST00000554966, ENST00000555167, ENST00000555393, ENST00000555453, ENST00000555590, ENST00000555802, ENST00000555821, ENST00000556169, ENST00000556279, ENST00000556302, ENST00000556759, ENST00000556957, ENST00000557028, ENST00000557451, ENST00000557674, ENST00000557767

RefSeq mRNA: 9 — MANE Select: NM_004554 NM_001136022, NM_001198965, NM_001198966, NM_001198967, NM_001288802, NM_001320043, NM_001363681, NM_001363682, NM_004554

CCDS: CCDS45089, CCDS55909, CCDS55910, CCDS55911, CCDS73625, CCDS86379, CCDS86380, CCDS9629

Canonical transcript exons

ENST00000250373 — 10 exons

Exon	Start	End
ENSE00001938123	24377638	24379601
ENSE00002470676	24368184	24368440
ENSE00003466995	24373695	24373867
ENSE00003483509	24375660	24375715
ENSE00003565805	24373171	24373370
ENSE00003592505	24375975	24376101
ENSE00003612235	24374326	24374466
ENSE00003628410	24376294	24376878
ENSE00003636127	24369499	24370594
ENSE00003678563	24372441	24372603

Expression profiles

Bgee: expression breadth ubiquitous, 142 present calls, max score 99.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.3944 / max 55.2824, expressed in 992 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139036	3.3944	992

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endocervix	UBERON:0000458	99.00	gold quality
right ovary	UBERON:0002118	98.93	gold quality
left ovary	UBERON:0002119	98.80	gold quality
stromal cell of endometrium	CL:0002255	98.68	gold quality
ovary	UBERON:0000992	98.44	gold quality
body of uterus	UBERON:0009853	98.35	gold quality
left uterine tube	UBERON:0001303	98.12	gold quality
myometrium	UBERON:0001296	98.02	gold quality
mucosa of stomach	UBERON:0001199	97.70	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.49	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.46	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.41	gold quality
lower esophagus	UBERON:0013473	97.40	gold quality
right coronary artery	UBERON:0001625	97.33	gold quality
right adrenal gland cortex	UBERON:0035827	97.26	gold quality
left coronary artery	UBERON:0001626	97.18	gold quality
uterine cervix	UBERON:0000002	97.14	gold quality
right adrenal gland	UBERON:0001233	97.09	gold quality
ectocervix	UBERON:0012249	97.08	gold quality
right testis	UBERON:0004534	96.96	gold quality
popliteal artery	UBERON:0002250	96.95	gold quality
tibial artery	UBERON:0007610	96.95	gold quality
right lobe of thyroid gland	UBERON:0001119	96.84	gold quality
vagina	UBERON:0000996	96.67	gold quality
ascending aorta	UBERON:0001496	96.53	gold quality
thoracic aorta	UBERON:0001515	96.53	gold quality
left testis	UBERON:0004533	96.52	gold quality
left adrenal gland cortex	UBERON:0035825	96.52	gold quality
descending thoracic aorta	UBERON:0002345	96.36	gold quality
urinary bladder	UBERON:0001255	96.31	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.11

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

45 targets.

Target	Regulation
ACHE	Activation
ADIPOQ	Repression
ADSS1	Activation
AXIN2	Repression
B3GAT3	Repression
BDNF	Activation
CAT
CD74
CGA	Activation
COL1A1	Activation
CRTC1
CTSD	Activation
DKK1	Repression
EGF
ESR1	Activation
ESR2	Activation
FSHB
GAP43
GJA1
GPC6	Activation
GSK3B
IL12B	Repression
IL2
ITPR1
LCN2	Repression
LEP
LPIN1
MYH7
MYL2
MYOZ1	Activation

JASPAR motifs

Motif	Name	Family
MA1525.1	NFATC4	NFAT-related factors
MA1525.2	NFATC4	NFAT-related factors
MA1525.3	NFATC4	NFAT-related factors

JASPAR matrix evidence (PMIDs): PMID:12374807

Upstream regulators (CollecTRI, top): AP1, ESR1, JUN, NFATC4, TP53

miRNA regulators (miRDB)

59 targeting NFATC4, 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-5193	100.00	67.26	1744
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-4452	99.50	68.45	1493
HSA-MIR-12113	99.32	67.54	1072
HSA-MIR-6719-3P	99.29	67.78	1387
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5690	99.25	67.58	1012
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-2054	99.20	68.89	1699
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987

Literature-anchored findings (GeneRIF, showing 29)

• Polymorphism of the NFATC4 gene plays a role in the development of human cardiac hypertrophy. (PMID:12939651)
• NFAT3 may play a role in estrogen receptor signaling in breast cancer cells (PMID:16219765)
• This study demonstrates that silica was able to activate NFAT3 in an oxygen radical-dependent manner, which was required for TNF-alpha induction. (PMID:16489119)
• ionizing radiation is able to enhance cyclin D1 transcription induced by B[a]PDE, and NFAT3 is involved in the regulation of cyclin D1 transcription by B[a]PDE or B[a]PDE plus ionizing radiation (PMID:16645724)
• Neuronal nuclear translocation of NFAT requires a functional cytoskeleton. (PMID:17044076)
• overexpression of NFAT3 in cell lines originated from kidney decreased dose-dependently both ERalpha and ERbeta transcriptional activities in a ligand-independent manner. (PMID:17194453)
• RSK2 is an important kinase for NFAT3 in mediating myotube differentiation (PMID:17213202)
• Results provided direct evidence for the anti-oncogenic potential of the NFAT3 transcription factor. (PMID:17875713)
• Data show that the calcineurin pathway is activated in hypertrophic myocardium as demonstrated by increased calcineurin activity and expression of calcineurin A-beta and B, and GATA-4, and a shift of cytoplasmic NFAT-3 into the nucleus. (PMID:18034994)
• estrogen receptor may play a critical role in regulation of NFAT3 transcriptional activity (PMID:18668201)
• Data show that inhibition of NFAT3 activation by shNFAT3 significantly downregulated tumor necrosis factor (TNF)-alpha induction, its receptor TNFR1, caspase 10, caspase 3, and poly (ADP-ribose) polymerase. (PMID:19784808)
• an earlier unknown NFAT3/LCN2 axis that critically controls motility in breast cancer (PMID:20101218)
• The expression of COX-2 was significantly associated with the expressions of transcription factors NFAT3 and c-Fos in nonsmall cell lung cancer. (PMID:21081043)
• Syndecan-4 is essential for development of concentric myocardial hypertrophy via stretch-induced activation of the calcineurin-NFAT pathway (PMID:22164265)
• Polymorphisms in the NFATc4 gene may confer certain protection or predisposition for new-onset diabetes after transplantation (NODAT). (PMID:22234350)
• Dendritic spine loss and dendritic branching simplification induced by amyloid-beta peptide exposure are mimicked by constitutively active NFATC4, and abolished when NFATC4 activation is blocked by the genetically encoded inhibitor VIVIT. (PMID:22378890)
• 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)
• Expression level of PPP3R1 and GATA4, and NFATC4 genes for transcription factors did not differ in studied subgroups of patients. (PMID:23888774)
• This is the first study to provide evidence of new and differential roles for NFAT3 and SMAD3 in the osteoarthritis process in the regulation of miR-140 transcription (PMID:24257415)
• 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)
• NFAT3 expression plays a role in regulating CXCR4 expression. (PMID:25514788)
• 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)
• Ca(2+)/calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) c4 axis is required for neuritin-induced Kv4.2 transcriptional expression and potentiation of IA densities in cerebellum granule neurons. (PMID:27307045)
• These results provided evidence supporting the oncogenic potential of NFAT3 and suggested that CDK3-mediated phosphorylation of NFAT3 has an important role in skin tumorigenesis. (PMID:27893713)
• NFATc1 knockdown strongly reduced the number and the surface area of myotubes, NFATc4 knockdown increased the surface area of myotubes and reduced the pool of reserve cells. (PMID:28760926)
• TBX5 deficiency-mediated downregulation of NFAT3 is crucial for the high cytokine-producing activity of T cells (PMID:29180489)
• NFATC4 promotes quiescence and chemotherapy resistance in ovarian cancer. (PMID:32182216)
• NULP1 Alleviates Cardiac Hypertrophy by Suppressing NFAT3 Transcriptional Activity. (PMID:32805187)
• The m7G Methyltransferase Mettl1 Drives Cardiac Hypertrophy by Regulating SRSF9-Mediated Splicing of NFATc4. (PMID:38810124)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nfatc4	ENSDARG00000054162
mus_musculus	Nfatc4	ENSMUSG00000023411
rattus_norvegicus	Nfatc4	ENSRNOG00000020482

Paralogs (4): NFATC3 (ENSG00000072736), NFATC2 (ENSG00000101096), NFAT5 (ENSG00000102908), NFATC1 (ENSG00000131196)

Protein

Protein identifiers

Nuclear factor of activated T-cells, cytoplasmic 4 — Q14934 (reviewed: Q14934)

Alternative names: T-cell transcription factor NFAT3

All UniProt accessions (4): Q14934, G3V4K1, G3V4U6, G3V5H0

UniProt curated annotations — full annotation on UniProt →

Function. Ca(2+)-regulated transcription factor that is involved in several processes, including the development and function of the immune, cardiovascular, musculoskeletal, and nervous systems. Involved in T-cell activation, stimulating the transcription of cytokine genes, including that of IL2 and IL4. Along with NFATC3, involved in embryonic heart development. Following JAK/STAT signaling activation and as part of a complex with NFATC3 and STAT3, binds to the alpha-beta E4 promoter region of CRYAB and activates transcription in cardiomyocytes. Involved in mitochondrial energy metabolism required for cardiac morphogenesis and function. Transactivates many genes involved in the cardiovascular system, including AGTR2, NPPB/BNP (in synergy with GATA4), NPPA/ANP/ANF and MYH7/beta-MHC. Involved in the regulation of adult hippocampal neurogenesis. Involved in BDNF-driven pro-survival signaling in hippocampal adult-born neurons. Involved in the formation of long-term spatial memory and long-term potentiation. In cochlear nucleus neurons, may play a role in deafferentation-induced apoptosis during the developmental critical period, when auditory neurons depend on afferent input for survival. Binds to and activates the BACE1/Beta-secretase 1 promoter, hence may regulate the proteolytic processing of the amyloid precursor protein (APP). Plays a role in adipocyte differentiation. May be involved in myoblast differentiation into myotubes. Binds the consensus DNA sequence 5’-GGAAAAT-3’. In the presence of CREBBP, activates TNF transcription. Binds to PPARG gene promoter and regulates its activity. Binds to PPARG and REG3G gene promoters.

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 NFAT proteins, such as NFATC3, or members of the activating protein-1 (AP-1) family and MAF can also bind the complex. NFAT proteins can bind DNA as monomers or dimers. Component of a promoter-binding complex composed of STAT3, NFATC3 and NFATC4; complex formation is enhanced by calcineurin. Interacts with CREBBP; this interaction potentiates transcription activation. Interacts with MAPK8/JNK1 and MAPK9/JNK2. Interacts with GATA4 (via the second Zn finger). Interacts (via N-terminus) with IRAK1 (via C-terminus). Interacts with RPS6KA3. Interacts with HOMER1, HOMER2 and HOMER3; this interaction competes with calcineurin/PPP3CA-binding and hence prevents NFATC4 dephosphorylation and activation. Interacts with ESR1 and ESR2; this interaction decreases NFATC4 transcriptional activity. Interacts with MTOR and MAPK7/ERK5. Interacts with TRIM17; this interaction prevents NFATC3 nuclear localization. Interacts with TCF25 (via C-terminus); the interaction leads to suppression of NFATC4 transcription factor activity and is reduced following stimulation with angiotensin-2.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed, with high levels in placenta, lung, kidney, testis and ovary. Weakly expressed in spleen and thymus. In the hippocampus, expressed in the granular layer of the dentate gyrus, in the pyramidal neurons of CA3 region, and in the hippocampal fissure. Expressed in the heart (at protein level).

Post-translational modifications. Phosphorylated by NFATC-kinases; dephosphorylated by calcineurin/PPP3CA. Phosphorylated on Ser-168 and Ser-170 by MTOR, IRAK1, MAPK7/ERK5 and MAPK14/p38, on Ser-213 and Ser-217 by MAPK8/JNK1 and MAPK9/JNK2, and on Ser-289 and Ser-344 by RPS6KA3. Phosphorylated by GSK3B. Phosphorylation by GSK3B markedly increases NFATC4 ubiquitination. Phosphorylation at Ser-168 and Ser-170 is stimulated by UV irradiation. Phosphorylation determines subcellular location: the hyperphosphorylated protein is cytosolic, while the dephosphorylated form is targeted to the nucleus. Ubiquitinated, leading to degradation by the proteasome. Ubiquitination may be stimulated by GSK3B-dependent phosphorylation. Polyubiquitin linkage mainly occurs through ‘Lys-48’.

Activity regulation. Transcriptional activity may be repressed by ESR1 and ESR2.

Domain organisation. Rel similarity domain (RSD) or Rel homology domain (RHD) allows DNA-binding and cooperative interactions with AP-1 factors.

Miscellaneous. Due to an intron retention. Due to an intron retention. Due to an intron retention. Due to an intron retention. Due to an intron retention. Due to an intron retention. Due to an intron retention. Due to an intron retention. Due to an intron retention. Due to an intron retention.

Isoforms (24)

UniProt ID	Names	Canonical?
Q14934-1	1, ID-IXL	yes
Q14934-2	2, IA-IXL
Q14934-3	3, IA-IXi
Q14934-4	4, IC-IXL
Q14934-5	5, IC-IXi
Q14934-6	6, IB-IXL
Q14934-7	7, IB-IXi
Q14934-8	8, ID-IXi
Q14934-9	9, IE-IXL
Q14934-10	10, IE-IXi
Q14934-11	11, IA-IXS
Q14934-12	12, IEi-IXL
Q14934-13	13, IEi-IXi
Q14934-14	14, IC-IXS
Q14934-15	15, IB-IXS
Q14934-16	16, ID-IXS
Q14934-17	17, IE-IXS
Q14934-18	18, IEi-IXS
Q14934-19	19, IV-IXL
Q14934-20	20, IV-IXi
Q14934-21	21, IV-IXS
Q14934-22	22, VI-IXL
Q14934-23	23, VI-IXi
Q14934-24	24, VI-IXS

RefSeq proteins (9): NP_001129494, NP_001185894, NP_001185895, NP_001185896, NP_001275731, NP_001306972, NP_001350610, NP_001350611, NP_004545* (*=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 (55 total): splice variant 9, compositionally biased region 8, strand 8, modified residue 6, region of interest 5, mutagenesis site 4, sequence variant 3, repeat 2, short sequence motif 2, domain 2, sequence conflict 2, chain 1, cross-link 1, turn 1, DNA-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2YRP	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14934-F1	59.61	0.27

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 (7): 168, 170, 213, 217, 289, 344, 689

Mutagenesis-validated functional residues (4):

Position	Phenotype
168	promotes nuclear localization and increases transcriptional activity; when associated with a-170.
170	promotes nuclear localization and increases transcriptional activity; when associated with a-168.
213	marked decrease in phosphorylation by mapk8 or mapk9. complete loss of phosphorylation by mapk8 or mapk9, but no effect
217	marked decrease in phosphorylation by mapk8 or mapk9. complete loss of phosphorylation by mapk8 or mapk9, but no effect

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 321 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_DENDRITE_DEVELOPMENT, GOBP_MEMORY, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, BIOCARTA_FMLP_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_COGNITION, WWTAAGGC_UNKNOWN, GOBP_BEHAVIOR, PAX4_01, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_INFLAMMATORY_RESPONSE

GO Biological Process (29): branching involved in blood vessel morphogenesis (GO:0001569), transcription by RNA polymerase II (GO:0006366), inflammatory response (GO:0006954), heart development (GO:0007507), long-term memory (GO:0007616), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), negative regulation of Wnt signaling pathway (GO:0030178), brain-derived neurotrophic factor receptor signaling pathway (GO:0031547), positive regulation of tumor necrosis factor production (GO:0032760), calcineurin-NFAT signaling cascade (GO:0033173), cellular response to UV (GO:0034644), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of neuron apoptotic process (GO:0043525), cellular respiration (GO:0045333), positive regulation of transcription by RNA polymerase II (GO:0045944), dendrite morphogenesis (GO:0048813), negative regulation of dendrite morphogenesis (GO:0050774), neuron apoptotic process (GO:0051402), synapse maturation (GO:0060074), long-term synaptic potentiation (GO:0060291), cellular response to lithium ion (GO:0071285), vascular associated smooth muscle cell development (GO:0097084), negative regulation of miRNA transcription (GO:1902894), negative regulation of synapse maturation (GO:2000297), positive regulation of apoptotic signaling pathway (GO:2001235), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), cell differentiation (GO:0030154), vascular associated smooth muscle cell differentiation (GO:0035886)

GO Molecular Function (8): transcription cis-regulatory region binding (GO:0000976), 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), 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), transcription regulator complex (GO:0005667), cytosol (GO:0005829), nuclear speck (GO:0016607), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of neuron apoptotic process	2
neuron apoptotic process	2
regulation of transcription by RNA polymerase II	2
angiogenesis	1
blood vessel morphogenesis	1
branching morphogenesis of an epithelial tube	1
DNA-templated transcription	1
defense response	1
animal organ development	1
circulatory system development	1
memory	1
DNA damage response	1
intrinsic apoptotic signaling pathway	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
cell surface receptor protein tyrosine kinase signaling pathway	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
calcineurin-mediated signaling	1
response to UV	1
cellular response to light stimulus	1
negative regulation of apoptotic process	1
positive regulation of apoptotic process	1
energy derivation by oxidation of organic compounds	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
dendrite development	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
negative regulation of cell projection organization	1
dendrite morphogenesis	1
regulation of dendrite morphogenesis	1
negative regulation of neurogenesis	1
apoptotic process	1
nervous system development	1
developmental maturation	1

Protein interactions and networks

STRING

1171 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NFATC4	SOX10	P56693	919
NFATC4	PPP3R1	P06705	863
NFATC4	GATA4	P43694	854
NFATC4	EGR2	P11161	752
NFATC4	CALML6	Q8TD86	722
NFATC4	CALML4	Q96GE6	722
NFATC4	CALML3	P27482	721
NFATC4	CALML5	Q9NZT1	721
NFATC4	CALM1	P02593	712
NFATC4	JUN	P05412	618
NFATC4	REL	Q04864	598
NFATC4	FOS	P01100	593
NFATC4	LPIN1	Q14693	589
NFATC4	RCAN1	P53805	573
NFATC4	TNF	P01375	556

IntAct

27 interactions, top by confidence:

A	B	Type	Score
PPP3CA	PPP3R1	psi-mi:“MI:0914”(association)	0.900
JUN	NFATC1	psi-mi:“MI:0914”(association)	0.610
NFATC4	UBC	psi-mi:“MI:0915”(physical association)	0.590
UBC	NFATC4	psi-mi:“MI:0915”(physical association)	0.590
PPP3CC	NFATC1	psi-mi:“MI:0914”(association)	0.530
Dlg4	NFATC4	psi-mi:“MI:0407”(direct interaction)	0.440
NFATC4	PASK	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
NFATC4	CCNG1	psi-mi:“MI:0915”(physical association)	0.370
NFATC4	GPR22	psi-mi:“MI:0915”(physical association)	0.370
JUP	NFATC4	psi-mi:“MI:0915”(physical association)	0.370
NFATC4	NR1I2	psi-mi:“MI:0915”(physical association)	0.370
M		psi-mi:“MI:0914”(association)	0.350
RYBP	PIPSL	psi-mi:“MI:0914”(association)	0.350
NFATC4	HSPE1	psi-mi:“MI:0914”(association)	0.350
NFATC4	GFAP	psi-mi:“MI:0914”(association)	0.350
PPP3CC	MAP2K7	psi-mi:“MI:0914”(association)	0.350
YWHAQ	NFATC4	psi-mi:“MI:0914”(association)	0.350
NFATC4	SEC16A	psi-mi:“MI:2364”(proximity)	0.270
GABARAP	TECPR2	psi-mi:“MI:2364”(proximity)	0.270
GABARAPL1	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
GABARAPL2	PALM3	psi-mi:“MI:2364”(proximity)	0.270
MAP1LC3A	BCL2L13	psi-mi:“MI:2364”(proximity)	0.270
MAPK14	NFATC4	psi-mi:“MI:2364”(proximity)	0.270
ANKRD28	TBKBP1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (49): NFATC4 (Affinity Capture-MS), NFATC4 (Affinity Capture-MS), MAPK14 (Co-localization), NFATC4 (Affinity Capture-MS), NFATC4 (Two-hybrid), NFATC4 (Affinity Capture-MS), NFATC4 (Affinity Capture-MS), NFATC4 (Affinity Capture-RNA), NFATC4 (Reconstituted Complex), NFATC4 (Affinity Capture-Western), NFATC4 (Affinity Capture-MS), SERPINA12 (Affinity Capture-MS), GFAP (Affinity Capture-MS), NFATC4 (Affinity Capture-MS), HNRNPA1L2 (Affinity Capture-MS)

ESM2 similar proteins: A4IHR5, A6H7J1, A6NKL6, A6NL88, A7UKY7, A7YY54, B8ZZ34, C9J069, C9JLR9, E9Q1P8, O15209, O35615, O35779, P04198, P15066, P17535, P39881, P52909, Q01101, Q0PHV7, Q14526, Q14934, Q15742, Q32KV8, Q4VA45, Q52KG4, Q5TJE2, Q61976, Q63ZV0, Q6NUJ5, Q6P0F9, Q7T3H2, Q7Z5L9, Q7Z6J2, Q8C3Q5, Q8IX07, Q8R4T5, Q8TF61, Q8VCG9, Q96B18

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

SIGNOR signaling

22 interactions.

A	Effect	B	Mechanism
MAPK1	up-regulates	NFATC4	phosphorylation
MAPK3	up-regulates	NFATC4	phosphorylation
RPS6KA3	up-regulates	NFATC4	phosphorylation
PPP3CA	up-regulates	NFATC4	dephosphorylation
Calcineurin	up-regulates	NFATC4	dephosphorylation
NFATC4	“up-regulates quantity by expression”	GPC6	“transcriptional regulation”
NFATC4	“up-regulates quantity by expression”	PTGS2	“transcriptional regulation”
Gbeta	up-regulates	NFATC4	phosphorylation
ERK1/2	up-regulates	NFATC4	phosphorylation
CDK3	“up-regulates activity”	NFATC4	phosphorylation
MAPK8	“up-regulates activity”	NFATC4	phosphorylation
MAPK9	“up-regulates activity”	NFATC4	phosphorylation
p38	down-regulates	NFATC4	phosphorylation
MAPK14	“down-regulates activity”	NFATC4	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 31 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.

GO biological processes:

GO term	Partners	Fold	FDR
mitophagy	5	56.8×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	122
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1924 predictions. Top by Δscore:

Variant	Effect	Δscore
14:24368374:GAATT:G	donor_gain	1.0000
14:24368404:G:GT	donor_gain	1.0000
14:24372165:G:GT	donor_gain	1.0000
14:24372599:TCAAG:T	donor_loss	1.0000
14:24372600:CAAG:C	donor_loss	1.0000
14:24372602:AGGTA:A	donor_loss	1.0000
14:24372603:GGT:G	donor_loss	1.0000
14:24372604:G:GC	donor_loss	1.0000
14:24372605:T:A	donor_loss	1.0000
14:24373165:T:A	acceptor_gain	1.0000
14:24373169:A:AG	acceptor_gain	1.0000
14:24373170:G:GG	acceptor_gain	1.0000
14:24373170:GC:G	acceptor_gain	1.0000
14:24373366:GCCAA:G	donor_gain	1.0000
14:24373367:CCAA:C	donor_gain	1.0000
14:24373368:CAA:C	donor_gain	1.0000
14:24373369:AA:A	donor_gain	1.0000
14:24373371:G:GG	donor_gain	1.0000
14:24373372:T:A	donor_loss	1.0000
14:24373863:GTGCT:G	donor_gain	1.0000
14:24373868:G:GG	donor_gain	1.0000
14:24374324:A:AG	acceptor_gain	1.0000
14:24374325:G:GG	acceptor_gain	1.0000
14:24374325:GCCCA:G	acceptor_gain	1.0000
14:24374463:CCTG:C	donor_loss	1.0000
14:24374467:G:A	donor_loss	1.0000
14:24374468:T:G	donor_loss	1.0000
14:24368362:GA:G	donor_gain	0.9900
14:24368394:G:GT	donor_gain	0.9900
14:24368394:G:T	donor_gain	0.9900

AlphaMissense

5722 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:24369745:T:A	I116N	1.000
14:24369745:T:C	I116T	1.000
14:24369751:T:C	I118T	1.000
14:24372500:T:A	L419Q	1.000
14:24372500:T:C	L419P	1.000
14:24372518:C:A	P425H	1.000
14:24372526:C:G	H428D	1.000
14:24372529:C:A	H429N	1.000
14:24372529:C:G	H429D	1.000
14:24372530:A:G	H429R	1.000
14:24372531:C:A	H429Q	1.000
14:24372531:C:G	H429Q	1.000
14:24372532:C:G	R430G	1.000
14:24372532:C:T	R430W	1.000
14:24372536:C:A	A431D	1.000
14:24372538:C:G	H432D	1.000
14:24372540:C:A	H432Q	1.000
14:24372540:C:G	H432Q	1.000
14:24372541:T:A	Y433N	1.000
14:24372541:T:C	Y433H	1.000
14:24372541:T:G	Y433D	1.000
14:24372542:A:G	Y433C	1.000
14:24372544:G:A	E434K	1.000
14:24372546:G:C	E434D	1.000
14:24372546:G:T	E434D	1.000
14:24372548:C:T	T435I	1.000
14:24372550:G:A	E436K	1.000
14:24372551:A:T	E436V	1.000
14:24372552:A:C	E436D	1.000
14:24372552:A:T	E436D	1.000

dbSNP variants (sampled 300 via entrez): RS1000253041 (14:24368641 T>G), RS1000379032 (14:24379515 A>G), RS1000471337 (14:24366960 G>A,C), RS1000958576 (14:24371527 G>C), RS1001115771 (14:24378111 T>C), RS1001130132 (14:24377995 C>G), RS1001255384 (14:24378789 C>G,T), RS1001443869 (14:24374540 T>C), RS1001643096 (14:24371658 G>A), RS1002242395 (14:24374841 G>A,T), RS1002396251 (14:24365463 G>A), RS1002703306 (14:24368127 A>C), RS1002925814 (14:24370811 G>A,T), RS1003018539 (14:24371187 T>A), RS1003135775 (14:24374845 C>A,T)

Disease associations

OMIM: gene MIM:602699 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000817_185	Height	2.000000e-18
GCST001956_26	Height	1.000000e-11
GCST002647_105	Height	3.000000e-22
GCST007094_10	Diastolic blood pressure	3.000000e-09
GCST90000025_530	Appendicular lean mass	3.000000e-37
GCST90020029_395	Waist circumference adjusted for body mass index	1.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0004980	appendicular lean mass
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1955915	NFATC4		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression, increases methylation	9
Estradiol	affects cotreatment, increases expression, decreases expression, decreases reaction, affects expression	4
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	affects expression, affects binding, increases activity, increases expression, increases reaction	3
Nickel	affects reaction, increases expression, decreases expression	3
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Ethanol	increases reaction, increases acetylation, increases expression, decreases expression, increases secretion (+3 more)	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	affects phosphorylation	1
dan-shen root extract	affects localization, decreases reaction, increases expression	1
20-hydroxy-5,8,11,14-eicosatetraenoic acid	increases localization, decreases reaction	1
azoxystrobin	decreases expression	1
pterostilbene	increases acetylation, affects reaction, decreases reaction, increases expression, increases secretion	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Calcimycin	affects cotreatment, increases expression, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects localization, decreases reaction, increases expression	1
Vorinostat	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Colchicine	decreases localization	1
Gallic Acid	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0J0	Ubigene HeLa NFATC4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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