NFAT5

Summary

NFAT5 (nuclear factor of activated T cells 5, HGNC:7774) is a protein-coding gene on chromosome 16q22.1, encoding Nuclear factor of activated T-cells 5 (O94916). Transcription factor involved, among others, in the transcriptional regulation of osmoprotective and inflammatory genes.

The product of this gene is a member of the nuclear factors of activated T cells family of transcription factors. Proteins belonging to this family play a central role in inducible gene transcription during the immune response. This protein regulates gene expression induced by osmotic stress in mammalian cells. Unlike monomeric members of this protein family, this protein exists as a homodimer and forms stable dimers with DNA elements. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10725 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inborn error of immunity (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 42
• Clinical variants (ClinVar): 915 total
• Transcription factor: yes — 53 downstream targets (CollecTRI)
• MANE Select transcript: NM_138713

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7774
Approved symbol	NFAT5
Name	nuclear factor of activated T cells 5
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	TONEBP, KIAA0827, NFATL1, OREBP, NFATZ, NF-AT5
Ensembl gene	ENSG00000102908
Ensembl biotype	protein_coding
OMIM	604708
Entrez	10725

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 10 protein_coding, 7 nonsense_mediated_decay, 6 retained_intron

ENST00000349945, ENST00000354436, ENST00000393742, ENST00000426654, ENST00000562429, ENST00000563474, ENST00000565301, ENST00000566899, ENST00000567239, ENST00000567990, ENST00000568832, ENST00000627621, ENST00000650987, ENST00000700076, ENST00000700077, ENST00000700078, ENST00000700079, ENST00000896455, ENST00000896456, ENST00000896457, ENST00000917858, ENST00000917859, ENST00000957741

RefSeq mRNA: 7 — MANE Select: NM_138713 NM_001113178, NM_001367709, NM_006599, NM_138713, NM_138714, NM_173214, NM_173215

CCDS: CCDS10881, CCDS45518, CCDS45519

Canonical transcript exons

ENST00000349945 — 15 exons

Exon	Start	End
ENSE00003462067	69565966	69566374
ENSE00003474687	69647028	69647586
ENSE00003481147	69677203	69677335
ENSE00003511933	69659727	69659899
ENSE00003514424	69655609	69655799
ENSE00003536947	69690940	69691088
ENSE00003540516	69691749	69694239
ENSE00003543868	69653236	69653428
ENSE00003549537	69684887	69684970
ENSE00003568009	69695136	69695379
ENSE00003575116	69626403	69626528
ENSE00003642437	69568495	69568548
ENSE00003651749	69670236	69670288
ENSE00003663447	69669977	69670111
ENSE00003865617	69696360	69704654

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 96.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.2564 / max 522.5211, expressed in 1816 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154827	18.5134	1807
154828	13.6093	1767
154842	0.8727	479
154832	0.6370	257
154829	0.4479	223
154831	0.3844	169
154849	0.3473	117
154830	0.2788	68
154833	0.1656	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	96.09	gold quality
nipple	UBERON:0002030	95.49	gold quality
caput epididymis	UBERON:0004358	95.25	gold quality
corpus epididymis	UBERON:0004359	94.75	gold quality
cauda epididymis	UBERON:0004360	94.51	gold quality
calcaneal tendon	UBERON:0003701	93.04	gold quality
saphenous vein	UBERON:0007318	92.60	gold quality
colonic epithelium	UBERON:0000397	91.74	gold quality
mammary duct	UBERON:0001765	91.69	gold quality
vena cava	UBERON:0004087	91.02	gold quality
adrenal tissue	UBERON:0018303	90.93	gold quality
epithelium of mammary gland	UBERON:0003244	90.73	gold quality
tibia	UBERON:0000979	90.70	gold quality
sural nerve	UBERON:0015488	90.49	gold quality
cranial nerve II	UBERON:0000941	90.28	gold quality
superior surface of tongue	UBERON:0007371	89.72	gold quality
tongue squamous epithelium	UBERON:0006919	89.09	silver quality
tendon	UBERON:0000043	89.06	gold quality
trigeminal ganglion	UBERON:0001675	88.31	gold quality
corpus callosum	UBERON:0002336	88.08	gold quality
cardia of stomach	UBERON:0001162	87.50	gold quality
pharyngeal mucosa	UBERON:0000355	87.10	gold quality
pericardium	UBERON:0002407	86.96	gold quality
pancreatic ductal cell	CL:0002079	86.75	gold quality
oral cavity	UBERON:0000167	86.67	gold quality
urethra	UBERON:0000057	86.57	gold quality
tongue	UBERON:0001723	86.47	gold quality
visceral pleura	UBERON:0002401	86.41	gold quality
pylorus	UBERON:0001166	86.35	gold quality
metanephros cortex	UBERON:0010533	85.96	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	30.27
E-MTAB-6678	no	3.71
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

53 targets.

Target	Regulation
ACAN	Unknown
ACTA2
AKR1B1
AQP1	Unknown
AQP2	Activation
AQP4	Activation
ATM
B3GAT3	Unknown
CASP8AP2
CCL2	Repression
CD24
CDKN2A
CIDEC
CISH
COL2A1	Unknown
CYP2E1
CYP3A7	Unknown
DDX17
DDX5
DHX9
DUSP16
ENPP2	Activation
HLA-DQA1
HSPA1A	Activation
HSPA1B
HSPA2	Activation
HSPA4
IAPP
IL10	Activation
IL6	Repression

Upstream regulators (CollecTRI, top): IFNG, IL4, NFAT5, SOX17, SRY

miRNA regulators (miRDB)

529 targeting NFAT5, 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-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6867-5P	100.00	82.21	3464
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-126-5P	100.00	72.71	3180
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761

Literature-anchored findings (GeneRIF, showing 40)

• Induced upon T cell activation in a calcineurin-dependent manner, which contrasts with the calcineurin-independent induction mediated by hyperosmotic stress. (PMID:11046013)
• cloning of the complete 14-kb cDNA sequence and genomic organization of NFAT5 gene (PMID:11528118)
• adopts a NF-kappaB-like structure upon binding to DNA; also encircles its DNA target which may lead to increased kinetic stability of the TonEBP-DNA complex (PMID:11780147)
• Activity of the TonEBP/OREBP transactivation domain varies directly with extracellular NaCl concentration (PMID:11792870)
• Recent data implicate NFAT in the control of gene expression influencing the development and adaptation of numerous mammalian cell types (PMID:11877454)
• modulates the glutathione peroxidase gene in response to oxygen tension (PMID:11936849)
• transcriptional activity of NFAT5 is induced by alpha(6)beta(4) clustering in the presence of chemo-attractants, resulting in enhanced cell migration (PMID:12080349)
• hypertonic activation by fyn and p38 signaling (PMID:12359721)
• nuclear expression of NFAT in B-CLL cells leads to enhanced activation of CD23b promoter and increased expression of CD23b isoform (PMID:12379312)
• PKA plays an important role in TonEBP/OREBP activation of tonicity-dependent gene expression. (PMID:12482947)
• Sodium/myo-inositol cotransproter, aldose reductase, and HSP70 genes are targets of TonEBP. (tonicity-responsive enhancer binding protein) (PMID:12538727)
• signaling via ATM is necessary for full activation of TonEBP/OREBP (PMID:15173573)
• activation of ATM contributes to high NaCl-induced nuclear translocation of TonEBP/OREBP (PMID:15840767)
• Aldose reductase is upregulated by the transcriptional factor NFAT5 under high-glucose conditions in both mononuclar leukocytes and mesangial cells. (PMID:16644704)
• Three protein motifs in OREBP/TonEBP control its proper subcellular localization under different extracellular osmolality, one of which is the nuclear localization signal motif. (PMID:16782704)
• PARP-1 and Hsp90 bind to TonEBP; PARP-1 expression reduces TonEBP transcriptional activity and the activity of its transactivating domain and Hsp90 enhances those activities. (PMID:17148781)
• Our results define a novel host factor-viral enhancer interaction that reveals a new regulatory role for NFAT5 and defines a functional DNA motif conserved across HIV-1 subtypes and representative simian immunodeficiency viruses. (PMID:17173480)
• the level of CYP2E1 is induced by hypertonic condition via TonEBP transactivation. The present study suggests that osmotic status may influence individual responses to the substrate of CYP2E1. (PMID:17440116)
• activation of p38 isoforms by hypertonicity does not contribute to activation of TonEBP/OREBP because of opposing effects of p38alpha and p38delta. (PMID:18367666)
• Ser-155 and Ser-158 have important roles in the nucleocytoplasmic trafficking of OREBP/TonEBP and CK1 plays a major role in regulating this process (PMID:18411282)
• Nup88 is up-regulated in response to hypertonic stress and acts to retain TonEBP in the nucleus, activating transcription of critical osmoprotective genes. (PMID:18606815)
• Results of these studies suggest that, in nucleus pulposus cells, osmotic pressure and calcium modulate AQP2 expression through TonEBP and are independent of the calcineurin-NFAT pathway (PMID:19138132)
• NFAT5 exclusion from mitotic chromatin resets its nucleo-cytoplasmic distribution in interphase (PMID:19750013)
• present in placenta at RNA and protein levels (PMID:19886771)
• The loss of nucleosome(s) was found to be initiated by an OREBP-independent mechanism, but was significantly potentiated in the presence of OREBP. (PMID:20041176)
• TonEBP/OREBP becomes phosphorylated at Y143, resulting in binding of PLC-gamma1 to that site, which contributes to TonEBP/OREBP transcriptional activity. (PMID:20080774)
• TonEBP/OREBP is extensively regulated by phosphatases, including SHP-1, whose inhibition by high NaCl increases phosphorylation of TonEBP/OREBP at Y143, contributing to the nuclear localization and activation of TonEBP/OREBP (PMID:20351292)
• c-Abl is the kinase responsible for high NaCl-induced phosphorylation of TonEBP/OREBP-Y143 (PMID:20585028)
• These findings reveal a novel role for TonEBP and Akt in NF-kappaB activation on the onset of hypertonic challenge. (PMID:20685965)
• NFAT5-null mice have constitutive, pronounced hypernatremia and suffer severe immunodeficiency with T cell lymphopenia, altered CD8 naive/memory homeostasis, and inability to reject allogeneic tumors. (PMID:21037089)
• High NaCl-induced increase of the overall abundance of TonEBP/OREBP, by itself, eventually raises its effective level in the nucleus, but its rapid CDK5-dependent nuclear localization accelerates the process. (PMID:21209322)
• this study demonstrates that hyperosmotic stress induces S100A4 through NFAT5, and Src and chromatin remodeling are involved. (PMID:21289293)
• Compared with control group, the levels of OREBP, HSP70-2 and MUC5AC in supernatant significantly increased after HBE16 cells were exposed to hypertonic media. (PMID:21418859)
• NF-AT5 regulates synovial proliferation and angiogenesis in chronic arthritis. (PMID:21717420)
• Non-invasive imaging of nuclear factor of activated T-cell 5 (NFAT5) activation follows middle cerebral artery occlusion (MCAO) in NFAT5-luciferase-expressing mice. (PMID:21749466)
• Identify NFAT5 as a novel regulator of vascular smooth muscle cell phenotypic modulation. (PMID:21757659)
• These results suggested that TonEBP played an important role in the epithelial cells of renal proximal tubule upon hypertonic stress by enhancing AAD expression, which could promote dopamine secretion to negative regulate Na+/K+-ATPase activity. (PMID:21982764)
• The nuclear transport of NFAT5a involves reversible palmitoylation. (PMID:22071693)
• Data indicate that transcriptional coregulator ddx5/ddx17 RNA helicases can simultaneously regulate the transcriptional activity and alternative splicing of NFAT5 transcription factor. (PMID:22266867)
• the innate immune response to MTb infection induces NFAT5 gene and protein expression, and NFAT5 plays a crucial role in MTb regulation of HIV-1 replication via a direct interaction with the viral promoter. (PMID:22496647)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nfat5a	ENSDARG00000020872
danio_rerio	nfat5b	ENSDARG00000102556
mus_musculus	Nfat5	ENSMUSG00000003847
rattus_norvegicus	Nfat5	ENSRNOG00000011879
drosophila_melanogaster	NFAT	FBGN0030505

Paralogs (4): NFATC3 (ENSG00000072736), NFATC4 (ENSG00000100968), NFATC2 (ENSG00000101096), NFATC1 (ENSG00000131196)

Protein

Protein identifiers

Nuclear factor of activated T-cells 5 — O94916 (reviewed: O94916)

Alternative names: T-cell transcription factor NFAT5, Tonicity-responsive enhancer-binding protein

All UniProt accessions (7): O94916, A0A494C020, A0A499FIS8, A0A499FJX5, H3BP21, J3KRL6, J3QKS5

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor involved, among others, in the transcriptional regulation of osmoprotective and inflammatory genes. Binds the DNA consensus sequence 5’-[ACT][AG]TGGAAA[CAT]A[TA][ATC][CA][ATG][GT][GAC][CG][CT]-3’. Mediates the transcriptional response to hypertonicity. Positively regulates the transcription of LCN2 and S100A4 genes; optimal transactivation of these genes requires the presence of DDX5/DDX17. Also involved in the DNA damage response by preventing formation of R-loops; R-loops are composed of a DNA:RNA hybrid and the associated non-template single-stranded DNA.

Subunit / interactions. Homodimer when bound to DNA, completely encircles its DNA target. Interacts with CIDEC; this interaction is direct and retains NFAT5 in the cytoplasm. Does not bind with Fos and Jun transcription factors. Interacts with DDX5 and DDX17; this interaction leads to DDX5/DDX17 recruitment to LNC2 and S100A4 promoters and NFAT5-mediated DDX5/DDX17-enhanced transactivation.

Subcellular location. Nucleus. Cytoplasm. Chromosome.

Tissue specificity. Widely expressed, with highest levels in skeletal muscle, brain, heart and peripheral blood leukocytes.

Post-translational modifications. Phosphorylated. Phosphorylated at Thr-135 by CDK5 in response to osmotic stress; this phosphorylation mediates its rapid nuclear localization. Poly-ADP-ribosylated by PARP1 in response to DNA damage, promoting recruitment to sites of R-loop-associated DNA damage.

Miscellaneous. The transcript encoding this isoform contains an alternative coding exon 4 which contains 2 stop codons and could target the transcript to nonsense-mediated mRNA decay after the pioneer round of translation, as suggested by the decreased NFAT5 protein levels when the number of exon 4-containing transcripts increases. The insertion of exon 4 is stimulated in the presence of DDX5 and DDX17. Isoform A sequence described in this entry starts at the first methionine downstream of exon 4 last stop codon. An alternative protein sequence can be predicted from this transcript starting at Met-1. This isoform encodes an 81 amino acid-long protein. The transcript encoding this isoform contains an alternative coding exon 4 which contains 2 stop codons and could target the transcript to nonsense-mediated mRNA decay after the pioneer round of translation, as suggested by the decreased NFAT5 protein levels when the number of exon 4-containing transcripts increases. The insertion of exon 4 is stimulated in the presence of DDX5 and DDX17.

Isoforms (5)

UniProt ID	Names	Canonical?
O94916-1	C	yes
O94916-2	A
O94916-3	B
O94916-4	D
O94916-5	E

RefSeq proteins (7): NP_001106649, NP_001354638, NP_006590, NP_619727, NP_619728, NP_775321, NP_775322 (=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
IPR015646	NFAT5_RHD_DNA-bd	Domain
IPR032397	RHD_dimer	Domain
IPR037059	RHD_DNA_bind_dom_sf	Homologous_superfamily

Pfam: PF00554, PF16179

UniProt features (78 total): strand 21, compositionally biased region 20, region of interest 10, modified residue 6, splice variant 5, cross-link 4, mutagenesis site 4, helix 3, sequence conflict 2, chain 1, domain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1IMH	X-RAY DIFFRACTION	2.86

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94916-F1	44.83	0.16

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 (10): 120, 122, 134, 135, 155, 561, 556, 556, 603, 573

Mutagenesis-validated functional residues (4):

Position	Phenotype
120	normal nuclear localization.
134	reduced nuclear localization.
135	reduced nuclear localization.
155	increased nuclear localization.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 537 (showing top): GGGACCA_MIR133A_MIR133B, GCACCTT_MIR18A_MIR18B, TGGTGCT_MIR29A_MIR29B_MIR29C, CREL_01, MODULE_416, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, chr16q22, MORF_MSH3, GOBP_RESPONSE_TO_PEPTIDE, TGCACTT_MIR519C_MIR519B_MIR519A, LFA1_Q6, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, MORF_BRCA1, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_HYPEROSMOTIC_RESPONSE

GO Biological Process (16): transcription by RNA polymerase II (GO:0006366), DNA damage response (GO:0006974), signal transduction (GO:0007165), positive regulation of gene expression (GO:0010628), calcineurin-NFAT signaling cascade (GO:0033173), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of transcription by RNA polymerase II (GO:0045944), R-loop processing (GO:0062176), regulation of calcineurin-NFAT signaling cascade (GO:0070884), cellular response to cytokine stimulus (GO:0071345), cellular hyperosmotic response (GO:0071474), positive regulation of leukocyte adhesion to vascular endothelial cell (GO:1904996), DNA-templated transcription (GO:0006351), regulation of DNA-templated transcription (GO:0006355), response to stress (GO:0006950), regulation of intracellular signal transduction (GO:1902531)

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 activator activity, RNA polymerase II-specific (GO:0001228), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (8): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytosol (GO:0005829), chromosome (GO:0005694), cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
DNA-templated transcription	2
gene expression	2
regulation of gene expression	2
regulation of transcription by RNA polymerase II	2
binding	2
cellular response to stress	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
positive regulation of macromolecule biosynthetic process	1
calcineurin-mediated signaling	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
chromatin remodeling	1
calcineurin-NFAT signaling cascade	1
regulation of calcineurin-mediated signaling	1
response to cytokine	1
hyperosmotic response	1
cellular response to osmotic stress	1
leukocyte adhesion to vascular endothelial cell	1
positive regulation of leukocyte cell-cell adhesion	1
regulation of leukocyte adhesion to vascular endothelial cell	1
RNA biosynthetic process	1
regulation of RNA biosynthetic process	1
response to stimulus	1
regulation of signal transduction	1
intracellular signal transduction	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1

Protein interactions and networks

STRING

1976 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NFAT5	SLC6A12	P48065	817
NFAT5	AKR1B1	P15121	785
NFAT5	SLC5A3	P53794	783
NFAT5	VEGFC	P49767	759
NFAT5	FOS	P01100	752
NFAT5	STAT3	P40763	721
NFAT5	REL	Q04864	654
NFAT5	CREB1	P16220	651
NFAT5	PPP3CA	Q08209	636
NFAT5	SLC6A6	P31641	622
NFAT5	AQP2	P41181	580
NFAT5	JUN	P05412	573
NFAT5	TP53	P04637	562
NFAT5	RELA	Q04206	553
NFAT5	EGR1	P18146	548

IntAct

27 interactions, top by confidence:

A	B	Type	Score
NFE2L2	NFAT5	psi-mi:“MI:0915”(physical association)	0.580
ORF	EIF3F	psi-mi:“MI:0914”(association)	0.560
DDX5	NFAT5	psi-mi:“MI:0915”(physical association)	0.560
NFAT5	DDX5	psi-mi:“MI:2364”(proximity)	0.560
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
NFAT5	DDX17	psi-mi:“MI:0915”(physical association)	0.470
DDX17	NFAT5	psi-mi:“MI:0915”(physical association)	0.470
NFAT5	DDX17	psi-mi:“MI:2364”(proximity)	0.470
TBC1D4	NFAT5	psi-mi:“MI:0915”(physical association)	0.370
BMI1	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
EPHA3	FHAD1	psi-mi:“MI:0914”(association)	0.350
DDX21	GTPBP10	psi-mi:“MI:0914”(association)	0.350
	POLR3A	psi-mi:“MI:0914”(association)	0.350
	NFAT5	psi-mi:“MI:0914”(association)	0.350
SOX2	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATF1	MYO1C	psi-mi:“MI:0914”(association)	0.350
SOX2	MYO1C	psi-mi:“MI:0914”(association)	0.350
EPHA3	FAM171A2	psi-mi:“MI:2364”(proximity)	0.270
TLK2	AQR	psi-mi:“MI:2364”(proximity)	0.270
NFAT5	mtfA	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (68): FOS (Affinity Capture-Western), JUN (Affinity Capture-Western), NFAT5 (Affinity Capture-Western), NFAT5 (Affinity Capture-Western), PRKACA (Affinity Capture-Western), NFAT5 (Affinity Capture-Western), NFAT5 (Affinity Capture-RNA), NFAT5 (Affinity Capture-RNA), NFAT5 (Two-hybrid), NFAT5 (Affinity Capture-MS), NFAT5 (Affinity Capture-RNA), SHPRH (Affinity Capture-MS), USP1 (Affinity Capture-MS), SHPRH (Affinity Capture-Western), NFAT5 (Affinity Capture-Western)

ESM2 similar proteins: A0AVK6, A1L1F6, A2A891, A3RK75, A4L7N3, A7XYJ6, D2HNW6, D3ZGB1, E1BE02, E1BPQ1, F1LMN3, F1QZ88, F7EA39, G3V7R4, O35589, O43524, O94916, P57095, P78312, P79944, Q12778, Q13506, Q14B70, Q53TQ3, Q566I1, Q58FA4, Q5DTH5, Q5RIX9, Q61122, Q62722, Q66JJ0, Q66JY2, Q68FE9, Q69ZF8, Q6EUW1, Q6EUW2, Q6ZSZ6, Q810W5, Q8C7R7, Q8CGI1

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

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
ATM	up-regulates	NFAT5	phosphorylation
CDK1	up-regulates	NFAT5	phosphorylation
CDK5	up-regulates	NFAT5	phosphorylation
PTPN6	“down-regulates activity”	NFAT5	dephosphorylation
CSNK1A1L	“up-regulates activity”	NFAT5	phosphorylation
“RNA helicases DDX5/DDX17”	“up-regulates activity”	NFAT5	binding
NFAT5	“up-regulates quantity by expression”	LCN2	“transcriptional regulation”
NFAT5	“up-regulates quantity by expression”	S100A4	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	558
Likely benign	300
Benign	35

Top pathogenic / likely-pathogenic (0)

SpliceAI

3398 predictions. Top by Δscore:

Variant	Effect	Δscore
16:69566370:GCGAG:G	donor_gain	1.0000
16:69566371:CGAG:C	donor_gain	1.0000
16:69566372:GAG:G	donor_gain	1.0000
16:69566372:GAGG:G	donor_gain	1.0000
16:69566373:AG:A	donor_gain	1.0000
16:69566373:AGG:A	donor_loss	1.0000
16:69566374:GG:G	donor_gain	1.0000
16:69566375:G:GG	donor_gain	1.0000
16:69626402:GA:G	acceptor_gain	1.0000
16:69626525:GCTG:G	donor_gain	1.0000
16:69626526:CTGGT:C	donor_loss	1.0000
16:69626527:TGGT:T	donor_loss	1.0000
16:69626529:G:GA	donor_loss	1.0000
16:69626530:T:A	donor_loss	1.0000
16:69653225:T:TA	acceptor_gain	1.0000
16:69653231:CTCAG:C	acceptor_loss	1.0000
16:69653232:TCAG:T	acceptor_loss	1.0000
16:69653234:A:AG	acceptor_gain	1.0000
16:69653235:G:GT	acceptor_gain	1.0000
16:69653235:GA:G	acceptor_gain	1.0000
16:69653235:GAA:G	acceptor_gain	1.0000
16:69653235:GAAC:G	acceptor_gain	1.0000
16:69653235:GAACA:G	acceptor_gain	1.0000
16:69653425:AAAGG:A	donor_loss	1.0000
16:69653426:AAGG:A	donor_loss	1.0000
16:69653428:GGTA:G	donor_loss	1.0000
16:69653429:GT:G	donor_loss	1.0000
16:69655592:A:AG	acceptor_gain	1.0000
16:69655592:AT:A	acceptor_gain	1.0000
16:69655593:T:G	acceptor_gain	1.0000

AlphaMissense

10231 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:69653322:T:C	L282P	1.000
16:69653328:T:A	I284K	1.000
16:69653340:C:A	P288H	1.000
16:69653351:C:G	H292D	1.000
16:69653352:A:G	H292R	1.000
16:69653353:C:A	H292Q	1.000
16:69653353:C:G	H292Q	1.000
16:69653354:C:G	R293G	1.000
16:69653355:G:C	R293P	1.000
16:69653358:C:A	A294D	1.000
16:69653363:T:C	Y296H	1.000
16:69653363:T:G	Y296D	1.000
16:69653364:A:G	Y296C	1.000
16:69653367:T:C	L297P	1.000
16:69653373:A:T	E299V	1.000
16:69653375:G:C	G300R	1.000
16:69653375:G:T	G300C	1.000
16:69653376:G:A	G300D	1.000
16:69653376:G:T	G300V	1.000
16:69653378:A:C	S301R	1.000
16:69653380:C:A	S301R	1.000
16:69653380:C:G	S301R	1.000
16:69653381:C:A	R302S	1.000
16:69653384:G:C	G303R	1.000
16:69653384:G:T	G303C	1.000
16:69653385:G:A	G303D	1.000
16:69653393:A:G	K306E	1.000
16:69653394:A:T	K306I	1.000
16:69653395:A:C	K306N	1.000
16:69653395:A:T	K306N	1.000

dbSNP variants (sampled 300 via entrez): RS1000010207 (16:69633998 C>T), RS1000018070 (16:69680126 A>G), RS1000020501 (16:69638423 T>G), RS1000026917 (16:69680349 G>A), RS1000029638 (16:69684047 C>G), RS1000032628 (16:69581813 C>T), RS1000144684 (16:69638220 A>G), RS1000182960 (16:69618413 C>G), RS1000188508 (16:69625780 C>G,T), RS1000226923 (16:69673981 G>A), RS1000278021 (16:69639569 A>T), RS1000297828 (16:69673805 T>C), RS1000361969 (16:69572453 T>A,G), RS1000363379 (16:69626071 A>G), RS1000412338 (16:69577319 C>G,T)

Disease associations

OMIM: gene MIM:604708 | disease phenotypes: MIM:300755

GenCC curated gene-disease

Disease	Classification	Inheritance
inborn error of immunity	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunodeficiency disease	Limited	AD

Mondo (2): immunodeficiency disease (MONDO:0021094), inborn error of immunity (MONDO:0003778)

Orphanet (0):

HPO phenotypes

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

GWAS associations

42 associations (top):

Study	Trait	p-value
GCST000880_7	Menarche (age at onset)	2.000000e-08
GCST001791_2	Urate levels	8.000000e-10
GCST002251_8	Homeostasis model assessment of beta-cell function (dietary factor interaction)	9.000000e-06
GCST002541_109	Menarche (age at onset)	6.000000e-21
GCST003993_35	Menarche (age at onset)	9.000000e-11
GCST004061_10	Sjögren’s syndrome	2.000000e-06
GCST004267_1	Blood osmolality (transformed sodium)	6.000000e-12
GCST004267_7	Blood osmolality (transformed sodium)	6.000000e-10
GCST004278_11	Pulse pressure	7.000000e-13
GCST004278_43	Pulse pressure	6.000000e-08
GCST004278_44	Pulse pressure	2.000000e-08
GCST005829_16	Hand grip strength	4.000000e-12
GCST005986_24	Blood urea nitrogen levels	6.000000e-11
GCST006030_15	Chloride levels	2.000000e-18
GCST006032_12	Sodium levels	5.000000e-16
GCST006461_7	Self-reported risk-taking behaviour	3.000000e-07
GCST006867_133	Type 2 diabetes	4.000000e-09
GCST006979_630	Heel bone mineral density	2.000000e-10
GCST007096_235	Pulse pressure	2.000000e-07
GCST007293_28	Body fat distribution (arm fat ratio)	3.000000e-12
GCST007293_6	Body fat distribution (arm fat ratio)	5.000000e-06
GCST007293_62	Body fat distribution (arm fat ratio)	2.000000e-17
GCST007295_15	Body fat distribution (leg fat ratio)	3.000000e-06
GCST007295_99	Body fat distribution (leg fat ratio)	5.000000e-06
GCST007344_2	Estimated glomerular filtration rate	3.000000e-08
GCST007344_67	Estimated glomerular filtration rate	3.000000e-06
GCST007725_21	Serum uric acid levels	2.000000e-10
GCST007876_123	Estimated glomerular filtration rate	1.000000e-08
GCST007916_17	Hyperuricemia	2.000000e-16
GCST007918_28	Serum uric acid levels	2.000000e-16

EFO canonical traits (18, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0004531	urate measurement
EFO:0004469	HOMA-B
EFO:0008111	diet measurement
EFO:0005763	pulse pressure measurement
EFO:0006941	grip strength measurement
EFO:0009282	sodium measurement
EFO:0008579	risk-taking behaviour
EFO:0009270	heel bone mineral density
EFO:0004341	body fat distribution
EFO:0004761	uric acid measurement
EFO:0009104	hyperuricemia
EFO:0005670	smoking initiation
EFO:0000195	metabolic syndrome
EFO:0004530	triglyceride measurement
EFO:0006935	thalamus volume
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007153	Immunologic Deficiency Syndromes	C20.673

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	increases expression, affects cotreatment, decreases expression, increases abundance	2
Vorinostat	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases mutagenesis	2
Formaldehyde	increases expression	2
Ozone	affects cotreatment, decreases expression, increases abundance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Quercetin	increases expression, decreases reaction	2
Sodium Chloride	decreases reaction, increases expression, increases activity, affects reaction, increases secretion (+1 more)	2
Tretinoin	increases expression	2
Uric Acid	affects abundance, affects localization	2
Cadmium Chloride	increases abundance, increases expression, decreases expression	2
bisphenol F	affects cotreatment, decreases expression	1
TAK-243	decreases sumoylation	1
geldanamycin	increases expression	1
testosterone enanthate	increases expression	1
ethylbenzene	increases expression	1
methylmercuric chloride	increases expression	1
oxybenzone	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
bisphenol A	affects cotreatment, decreases expression	1
geraniol	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
2-xylene	increases expression	1
periodate-oxidized adenosine	affects expression	1
coumarin	affects phosphorylation	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2DW	HAP1 NFAT5 (-) 1	Cancer cell line	Male
CVCL_E2DX	HAP1 NFAT5 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03677557	PHASE4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT00001542	PHASE4	COMPLETED	Fluconazole Prophylaxis of Thrush in AIDS
NCT00144157	PHASE4	COMPLETED	Open Label Study of NVP+CBV Treatment in Women Who Have Received sdNVP for the pMTCT of HIV
NCT00162643	PHASE4	UNKNOWN	PI Vs. NNRTI Based Therapy for HIV Advanced Disease
NCT00273988	PHASE4	COMPLETED	Pharmacokinetic Study of Interaction Between Nevirapine and Methadone in HIV-1 Infected, Opioid-dependent Adults
NCT00981318	PHASE4	TERMINATED	Pilot Assessment of Lopinavir/Ritonavir and Maraviroc
NCT01086878	PHASE4	COMPLETED	Safety of Cotrimoxazole in HIV- and HAART-exposed Infants
NCT01090102	PHASE4	COMPLETED	Mesalamine to Reduce T Cell Activation in HIV Infection
NCT01147042	PHASE4	TERMINATED	Biochemical Response to Interferon-Gamma in Subjects With Specific Gene Mutation in Chronic Granulomatous Disease
NCT01230580	PHASE4	UNKNOWN	Protease Inhibitor Monotherapy Versus Ongoing Triple-therapy in the Long Term Management of HIV Infection (PIVOT)
NCT01465958	PHASE4	COMPLETED	Pharmacokinetics, Safety, and Tolerability of Subcutaneous GAMUNEX-C in Pediatric Subjects With Primary Immunodeficiency
NCT02274662	PHASE4	COMPLETED	Expanded Access Protocol Thymus Transplantation
NCT02348177	PHASE4	COMPLETED	Pharmacokinetics of Lopinavir/Ritonavir Superboosting in Infants and Young Children Co-infected With HIV and TB
NCT02396979	PHASE4	COMPLETED	Intervention of HIV, Drug Use and the Criminal Justice System in Malaysia
NCT02490956	PHASE4	UNKNOWN	Diagnostic Immunization With Rabies Vaccine in Patients With PID
NCT02503293	PHASE4	COMPLETED	A Study to Compare Quality of Life and Satisfaction in Primary Immunodeficient Patients Treated With Subcutaneous Injections of Gammanorm® 165 mg/mL Administered With Two Different Delivery Devices: Injections Using Pump or Rapid Push
NCT02881437	PHASE4	COMPLETED	IgG Level in Primary Immunodeficiency Switching From Standard SCIG to Every Other Week HyQvia
NCT03033745	PHASE4	COMPLETED	Safety and Tolerability of Higher Infusion Parameters of IgPro20 (Hizentra) in Subjects With Primary Immunodeficiency (PID)
NCT04192487	PHASE4	COMPLETED	Effects of Crofelemer on the Gut Microbiome in Healthy Volunteers and in HIV+ Patients With Non-Infectious Diarrhea
NCT04566692	PHASE4	COMPLETED	A Study to Evaluate IGSC 20% Biweekly Dosing in Treatment-Experienced Participants and Loading/Maintenance Dosing in Treatment-Naïve Participants With Primary Immunodeficiency
NCT05493969	PHASE4	NOT_YET_RECRUITING	Efficacy and Tolerability of DTG Plus 3TC in HIV Infected Adults With Virologically Suppression and TDF Toxicity
NCT06576024	PHASE4	COMPLETED	Immunogenicity and Safety of Inactivated Hepatitis A Vaccine in HIV-infected People
NCT06634641	PHASE4	RECRUITING	Clozapine-related Immunodeficiency in Parkinsons Disease
NCT07076446	PHASE4	ACTIVE_NOT_RECRUITING	An Open-label, Multicenter Study to Assess the Pharmacokinetics (PK), Safety, and Tolerability of Subcutaneous IgPro20 in Immunoglobulin (IG) Treatment-naïve Participants With Primary Immunodeficiency (PID)
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT00468273	PHASE3	COMPLETED	A Clinical Study of Intravenous Immunoglobulin
NCT00811174	PHASE3	TERMINATED	Efficacy, Safety and Kinetics Study of Octagam 10% in Primary Immunodeficiency Diseases
NCT01012323	PHASE3	COMPLETED	A Study of NewGam, Human Immunoglobulin 10%, in Patients With Primary Immunodeficiency Diseases
NCT01313507	PHASE3	COMPLETED	High Infusion Rate Study of Immunoglobulin Intravenous (Human) 10% (NewGam)
NCT01406470	PHASE3	COMPLETED	Phase 3 Study of Immune Globulin Intravenous (Human)IVIG-SN™ in Subjects With Primary Immunodeficiency
NCT02783482	PHASE3	COMPLETED	Study of Immune Globulin Intravenous (Human) GC5107 in Subjects With Primary Humoral Immunodeficiency
NCT02810444	PHASE3	COMPLETED	Study to Investigate Efficacy, Safety and Pharmacokinetics of BT595 in Subjects With PID
NCT03961009	PHASE3	COMPLETED	Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in PID Patients
NCT04842643	PHASE3	COMPLETED	An Extension Study of TAK-664 for Japanese People With Primary Immunodeficiency Disease
NCT04944979	PHASE3	ACTIVE_NOT_RECRUITING	Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in Pediatric PID Patients (KIDCARES10)
NCT06089122	PHASE3	UNKNOWN	Efficacy, Safety, and Pharmacokinetics of Shu Yang IVIG
NCT06150833	PHASE3	UNKNOWN	Efficacy and Safety and Pharmacokinetics of Boya IVIG
NCT07346859	PHASE3	RECRUITING	Study of BP-SCIG 20% in Patients With Primary Immunodeficiency (PID)
NCT00000118	PHASE3	COMPLETED	Ganciclovir Implant Study for Cytomegalovirus Retinitis