NFATC2IP

Summary

NFATC2IP (nuclear factor of activated T cells 2 interacting protein, HGNC:25906) is a protein-coding gene on chromosome 16p11.2, encoding NFATC2-interacting protein (Q8NCF5). In T-helper 2 (Th2) cells, regulates the magnitude of NFAT-driven transcription of a specific subset of cytokine genes, including IL3, IL4, IL5 and IL13, but not IL2. It is a selective cancer dependency (DepMap: 23.0% of cell lines).

Predicted to be involved in positive regulation of transcription by RNA polymerase II. Predicted to be located in cytoplasm and nucleus.

Source: NCBI Gene 84901 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 63 total — 2 pathogenic, 1 likely-pathogenic
• Cancer dependency (DepMap): dependent in 23.0% of screened cell lines
• MANE Select transcript: NM_032815

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25906
Approved symbol	NFATC2IP
Name	nuclear factor of activated T cells 2 interacting protein
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ14639, NIP45, RAD60, ESC2
Ensembl gene	ENSG00000176953
Ensembl biotype	protein_coding
OMIM	614525
Entrez	84901

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000320805, ENST00000562977, ENST00000564978, ENST00000565752, ENST00000565919, ENST00000568148, ENST00000568998, ENST00000895632, ENST00000895633

RefSeq mRNA: 4 — MANE Select: NM_032815 NM_001394784, NM_001394785, NM_001394786, NM_032815

CCDS: CCDS10645

Canonical transcript exons

ENST00000320805 — 8 exons

Exon	Start	End
ENSE00001222324	28958991	28959100
ENSE00001222368	28963705	28967092
ENSE00001730472	28954565	28954682
ENSE00001799531	28956151	28956337
ENSE00002618902	28950937	28951398
ENSE00003480622	28952132	28952204
ENSE00003663131	28955978	28956058
ENSE00003672383	28958717	28958861

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 95.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.4803 / max 371.2650, expressed in 1817 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153438	25.4803	1817

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	95.50	gold quality
pylorus	UBERON:0001166	95.41	gold quality
visceral pleura	UBERON:0002401	95.24	gold quality
renal medulla	UBERON:0000362	94.59	gold quality
nipple	UBERON:0002030	94.56	gold quality
cardia of stomach	UBERON:0001162	94.49	gold quality
caecum	UBERON:0001153	94.27	gold quality
superior surface of tongue	UBERON:0007371	94.23	gold quality
granulocyte	CL:0000094	94.19	gold quality
buccal mucosa cell	CL:0002336	94.10	gold quality
oocyte	CL:0000023	93.95	gold quality
vermiform appendix	UBERON:0001154	93.74	gold quality
skin of hip	UBERON:0001554	93.73	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.49	gold quality
parietal pleura	UBERON:0002400	93.41	gold quality
lymph node	UBERON:0000029	93.33	gold quality
spleen	UBERON:0002106	93.27	gold quality
pharyngeal mucosa	UBERON:0000355	93.26	gold quality
upper leg skin	UBERON:0004262	93.26	gold quality
secondary oocyte	CL:0000655	93.24	gold quality
rectum	UBERON:0001052	93.00	gold quality
pleura	UBERON:0000977	92.96	gold quality
small intestine	UBERON:0002108	92.95	gold quality
mucosa of urinary bladder	UBERON:0001259	92.91	gold quality
transverse colon	UBERON:0001157	92.90	gold quality
cerebellar vermis	UBERON:0004720	92.82	gold quality
blood vessel layer	UBERON:0004797	92.49	gold quality
pons	UBERON:0000988	92.36	gold quality
tendon of biceps brachii	UBERON:0008188	92.32	silver quality
cerebellum	UBERON:0002037	92.30	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.96
E-MTAB-6379	no	694.77
E-MTAB-8271	no	522.74
E-GEOD-100618	no	204.80

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HAND2, NFATC1, NFATC2

miRNA regulators (miRDB)

89 targeting NFATC2IP, 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-4262	100.00	73.26	3931
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-4428	99.73	66.41	1733

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 23.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 5)

• ZBTB25 functions as a negative regulator of nuclear factor of activated T cells (NF-AT) activation, such that RNA interference mediated knockdown resulted in enhanced activation of target genes. (PMID:20410506)
• interactions of fat intake with the genetic (rs11150675) and transcriptional (ILMN_1725441) variations at the NFATC2IP locus on 2-year weight change. cis-DNA methylation at cg26663590 of the NFATC2IP locus showed an opposite impact on weight-loss in response to high-fat vs low-fat diet. baseline methylation at cg26663590 causally mediated 52.8% of the effect of rs11150675 on 2-year weight-loss in the high-fat diet group (PMID:29693310)
• Targeted deletion of NFAT-Interacting-Protein-(NIP) 45 resolves experimental asthma by inhibiting Innate Lymphoid Cells group 2 (ILC2). (PMID:31666531)
• Calcium channel TRPV6 promotes breast cancer metastasis by NFATC2IP. (PMID:34265397)
• NFATC2IP is a mediator of SUMO-dependent genome integrity. (PMID:38503515)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nfatc2ip	ENSDARG00000011360
mus_musculus	Nfatc2ip	ENSMUSG00000030722
rattus_norvegicus	Nfatc2ip	ENSRNOG00000057384

Paralogs (3): SUMO4 (ENSG00000177688), SUMO3 (ENSG00000184900), SUMO2 (ENSG00000188612)

Protein

Protein identifiers

NFATC2-interacting protein — Q8NCF5 (reviewed: Q8NCF5)

Alternative names: 45 kDa NF-AT-interacting protein, Nuclear factor of activated T-cells, cytoplasmic 2-interacting protein

All UniProt accessions (2): Q8NCF5, H3BSZ7

UniProt curated annotations — full annotation on UniProt →

Function. In T-helper 2 (Th2) cells, regulates the magnitude of NFAT-driven transcription of a specific subset of cytokine genes, including IL3, IL4, IL5 and IL13, but not IL2. Recruits PRMT1 to the IL4 promoter; this leads to enhancement of histone H4 ‘Arg-3’-methylation and facilitates subsequent histone acetylation at the IL4 locus, thus promotes robust cytokine expression. Down-regulates formation of poly-SUMO chains by UBE2I/UBC9.

Subunit / interactions. Interacts with NFATC2, TRAF1, TRAF2 and PRMT1. Interacts with UBE2I/UBC9.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. Methylation at the N-terminus by PRMT1 modulates interaction with the NFAT complex and results in augmented cytokine production.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NCF5-1	1	yes
Q8NCF5-2	2
Q8NCF5-3	3

RefSeq proteins (4): NP_001381713, NP_001381714, NP_001381715, NP_116204* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000626	Ubiquitin-like_dom	Domain
IPR022617	Rad60/SUMO-like_dom	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR052324	NFATC2-Int_DNA_Repair	Family

Pfam: PF11976

UniProt features (44 total): modified residue 15, strand 11, helix 5, compositionally biased region 3, region of interest 2, cross-link 2, splice variant 2, chain 1, domain 1, sequence variant 1, coiled-coil region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3RD2	X-RAY DIFFRACTION	1.6
2JXX	SOLUTION NMR
2L76	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NCF5-F1	65.48	0.24

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 (17): 88, 90, 92, 127, 198, 201, 204, 220, 314, 316, 318, 369, 390, 129, 131, 54, 84

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 180 (showing top): E2F_Q4, MULLIGHAN_NPM1_SIGNATURE_3_UP, E2F4DP1_01, MITSIADES_RESPONSE_TO_APLIDIN_DN, GGAMTNNNNNTCCY_UNKNOWN, PUJANA_CHEK2_PCC_NETWORK, BROWNE_HCMV_INFECTION_24HR_UP, GOBP_PEPTIDYL_LYSINE_MODIFICATION, MORF_RAF1, E2F1DP1_01, ONKEN_UVEAL_MELANOMA_UP, E2F_Q3, E2F1DP2_01, chr16p11, RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN

GO Biological Process (2): protein sumoylation (GO:0016925), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidyl-lysine modification	1
protein modification by small protein conjugation	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3309 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NFATC2IP	UBE2I	P50550	772
NFATC2IP	PRMT1	Q99873	767
NFATC2IP	SMC5	Q8IY18	757
NFATC2IP	NFATC2	Q13469	606
NFATC2IP	RABEP2	Q9H5N1	571
NFATC2IP	ATXN2L	Q8WWM7	548
NFATC2IP	NSMCE2	Q96MF7	507
NFATC2IP	SPNS1	Q9H2V7	475
NFATC2IP	RNF4	P78317	474
NFATC2IP	TRAF6	Q9Y4K3	472
NFATC2IP	MUS81	Q96NY9	464
NFATC2IP	SMC6	Q96SB8	451
NFATC2IP	VPS9D1	Q9Y2B5	445
NFATC2IP	FKBP1A	P20071	427
NFATC2IP	SH2B1	Q9NRF2	404

IntAct

21 interactions, top by confidence:

A	B	Type	Score
P4HA3	FAM171A2	psi-mi:“MI:0914”(association)	0.640
NFATC2IP	ZNHIT1	psi-mi:“MI:0914”(association)	0.530
DAAM2	SCGB2A1	psi-mi:“MI:0914”(association)	0.530
NFATC2IP	RPL26	psi-mi:“MI:0915”(physical association)	0.400
RNF4	NFATC2IP	psi-mi:“MI:0915”(physical association)	0.400
ZDHHC17	NFATC2IP	psi-mi:“MI:0915”(physical association)	0.370
FOS	TRAPPC13	psi-mi:“MI:0914”(association)	0.350
NTAQ1	SBNO1	psi-mi:“MI:0914”(association)	0.350
COL8A1	CCDC85C	psi-mi:“MI:0914”(association)	0.350
	SUPT5H	psi-mi:“MI:0914”(association)	0.350
SERF2	WDR46	psi-mi:“MI:0914”(association)	0.350
GNL2	POLR1G	psi-mi:“MI:0914”(association)	0.350
CALM1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
WDCP	NFATC2IP	psi-mi:“MI:0914”(association)	0.350
H2BC10	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
RAVER1	KDM6A	psi-mi:“MI:2364”(proximity)	0.270
SMNDC1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (85): NFATC2IP (Affinity Capture-RNA), NFATC2IP (Affinity Capture-RNA), NFATC2IP (Two-hybrid), NFATC2IP (Co-fractionation), NFATC2IP (Co-fractionation), NFATC2IP (Co-fractionation), NFATC2IP (Co-fractionation), NFATC2IP (Co-fractionation), NFATC2IP (Co-fractionation), NFATC2IP (Proximity Label-MS), NFATC2IP (Affinity Capture-MS), NFATC2IP (Affinity Capture-MS), NFATC2IP (Affinity Capture-MS), CHD8 (Affinity Capture-MS), ACTR6 (Affinity Capture-MS)

ESM2 similar proteins: A0JNI1, E9Q0S6, O94983, O95402, P80192, Q08AE8, Q1JQA8, Q1LZH7, Q28DG6, Q3B7I8, Q3KPL3, Q3U1V8, Q4VAC9, Q53LP3, Q5BJT1, Q5DU25, Q5HZA4, Q5JU85, Q5M836, Q5PQ30, Q5RBI7, Q5REP3, Q5XG99, Q5ZKK0, Q69YU3, Q6DCC7, Q6DEF4, Q6IPM2, Q6IQA2, Q6P606, Q76G19, Q7TSI1, Q7Z3D4, Q80Y50, Q86UU1, Q8BL43, Q8BY98, Q8C0J6, Q8CC84, Q8IV50

Diamond homologs: A7WLH8, A7WLI0, B3H5R8, G2XKQ0, O09130, O13351, O57686, P55852, P55853, P55854, P55857, P61955, P61956, P61957, P61958, P61959, P63165, P63166, Q0P4K8, Q12306, Q17QV3, Q28H04, Q2EF74, Q2PFW2, Q3E8A8, Q5E9D1, Q5EAX4, Q5I0H3, Q5R6J4, Q5XIF4, Q5ZHQ1, Q5ZJM9, Q6AYG7, Q6DEP7, Q6DHL4, Q6DI05, Q6DK72, Q6EEV6, Q6GPW2, Q6LDZ8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	50
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1808612	GRCh37/hg19 16p11.2(chr16:28763835-29051191)x1	Pathogenic
812191	Single allele	Pathogenic
202225	GRCh37/hg19 16p11.2(chr16:28833437-29046252)x3	Likely pathogenic

SpliceAI

1374 predictions. Top by Δscore:

Variant	Effect	Δscore
16:28951395:G:GT	donor_gain	1.0000
16:28951395:G:T	donor_gain	1.0000
16:28951396:A:T	donor_gain	1.0000
16:28952127:TGCA:T	acceptor_loss	1.0000
16:28952128:GCA:G	acceptor_loss	1.0000
16:28952130:A:AC	acceptor_loss	1.0000
16:28952130:A:AG	acceptor_gain	1.0000
16:28952130:AG:A	acceptor_gain	1.0000
16:28952131:G:A	acceptor_loss	1.0000
16:28952131:G:GG	acceptor_gain	1.0000
16:28952131:GG:G	acceptor_gain	1.0000
16:28952131:GGTT:G	acceptor_gain	1.0000
16:28952131:GGTTA:G	acceptor_gain	1.0000
16:28952200:GGAAG:G	donor_gain	1.0000
16:28952201:G:GT	donor_gain	1.0000
16:28952201:GAAGG:G	donor_loss	1.0000
16:28952202:A:T	donor_gain	1.0000
16:28952202:AAGGT:A	donor_loss	1.0000
16:28952204:GGT:G	donor_loss	1.0000
16:28952205:GTAAG:G	donor_loss	1.0000
16:28952206:T:A	donor_loss	1.0000
16:28954683:G:GG	donor_gain	1.0000
16:28956054:T:G	donor_gain	1.0000
16:28958990:GACT:G	acceptor_gain	1.0000
16:28959083:G:GT	donor_gain	1.0000
16:28959083:G:T	donor_gain	1.0000
16:28959099:GA:G	donor_gain	1.0000
16:28959101:G:GG	donor_gain	1.0000
16:28951365:G:T	donor_gain	0.9900
16:28952127:T:TA	acceptor_gain	0.9900

AlphaMissense

2661 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:28958787:T:C	L306S	0.998
16:28958859:T:A	I330N	0.998
16:28963847:T:A	I415N	0.997
16:28958993:T:C	C332R	0.996
16:28963775:T:C	F391S	0.996
16:28958750:G:C	A294P	0.995
16:28958781:T:C	I304T	0.995
16:28958781:T:G	I304S	0.995
16:28958784:T:C	L305P	0.995
16:28958781:T:A	I304N	0.994
16:28963735:T:G	Y378D	0.994
16:28963774:T:C	F391L	0.994
16:28963776:C:A	F391L	0.994
16:28963776:C:G	F391L	0.994
16:28956300:G:C	R270P	0.993
16:28958751:C:A	A294D	0.993
16:28958995:T:G	C332W	0.993
16:28959054:T:A	V352E	0.993
16:28963787:G:T	G395V	0.993
16:28958859:T:G	I330S	0.992
16:28959048:T:A	L350H	0.992
16:28963724:T:A	L374H	0.992
16:28963829:T:C	M409T	0.992
16:28956297:T:A	I269N	0.991
16:28963796:T:A	L398H	0.991
16:28963847:T:G	I415S	0.991
16:28958790:T:C	L307P	0.990
16:28959048:T:C	L350P	0.990
16:28963735:T:A	Y378N	0.990
16:28956291:T:A	L267H	0.989

dbSNP variants (sampled 300 via entrez): RS1000024985 (16:28949773 T>A), RS1000558574 (16:28954988 C>G,T), RS1000777265 (16:28960915 G>A), RS1000801723 (16:28960619 G>A), RS1001020308 (16:28967386 C>G), RS1001183244 (16:28961590 T>A,C), RS1001373215 (16:28954603 G>T), RS1001540347 (16:28949501 G>A), RS1001608392 (16:28961477 C>T), RS1001714561 (16:28960753 G>T), RS1002192213 (16:28959942 C>A), RS1002415928 (16:28954109 T>G), RS1002421851 (16:28966394 A>G), RS1002562893 (16:28951984 G>A), RS1002720338 (16:28958031 G>A)

Disease associations

OMIM: gene MIM:614525 | disease phenotypes: MIM:611913

GenCC curated gene-disease

Mondo (1): proximal 16p11.2 microdeletion syndrome (MONDO:0012756)

Orphanet (1): Proximal 16p11.2 microdeletion syndrome (Orphanet:261197)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002598_62	Educational attainment	1.000000e-06
GCST005990_20	Non-albumin protein levels	7.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004784	self reported educational attainment

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C579850	16p11.2 Deletion Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation	3
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
testosterone enanthate	affects expression	1
pyrimidin-2-one beta-ribofuranoside	increases expression	1
sodium arsenite	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	affects phosphorylation	1
resorcinol	increases expression	1
torcetrapib	increases expression	1
Leflunomide	decreases expression	1
Caffeine	affects phosphorylation	1
Coumestrol	affects cotreatment, increases expression	1
Estradiol	decreases expression	1
Ivermectin	decreases expression	1
Nickel	increases expression	1
Niclosamide	decreases expression	1
Quercetin	increases phosphorylation	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Valproic Acid	increases expression	1
Cyclosporine	decreases expression	1
Lactic Acid	increases expression	1
tert-Butylhydroperoxide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04271332	PHASE2	ACTIVE_NOT_RECRUITING	Safety, Tolerability, and Efficacy of Arbaclofen in 16p11.2 Deletion
NCT01238250	Not specified	RECRUITING	Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight