NR2F1

Summary

NR2F1 (nuclear receptor subfamily 2 group F member 1, HGNC:7975) is a protein-coding gene on chromosome 5q15, encoding COUP transcription factor 1 (P10589). Coup (chicken ovalbumin upstream promoter) transcription factor binds to the ovalbumin promoter and, in conjunction with another protein (S300-II) stimulates initiation of transcription. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a nuclear hormone receptor and transcriptional regulator. The encoded protein acts as a homodimer and binds to 5’-AGGTCA-3’ repeats. Defects in this gene are a cause of Bosch-Boonstra optic atrophy syndrome (BBOAS).

Source: NCBI Gene 7025 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Bosch-Boonstra-Schaaf optic atrophy syndrome (Definitive, ClinGen)
• GWAS associations: 8
• Clinical variants (ClinVar): 425 total — 46 pathogenic, 51 likely-pathogenic
• Phenotypes (HPO): 52
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 70 downstream targets (CollecTRI)
• MANE Select transcript: NM_005654

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7975
Approved symbol	NR2F1
Name	nuclear receptor subfamily 2 group F member 1
Location	5q15
Locus type	gene with protein product
Status	Approved
Aliases	EAR-3, COUP-TFI, TCFCOUP1, SVP44, COUPTF1
Ensembl gene	ENSG00000175745
Ensembl biotype	protein_coding
OMIM	132890
Entrez	7025

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000327111, ENST00000502982, ENST00000506162, ENST00000512697, ENST00000615873, ENST00000647447, ENST00000700211

RefSeq mRNA: 2 — MANE Select: NM_005654 NM_001410754, NM_005654

CCDS: CCDS4068, CCDS93743

Canonical transcript exons

ENST00000327111 — 3 exons

Exon	Start	End
ENSE00001249995	93587917	93588444
ENSE00001250011	93583222	93585486
ENSE00003816221	93593562	93594611

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 98.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.2210 / max 804.8622, expressed in 1263 samples.

FANTOM5 promoters (25 alternative TSS)

Promoter ID	TPM avg	Samples expressed
57561	17.5012	1108
57560	6.9117	1083
57564	2.7109	626
57568	1.8258	496
57562	1.8092	583
57563	1.6883	563
57557	1.3231	408
57559	1.1783	462
57569	0.9717	392
57575	0.9407	282

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.27	gold quality
cranial nerve II	UBERON:0000941	97.81	gold quality
seminal vesicle	UBERON:0000998	97.79	gold quality
trigeminal ganglion	UBERON:0001675	97.75	gold quality
left uterine tube	UBERON:0001303	97.68	gold quality
germinal epithelium of ovary	UBERON:0001304	97.54	gold quality
ganglionic eminence	UBERON:0004023	97.51	gold quality
parietal pleura	UBERON:0002400	97.24	gold quality
lower lobe of lung	UBERON:0008949	97.22	gold quality
primary visual cortex	UBERON:0002436	97.08	gold quality
dorsal root ganglion	UBERON:0000044	97.00	gold quality
visceral pleura	UBERON:0002401	96.88	gold quality
caput epididymis	UBERON:0004358	96.87	gold quality
pleura	UBERON:0000977	96.85	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.83	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.81	gold quality
occipital lobe	UBERON:0002021	96.70	gold quality
right ovary	UBERON:0002118	96.51	gold quality
cerebellar hemisphere	UBERON:0002245	96.43	gold quality
cerebellar cortex	UBERON:0002129	96.39	gold quality
cerebellum	UBERON:0002037	96.35	gold quality
corpus epididymis	UBERON:0004359	96.17	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	95.83	gold quality
left ovary	UBERON:0002119	95.81	gold quality
right uterine tube	UBERON:0001302	95.78	gold quality
olfactory bulb	UBERON:0002264	95.78	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.70	gold quality
superficial temporal artery	UBERON:0001614	95.66	gold quality
right frontal lobe	UBERON:0002810	95.59	gold quality
entorhinal cortex	UBERON:0002728	95.50	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	924.87
E-MTAB-8894	yes	872.58
E-MTAB-10018	yes	516.55
E-GEOD-135922	yes	54.67
E-HCAD-10	yes	51.99
E-MTAB-10553	yes	46.65
E-HCAD-1	yes	18.33
E-HCAD-9	yes	15.90
E-CURD-46	yes	13.55
E-CURD-112	yes	12.83
E-ANND-3	yes	9.67
E-MTAB-9067	yes	7.12
E-GEOD-130148	yes	4.49
E-MTAB-6108	no	475.50
E-MTAB-9543	no	1.22

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

70 targets.

Target	Regulation
ACADM	Repression
ADAM2
AGT	Repression
APOA2	Unknown
APOA4	Repression
APOB	Unknown
APOC3	Unknown
BMP4	Unknown
CALR
CAMK4
CAT
CD44
CERK
CIP2A
COL7A1	Activation
CPT2	Repression
CYP11B1
CYP11B2
CYP17A1	Repression
CYP19A1	Unknown
CYP1A1	Repression
CYP2D6	Repression
CYP2E1
CYP3A4
DLST
DR1	Repression
EGR1	Activation
EPO	Repression
ESR1
FABP7

JASPAR motifs

Motif	Name	Family
MA0017.1	NR2F1	RXR-related receptors (NR2)
MA0017.2	NR2F1	RXR-related receptors (NR2)
MA0017.3	NR2F1	RXR-related receptors (NR2)
MA1537.1	NR2F1	RXR-related receptors (NR2)
MA1537.2	NR2F1	RXR-related receptors (NR2)
MA1538.1	NR2F1	RXR-related receptors (NR2)

JASPAR matrix evidence (PMIDs): PMID:8496174, PMID:14559106

Upstream regulators (CollecTRI, top): CREB1, ESRRA, ETS1, GLI2, MEF2C, NCOR2, NKX2-5, TWIST1, TWIST2

miRNA regulators (miRDB)

72 targeting NR2F1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-9902	99.89	69.15	2250
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-3923	99.52	69.21	446
HSA-MIR-486-5P	99.51	70.39	707

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Inhibit aldehyde dehydrogenase 2 gene expression (PMID:11811951)
• Regulation of retinoic acid-induced inhibition of AP-1 activity by orphan receptor chicken ovalbumin upstream promoter-transcription factor. (PMID:11934895)
• Formation of an hER alpha-COUP-TFI complex enhances hER alpha AF-1 through Ser118 phosphorylation by MAPK. (PMID:12093745)
• regulates transcription of hepatitis B virus (PMID:12551987)
• Transcription of the LHR gene is repressed by EAR3. (PMID:12972613)
• COUP-TF may be involved in repression of the human MGP gene promoter at the myoblast stage (PMID:15157742)
• findings show that enhancer II of HBV genotype A is also repressed by COUP-TF1; in contrast, two different enhancer II constructs of HBV genotype D were activated by COUP-TF1 (PMID:17009409)
• COUP-TFI selectively regulates the expression of endogenous E2-target genes and consequently modifies ER alpha positive mammary cells response to E2. (PMID:17674191)
• Regulation of vascular endothelial growth factor D by hepatocyte nuclear factor-4 alpha and chicken ovalbumin upstream promoter transcription factors 1 and 2. (PMID:18199540)
• A chicken ovalbumin upstream promoter transcription factor I (COUP-TFI) complex represses expression of the gene encoding tumor necrosis factor alpha-induced protein 8 (TNFAIP8). (PMID:19112178)
• study identifies two unique corticotroph tumor populations which differ in their expression of COUP-TFI, the presence of which occurs more frequently in macroadenomas. (PMID:19526345)
• Transcriptional and posttranscriptional mechanisms involving NR2F1 and IRE1beta ensure low microsomal triglyceride transfer protein expression in undifferentiated intestinal cells and avoid apolipoprotein B lipoprotein biosynthesis. (PMID:20007910)
• provide detailed experimental validation of each step and, as a proof of principle, utilize the methodology to identify novel direct targets of the orphan nuclear receptor NR2F1 (COUP-TFI) (PMID:20111703)
• a novel mechanism of MTP repression that involves binding of NR2F1 to the DR1 element and recruitment of corepressors (PMID:22357705)
• COUP-TFI and related NRs such as the COUPTFs and PNR can selectively associate with the developmental corepressor BCL11A via a conserved motif F/YSXXLXXL/Y within the RID1 and RID2 domains. The interaction with BCL11A facilitates COUP-TFII-mediated repression of the RARb2 gene. (PMID:23975195)
• Interaction of NSD1 with the NR2E/F subfamily including COUP-TFI, COUP-TFII, EAR2 and TLX requires an F/YSXXLXXL/Y motif. Interactions of NSD1 with liganded NRs require an overlapping LXXLL motif. (PMID:23975195)
• NR2F1 has an important role in the development of the visual system and that haploinsuffiency can lead to optic atrophy with intellectual impairment. (PMID:24462372)
• our mechanistic in vitro assays and in vivo results suggest that a reduction in chemokine CXCL12 expression, with an enhancement of CXCR4 expression, provoked by COUP-TFI, could be associated with an increase in the invasive potential of breast cancer (PMID:24906407)
• COUP-TFII is expressed in a diverse subset of GABAergic interneurons predominantly innervating small dendritic shafts originating from both interneurons and pyramidal cells. (PMID:25787832)
• Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS)encompasses a broad range of clinical phenotypes. Functional studies help determine the severity of novel NR2F1 variants. Some genotype-phenotype correlations seem to exist, with missense mutations in the DNA-binding domain causing the most severe phenotypes (PMID:26986877)
• fifth of COUP-TFI cells also co-expressed COUP-TFII, and cells expressing either transcription factor followed posterior or anterio-lateral pathways into the cortex (PMID:28922831)
• Whole-exome sequencing identified a novel missense NR2F1 variant in each case, Cys86Phe in the DNA-binding domain in Case 1, and a Leu372Pro in the ligand-binding domain in Case 2. Using molecular modeling we are also able to demonstrate the putative effect of the two missenses on protein function, generating a hitherto undescribed molecular model for the ligand-binding domain of NR2F1 in the process. (PMID:28963436)
• Findings from basic biological analysis of disseminated tumor cells (DTCs) dormancy to the clinical situation and supports further clinical studies of nuclear receptor subfamily 2 group F member 1 (NR2F1) as a marker of dormancy. (PMID:30322396)
• functional studies on NR2F1 transfected cells, during osteoblast differentiation in combination with TGFbeta1 and BMP-2, showed that TGFb1 does not recover osteoblast differentiation, whereas BMP-2 rescues osteoblast differentiation in NR2F1 siRNA transfected cells. Thus, our results showed that BMP-2 could intervene in NR2F1 down-regulated signaling pathways to recover osteoblast differentiation. (PMID:30445268)
• The NR2F1-induced NR2F1-AS1 promotes ESCC progression through activation of Hedgehog signaling pathway. (PMID:31530388)
• Clinical and neurocognitive issues associated with Bosch-Boonstra-Schaaf optic atrophy syndrome: A case study. (PMID:31729143)
• Bosch-Boonstra-Schaaf Optic Atrophy Syndrome Presenting as New-Onset Psychosis in a 32-Year-Old Man: A Case Report and Literature Review. (PMID:31913971)
• lncRNA NR2F1-AS1 Regulates miR-17/SIK1 Axis to Suppress the Invasion and Migration of Cervical Squamous Cell Carcinoma Cells. (PMID:31994002)
• Phenotypic expansion of Bosch-Boonstra-Schaaf optic atrophy syndrome and further evidence for genotype-phenotype correlations. (PMID:32275123)
• NR2F1 regulates regional progenitor dynamics in the mouse neocortex and cortical gyrification in BBSOAS patients. (PMID:32484994)
• Dynamic expression of NR2F1 and SOX2 in developing and adult human cortex: comparison with cortical malformations. (PMID:33661352)
• Long non-coding RNA NR2F1-AS1 induces breast cancer lung metastatic dormancy by regulating NR2F1 and DeltaNp63. (PMID:34475402)
• The Parkinson’s-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1. (PMID:34686322)
• Long noncoding RNA NR2F1-AS1 plays a carcinogenic role in gastric cancer by recruiting transcriptional factor SPI1 to upregulate ST8SIA1 expression. (PMID:34738863)
• An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy. (PMID:34812843)
• NR2F1 database: 112 variants and 84 patients support refining the clinical synopsis of Bosch-Boonstra-Schaaf optic atrophy syndrome. (PMID:34837429)
• Metabolic Switch Under Glucose Deprivation Leading to Discovery of NR2F1 as a Stimulus of Osteoblast Differentiation. (PMID:35462433)
• NR2F1 Is a Barrier to Dissemination of Early-Stage Breast Cancer Cells. (PMID:35471456)
• Spatial control of astrogenesis progression by cortical arealization genes. (PMID:35818636)
• METTL3 inhibits inflammation of retinal pigment epithelium cells by regulating NR2F1 in an m(6)A-dependent manner. (PMID:35936005)

Cross-species orthologs

28 orthologs

Organism	Symbol	Gene ID
danio_rerio	nr2f1b	ENSDARG00000017168
danio_rerio	nr2f1a	ENSDARG00000052695
mus_musculus	Nr2f1	ENSMUSG00000069171
rattus_norvegicus	Nr2f1	ENSRNOG00000014795
drosophila_melanogaster	Hr83	FBGN0037436
caenorhabditis_elegans		WBGENE00003626
caenorhabditis_elegans		WBGENE00003650
caenorhabditis_elegans	nhr-69	WBGENE00003659
caenorhabditis_elegans		WBGENE00003683
caenorhabditis_elegans		WBGENE00003706
caenorhabditis_elegans		WBGENE00003719
caenorhabditis_elegans		WBGENE00003726
caenorhabditis_elegans		WBGENE00007547
caenorhabditis_elegans		WBGENE00008221
caenorhabditis_elegans		WBGENE00011097
caenorhabditis_elegans		WBGENE00011098
caenorhabditis_elegans		WBGENE00011099
caenorhabditis_elegans		WBGENE00011100
caenorhabditis_elegans		WBGENE00015395
caenorhabditis_elegans		WBGENE00015396
caenorhabditis_elegans		WBGENE00015397
caenorhabditis_elegans		WBGENE00015705
caenorhabditis_elegans		WBGENE00016975
caenorhabditis_elegans		WBGENE00017198
caenorhabditis_elegans		WBGENE00017787
caenorhabditis_elegans		WBGENE00020748
caenorhabditis_elegans		WBGENE00021848
caenorhabditis_elegans		WBGENE00044354

Paralogs (11): HNF4A (ENSG00000101076), NR2E1 (ENSG00000112333), NR2C1 (ENSG00000120798), RXRG (ENSG00000143171), NR2F6 (ENSG00000160113), HNF4G (ENSG00000164749), NR2C2 (ENSG00000177463), NR2F2 (ENSG00000185551), RXRA (ENSG00000186350), RXRB (ENSG00000204231), NR2E3 (ENSG00000278570)

Protein

Protein identifiers

COUP transcription factor 1 — P10589 (reviewed: P10589)

Alternative names: COUP transcription factor I, Nuclear receptor subfamily 2 group F member 1, V-erbA-related protein 3

All UniProt accessions (5): A0A8V8TPV3, A0A8V8TQQ6, F1DAL7, F1DAL9, P10589

UniProt curated annotations — full annotation on UniProt →

Function. Coup (chicken ovalbumin upstream promoter) transcription factor binds to the ovalbumin promoter and, in conjunction with another protein (S300-II) stimulates initiation of transcription. Binds to both direct repeats and palindromes of the 5’-AGGTCA-3’ motif. Represses transcriptional activity of LHCG.

Subunit / interactions. Binds DNA as dimer; homodimer and probable heterodimer with NR2F6. Interacts with GTF2B; this interaction is direct. Interacts with COPS2.

Subcellular location. Nucleus.

Disease relevance. Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) [MIM:615722] An autosomal dominant disorder characterized by optic atrophy associated with developmental delay and intellectual disability. Most patients also have evidence of cerebral visual impairment. The disease is caused by variants affecting the gene represented in this entry.

Induction. Inhibited by gonadotropin in granulosa cells.

Similarity. Belongs to the nuclear hormone receptor family. NR2 subfamily.

RefSeq proteins (2): NP_001397683, NP_005645* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001628	Znf_hrmn_rcpt	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR013088	Znf_NHR/GATA	Homologous_superfamily
IPR035500	NHR-like_dom_sf	Homologous_superfamily
IPR050274	Nuclear_hormone_rcpt_NR2	Family

Pfam: PF00104, PF00105

UniProt features (19 total): sequence variant 5, helix 3, turn 2, strand 2, zinc finger region 2, chain 1, domain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2EBL	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10589-F1	76.81	0.50

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-383280	Nuclear Receptor transcription pathway

MSigDB gene sets: 409 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, RRAGTTGT_UNKNOWN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, WWTAAGGC_UNKNOWN, TSENG_IRS1_TARGETS_UP, GAANYNYGACNY_UNKNOWN, PAL_PRMT5_TARGETS_UP, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_NEUROGENESIS, MEF2_02, CHX10_01, GGGTGGRR_PAX4_03, AAAYRNCTG_UNKNOWN, MORF_RAD51L3

GO Biological Process (8): negative regulation of transcription by RNA polymerase II (GO:0000122), signal transduction (GO:0007165), nervous system development (GO:0007399), negative regulation of neuron projection development (GO:0010977), cell differentiation (GO:0030154), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of DNA-templated transcription (GO:0006355), intracellular receptor signaling pathway (GO:0030522)

GO Molecular Function (11): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription factor activity (GO:0003700), nuclear receptor activity (GO:0004879), zinc ion binding (GO:0008270), sequence-specific DNA binding (GO:0043565), retinoic acid-responsive element binding (GO:0044323), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
system development	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
cellular developmental process	1
positive regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
intracellular signal transduction	1
cis-regulatory region sequence-specific DNA binding	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription repressor activity	1
transcription cis-regulatory region binding	1
regulation of DNA-templated transcription	1
transcription regulator activity	1
intracellular receptor signaling pathway	1
signaling receptor activity	1
ligand-modulated transcription factor activity	1
transition metal ion binding	1
DNA binding	1
RNA polymerase II cis-regulatory region sequence-specific DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

1814 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NR2F1	BCL11B	Q9C0K0	982
NR2F1	NCOR1	O75376	751
NR2F1	SERPINA6	P08185	648
NR2F1	HNF1A	P20823	645
NR2F1	SATB2	Q9UPW6	631
NR2F1	EMX2	Q04743	626
NR2F1	ISL1	P20663	609
NR2F1	FOXA1	P55317	601
NR2F1	PAX6	P26367	596
NR2F1	SOX5	P35711	591
NR2F1	SP8	Q8IXZ3	584
NR2F1	BCL11A	Q9H165	584
NR2F1	ARB2A	Q8WUF8	577
NR2F1	TFAP2A	P05549	575
NR2F1	BHLHE41	Q9C0J9	552

IntAct

50 interactions, top by confidence:

A	B	Type	Score
MPPED1	TXNDC9	psi-mi:“MI:0914”(association)	0.640
MPPED1	CLUH	psi-mi:“MI:0914”(association)	0.640
GTF2B	NR2F1	psi-mi:“MI:0407”(direct interaction)	0.540
NR2F1	GTF2B	psi-mi:“MI:0407”(direct interaction)	0.540
NR2F1	GTF2B	psi-mi:“MI:0915”(physical association)	0.540
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
MPPED2	NR2F6	psi-mi:“MI:0914”(association)	0.530
	NR2F1	psi-mi:“MI:0915”(physical association)	0.370
CCL22	NR2F1	psi-mi:“MI:0915”(physical association)	0.370
CCL24	NR2F1	psi-mi:“MI:0915”(physical association)	0.370
IFNA16	NR2F1	psi-mi:“MI:0915”(physical association)	0.370
IFNA17	NR2F1	psi-mi:“MI:0915”(physical association)	0.370
IFNA8	NR2F1	psi-mi:“MI:0915”(physical association)	0.370
IL17A	NR2F1	psi-mi:“MI:0915”(physical association)	0.370
IL37	NR2F1	psi-mi:“MI:0915”(physical association)	0.370
XCL1	NR2F1	psi-mi:“MI:0915”(physical association)	0.370
NR2F1	PFDN1	psi-mi:“MI:0915”(physical association)	0.370
FOS	NFIX	psi-mi:“MI:0914”(association)	0.350
FOXA3	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXC2	ZNF536	psi-mi:“MI:0914”(association)	0.350

BioGRID (78): NR2F1 (Affinity Capture-MS), NR2F1 (Affinity Capture-MS), NCOA2 (Two-hybrid), NR2F1 (Affinity Capture-MS), NR2F1 (Affinity Capture-MS), NR2F1 (Affinity Capture-MS), NR2F1 (Affinity Capture-MS), NR2F1 (Affinity Capture-MS), NR2F1 (Affinity Capture-MS), NR2F1 (Affinity Capture-MS), AHR (Reconstituted Complex), NR2F1 (Affinity Capture-MS), NR2F1 (Affinity Capture-MS), NR2F1 (Two-hybrid), NR2F1 (Affinity Capture-RNA)

ESM2 similar proteins: O08580, O09017, O09018, O75064, O95718, P10588, P10589, P11474, P11475, P12813, P22736, P22829, P24468, P28702, P28704, P33242, P43135, P43136, P49743, P49870, P50569, P51666, P54779, P55055, P79387, Q03181, Q04752, Q06725, Q0V8F0, Q0ZAQ8, Q13285, Q3U1Y4, Q5BIS6, Q5QJV7, Q5TJF7, Q60632, Q60644, Q61539, Q62755, Q6QMY5

Diamond homologs: A0JNE3, A0P8Z4, A2T928, A4IIG7, F1QJF4, F1QLY4, O01639, O09018, O18924, O18971, O35507, O62807, O77245, O88275, P10276, P10589, P10826, P11416, P13055, P13056, P13631, P16375, P16376, P17671, P18514, P18515, P18516, P18911, P22448, P22605, P24468, P28699, P31396, P33244, P35398, P37231, P37233, P37238, P41828, P41829

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
CREB1	“down-regulates quantity by repression”	NR2F1	“transcriptional regulation”
ESRRA	“down-regulates quantity by repression”	NR2F1	“transcriptional regulation”
TWIST2	“up-regulates quantity by expression”	NR2F1	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	NR2F1	“transcriptional regulation”
NR2F1	up-regulates	RXRA	binding
NR2F2	up-regulates	NR2F1	binding
RXRB	up-regulates	NR2F1	binding
NR2F1	“up-regulates quantity by expression”	PCDH19	“transcriptional regulation”
NR2F1	“down-regulates quantity by repression”	LHCGR	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	46
Likely pathogenic	51
Uncertain significance	159
Likely benign	129
Benign	9

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1048564	NM_005654.6(NR2F1):c.513C>G (p.Tyr171Ter)	Pathogenic
1194663	NM_005654.6(NR2F1):c.359dup (p.Tyr120Ter)	Pathogenic
126493	NM_005654.6(NR2F1):c.344G>C (p.Arg115Pro)	Pathogenic
126494	NM_005654.6(NR2F1):c.339C>A (p.Ser113Arg)	Pathogenic
1451360	NM_005654.6(NR2F1):c.597dup (p.Thr200fs)	Pathogenic
1460081	NC_000005.9:g.(?92920730)(92929548_?)del	Pathogenic
1699474	NM_005654.6(NR2F1):c.827T>A (p.Leu276Ter)	Pathogenic
1700111	NM_005654.6(NR2F1):c.704G>T (p.Arg235Leu)	Pathogenic
1700379	NM_005654.6(NR2F1):c.1A>C (p.Met1Leu)	Pathogenic
1701480	NM_005654.6(NR2F1):c.427_429delinsTT (p.Lys144fs)	Pathogenic
1708261	NM_005654.6(NR2F1):c.1077_1084del (p.Tyr360fs)	Pathogenic
1711198	NM_005654.6(NR2F1):c.907C>T (p.Gln303Ter)	Pathogenic
1999860	NM_005654.6(NR2F1):c.291_294dup (p.Gly99fs)	Pathogenic
2042153	NM_005654.6(NR2F1):c.991+2T>A	Pathogenic
2123487	NM_005654.6(NR2F1):c.121C>T (p.Gln41Ter)	Pathogenic
2227203	NM_005654.6(NR2F1):c.94_157del (p.Gly32fs)	Pathogenic
2572229	NM_005654.6(NR2F1):c.282C>A (p.Ser94Arg)	Pathogenic
2613241	NM_005654.6(NR2F1):c.547del (p.Cys183fs)	Pathogenic
265667	NM_005654.6(NR2F1):c.262G>A (p.Val88Met)	Pathogenic
2683748	NM_005654.6(NR2F1):c.3G>A (p.Met1Ile)	Pathogenic
2708042	NM_005654.6(NR2F1):c.597del (p.Thr200fs)	Pathogenic
2735897	NM_005654.6(NR2F1):c.240_255del (p.Gln81fs)	Pathogenic
280458	NM_005654.6(NR2F1):c.417A>T (p.Gln139His)	Pathogenic
2844506	NM_005654.6(NR2F1):c.348del (p.Asn117fs)	Pathogenic
3237371	NM_005654.6(NR2F1):c.1065del (p.Glu354_Tyr355insTer)	Pathogenic
3250030	NC_000005.10:g.(?93585023)(93593843_?)del	Pathogenic
3254585	NM_005654.6(NR2F1):c.274A>T (p.Lys92Ter)	Pathogenic
3375751	NM_005654.6(NR2F1):c.2T>A (p.Met1Lys)	Pathogenic
3377104	NM_005654.6(NR2F1):c.763dup (p.Thr255fs)	Pathogenic
3407655	NM_005654.6(NR2F1):c.1075C>T (p.Gln359Ter)	Pathogenic

SpliceAI

484 predictions. Top by Δscore:

Variant	Effect	Δscore
5:93587915:A:AG	acceptor_gain	1.0000
5:93587915:AGC:A	acceptor_gain	1.0000
5:93587916:G:GG	acceptor_gain	1.0000
5:93587916:GCG:G	acceptor_gain	1.0000
5:93593532:T:TA	acceptor_gain	1.0000
5:93593545:T:A	acceptor_gain	1.0000
5:93593547:T:TA	acceptor_gain	1.0000
5:93593548:G:A	acceptor_gain	1.0000
5:93593551:T:TA	acceptor_gain	1.0000
5:93593555:T:TA	acceptor_gain	1.0000
5:93593556:G:A	acceptor_gain	1.0000
5:93585484:A:T	donor_gain	0.9900
5:93587911:T:A	acceptor_gain	0.9900
5:93587912:GTCAG:G	acceptor_loss	0.9900
5:93587913:TCAGC:T	acceptor_loss	0.9900
5:93587915:AGCG:A	acceptor_gain	0.9900
5:93587916:G:T	acceptor_loss	0.9900
5:93587916:GC:G	acceptor_gain	0.9900
5:93587916:GCGG:G	acceptor_gain	0.9900
5:93587917:C:CA	acceptor_gain	0.9900
5:93593558:GCAG:G	acceptor_loss	0.9900
5:93593559:CA:C	acceptor_loss	0.9900
5:93593560:A:AG	acceptor_gain	0.9900
5:93593560:AGAC:A	acceptor_gain	0.9900
5:93593561:G:GT	acceptor_gain	0.9900
5:93593561:GAC:G	acceptor_gain	0.9900
5:93593561:GACG:G	acceptor_gain	0.9900
5:93593561:GACGC:G	acceptor_gain	0.9900
5:93585455:G:GT	donor_gain	0.9800
5:93585483:G:GT	donor_gain	0.9800

AlphaMissense

2762 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:93585279:T:A	C86S	1.000
5:93585279:T:C	C86R	1.000
5:93585280:G:A	C86Y	1.000
5:93585280:G:C	C86S	1.000
5:93585280:G:T	C86F	1.000
5:93585281:C:G	C86W	1.000
5:93585285:G:A	V88M	1.000
5:93585286:T:A	V88E	1.000
5:93585288:T:A	C89S	1.000
5:93585288:T:C	C89R	1.000
5:93585288:T:G	C89G	1.000
5:93585289:G:A	C89Y	1.000
5:93585289:G:C	C89S	1.000
5:93585289:G:T	C89F	1.000
5:93585290:C:G	C89W	1.000
5:93585294:G:C	D91H	1.000
5:93585294:G:T	D91Y	1.000
5:93585295:A:C	D91A	1.000
5:93585295:A:G	D91G	1.000
5:93585295:A:T	D91V	1.000
5:93585301:C:T	S93L	1.000
5:93585303:A:C	S94R	1.000
5:93585304:G:A	S94N	1.000
5:93585305:C:A	S94R	1.000
5:93585305:C:G	S94R	1.000
5:93585306:G:A	G95S	1.000
5:93585306:G:C	G95R	1.000
5:93585306:G:T	G95C	1.000
5:93585307:G:A	G95D	1.000
5:93585307:G:C	G95A	1.000

dbSNP variants (sampled 300 via entrez): RS1000061679 (5:93583209 A>T), RS1000269734 (5:93590008 C>G,T), RS1000504619 (5:93587306 T>C), RS1000606958 (5:93594635 G>A), RS1000876561 (5:93591483 C>T), RS1000979080 (5:93594910 G>A), RS1001061748 (5:93588110 C>T), RS1001120498 (5:93587618 G>A), RS1001253582 (5:93584176 G>A,C), RS1001257131 (5:93589341 G>A,C), RS1001289829 (5:93589013 C>T), RS1001629655 (5:93590742 T>C), RS1002236878 (5:93593971 G>C,T), RS1002244819 (5:93587189 G>A), RS1002297052 (5:93586564 A>C,G)

Disease associations

OMIM: gene MIM:132890 | disease phenotypes: MIM:615722

GenCC curated gene-disease

Disease	Classification	Inheritance
Bosch-Boonstra-Schaaf optic atrophy syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Bosch-Boonstra-Schaaf optic atrophy syndrome	Definitive	AD

Mondo (5): Bosch-Boonstra-Schaaf optic atrophy syndrome (MONDO:0014320), inherited retinal dystrophy (MONDO:0019118), autism spectrum disorder (MONDO:0005258), epilepsy (MONDO:0005027), optic atrophy (MONDO:0003608)

Orphanet (3): Optic atrophy-intellectual disability syndrome (Orphanet:401777), OBSOLETE: Inherited retinal disorder (Orphanet:71862), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000154	Wide mouth
HP:0000218	High palate
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000307	Pointed chin
HP:0000365	Hearing impairment
HP:0000395	Prominent antihelix
HP:0000411	Protruding ear
HP:0000426	Prominent nasal bridge
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000540	Hypermetropia
HP:0000543	Optic disc pallor
HP:0000545	Myopia
HP:0000563	Keratoconus
HP:0000565	Esotropia
HP:0000577	Exotropia
HP:0000582	Upslanted palpebral fissure
HP:0000609	Optic nerve hypoplasia
HP:0000639	Nystagmus
HP:0000646	Amblyopia
HP:0000648	Optic atrophy
HP:0000717	Autism
HP:0000722	Compulsive behaviors
HP:0000729	Autistic behavior
HP:0001123	Visual field defect
HP:0001182	Tapered finger
HP:0001212	Prominent fingertip pads
HP:0001249	Intellectual disability

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST010320_146	PR interval	8.000000e-11
GCST010321_1	PR interval	2.000000e-10
GCST010701_76	Cortical surface area (MOSTest)	4.000000e-09
GCST010702_129	Subcortical volume (MOSTest)	2.000000e-15
GCST010703_4	Brain morphology (MOSTest)	5.000000e-34
GCST010988_100	Adult body size	2.000000e-08
GCST011616_1	Cortical volume	3.000000e-13
GCST90010427_9	Left–right brain asymmetry	3.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004462	PR interval
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1961789 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: nhr — 2F. COUP-TF-like receptors

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation, affects cotreatment, increases expression	8
trichostatin A	affects cotreatment, increases expression	3
Cyclosporine	decreases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Temozolomide	affects response to substance, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
fluorene-9-bisphenol	increases expression	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
1,12-benzoperylene	increases expression, decreases reaction, affects reaction	1
bisphenol A	increases methylation	1
geraniol	decreases expression	1
titanium dioxide	increases methylation	1
alpha-naphthoflavone	affects binding	1
ascorbate-2-phosphate	affects cotreatment, increases expression, affects binding	1
beta-lapachone	decreases expression	1
sodium arsenite	affects expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
rutecarpine	decreases expression	1
triacsin C	decreases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
ciglitazone	affects cotreatment, increases expression, increases reaction	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
diallyl trisulfide	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1961852	Binding	Effect on TFCOUP1(NR2F1) dependent reporter activity in HEK293 cells at 20 uM	Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. — Nature

Cellosaurus cell lines

4 cell lines: 4 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4V4	SEES3-1V human NR2F1, clone1	Embryonic stem cell	Male
CVCL_A4V5	SEES3-1V human NR2F1, clone2	Embryonic stem cell	Male
CVCL_A4V6	SEES3-1V human NR2F1, clone3	Embryonic stem cell	Male
CVCL_BW90	ES-R1 CAG-S-hCOUP-TFI	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances