RBFOX2

Summary

RBFOX2 (RNA binding fox-1 homolog 2, HGNC:9906) is a protein-coding gene on chromosome 22q12.3, encoding RNA binding protein fox-1 homolog 2 (O43251). RNA-binding protein that regulates alternative splicing events by binding to 5’-UGCAUGU-3’ elements.

This gene is one of several human genes similar to the C. elegans gene Fox-1. This gene encodes an RNA binding protein that is thought to be a key regulator of alternative exon splicing in the nervous system and other cell types. The protein binds to a conserved UGCAUG element found downstream of many alternatively spliced exons and promotes inclusion of the alternative exon in mature transcripts. The protein also interacts with the estrogen receptor 1 transcription factor and regulates estrogen receptor 1 transcriptional activity. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 23543 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Strong, ClinGen) — +2 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 142 total — 2 pathogenic, 2 likely-pathogenic
• MANE Select transcript: NM_001349999

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9906
Approved symbol	RBFOX2
Name	RNA binding fox-1 homolog 2
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Aliases	HNRBP2, FOX-2, HRNBP2
Ensembl gene	ENSG00000100320
Ensembl biotype	protein_coding
OMIM	612149
Entrez	23543

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 32 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000262829, ENST00000359369, ENST00000397303, ENST00000397305, ENST00000405409, ENST00000408983, ENST00000414461, ENST00000416721, ENST00000438146, ENST00000449924, ENST00000463509, ENST00000473487, ENST00000491982, ENST00000495377, ENST00000695803, ENST00000695804, ENST00000695805, ENST00000695806, ENST00000695807, ENST00000695854, ENST00000908669, ENST00000908670, ENST00000908671, ENST00000908672, ENST00000908673, ENST00000908674, ENST00000908675, ENST00000921513, ENST00000921514, ENST00000921515, ENST00000921516, ENST00000921517, ENST00000921518, ENST00000953675, ENST00000953676, ENST00000953677, ENST00000953678

RefSeq mRNA: 26 — MANE Select: NM_001349999 NM_001031695, NM_001082576, NM_001082577, NM_001082578, NM_001082579, NM_001349982, NM_001349983, NM_001349989, NM_001349990, NM_001349991, NM_001349992, NM_001349994, NM_001349995, NM_001349996, NM_001349997, NM_001349998, NM_001349999, NM_001394108, NM_001394109, NM_001394110, NM_001394111, NM_001394112, NM_001394113, NM_001394114, NM_001394115, NM_014309

CCDS: CCDS13921, CCDS43013, CCDS46699, CCDS46700, CCDS46701, CCDS93157

Canonical transcript exons

ENST00000625456 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 99.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.5058 / max 617.2054, expressed in 1581 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193859	9.2431	1455
193837	8.1513	1315
193854	4.7667	1362
193848	2.4633	357
193836	2.2658	993
193860	0.9587	501
193853	0.9104	575
193838	0.6907	231
193858	0.5499	343
193849	0.3933	99

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.11	gold quality
embryo	UBERON:0000922	97.79	gold quality
ganglionic eminence	UBERON:0004023	97.79	gold quality
cerebellar cortex	UBERON:0002129	97.75	gold quality
cerebellum	UBERON:0002037	97.74	gold quality
cerebellar hemisphere	UBERON:0002245	97.74	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.55	gold quality
smooth muscle tissue	UBERON:0001135	97.06	gold quality
stromal cell of endometrium	CL:0002255	96.94	gold quality
superior frontal gyrus	UBERON:0002661	96.55	gold quality
calcaneal tendon	UBERON:0003701	96.41	gold quality
body of uterus	UBERON:0009853	96.08	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.95	gold quality
mucosa of stomach	UBERON:0001199	95.51	gold quality
myometrium	UBERON:0001296	95.48	gold quality
muscle tissue	UBERON:0002385	95.02	gold quality
ovary	UBERON:0000992	94.87	gold quality
primary visual cortex	UBERON:0002436	94.77	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.76	gold quality
uterus	UBERON:0000995	94.75	gold quality
right ovary	UBERON:0002118	94.73	gold quality
left ovary	UBERON:0002119	94.66	gold quality
descending thoracic aorta	UBERON:0002345	94.66	gold quality
skeletal muscle tissue	UBERON:0001134	94.54	gold quality
islet of Langerhans	UBERON:0000006	94.38	gold quality
placenta	UBERON:0001987	94.34	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.34	gold quality
lower esophagus	UBERON:0013473	94.29	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.28	gold quality
popliteal artery	UBERON:0002250	94.18	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-98556	yes	317.83
E-HCAD-5	yes	44.67
E-HCAD-13	yes	26.14
E-GEOD-93593	yes	18.40
E-ANND-3	yes	13.26
E-GEOD-137537	yes	6.46

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
ESR1	Repression

Upstream regulators (CollecTRI, top): AP1, CEBPG, FOS, HEY1, JUN, MYC, XBP1

miRNA regulators (miRDB)

337 targeting RBFOX2, 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-6873-3P	100.00	71.42	2626
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-1193	100.00	65.93	529
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-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784

Literature-anchored findings (GeneRIF, showing 40)

• Fox-1 and Fox-2 isoforms specifically activate splicing of neuronally regulated exons, which requires UGCAUG enhancer elements (PMID:16260614)
• Fox-1 and Fox-2 splicing factors have roles in alternative splicing of protein 4.1R (PMID:16537540)
• Fox-1/Fox-2 proteins block prespliceosome complex formation at two distinct steps through binding to two functionally important UGCAUG elements. (PMID:18573872)
• These results establish hnRNP H and hnRNP F as being repressors of exon inclusion and suggest that Fox proteins enhance their ability to antagonize ASF/SF2. (PMID:18573884)
• predict thousands of Fox-1/2 targets with conserved binding sites, at a false discovery rate of approximately 24%, including many validated experimentally, suggesting a surprisingly extensive splicing regulatory networks (PMID:18794351)
• These findings suggest that FOX2 functions as a critical regulator of a splicing network, and that FOX2 is important for the survival of human embryonic stem cells. (PMID:19136955)
• Fox-2 plays an integral role in the regulation of LH2 splicing and knockdown of Fox-2 may suggest a novel approach to strategies directed against scleroderma. (PMID:20131247)
• the negative regulation of Rbfox2 by Rbfox3 through a novel mechanism (PMID:21747913)
• functional significance of EMT-associated alternative splicing depletion of RBFOX2 in mesenchymal cells (PMID:21876675)
• This study characterizes the mechanism by which RBFOX2 regulates protein 4.1R exon 16 splicing through the downstream intronic element UGCAUG. (PMID:22083953)
• FOX-2 is involved in splicing of ataxin-2 transcripts and that this splicing event is altered by overexpression of ataxin-1 (PMID:22666429)
• RBFOX2 polymorphism is associated with breast cancer. (PMID:23143756)
• RBFOX2 drives mesenchymal tissue-specific splicing in both normal and cancer tissues. (PMID:23149937)
• MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation. (PMID:24048253)
• RBFOX2 SNPs showed evidence for effects across multiple reading and language traits. (PMID:25065397)
• Results show that the conserved Rbfox2 RNA binding protein regulates 30% of the splicing transitions observed during myogenesis and is required for the specific step of myoblast fusion. (PMID:25087874)
• RBFOX proteins can facilitate the splicing of micro-exons. We also found that PTBP1 likely regulates the inclusion of micro-exons, possibly by repressing the inclusion of micro-exons that are enhanced by RBFOX proteins and other splicing factors.[RBFOX] (PMID:25524026)
• CPSF2 and SYMPK, are RBFOX2 cofactors for both inclusion and exclusion of internal exons. (PMID:25921069)
• Some of the widespread cellular functions of Rbfox2 protein are attributable to regulation of miRNA biogenesis, and might include the mis-regulation of miR-20b and miR-107 in cancer and neurodegeneration. (PMID:27001519)
• Data show that while RBFOX1 and RBFOX2 do not mediate neuron-specific processing of UBE3A-ATS, these proteins play important roles in developing neurons and are not completely functionally redundant. (PMID:27146458)
• RBFox2 interactis with chromatin in a nascent RNA-dependent manner. RBFox2 inactivation eradicates PRC2 targeting on the majority of bivalent gene promoters and leads to transcriptional de-repression. (PMID:27211866)
• RBFOX2 dysregulation by dominant-negative RBFOX2 is an early pathogenic event in diabetic hearts. (PMID:27239029)
• Rbfox2 nonsense mutation is associated with hypoplastic left heart syndrome. (PMID:27485310)
• Results showed that the expression patterns of these genes were indicative of the onset of EMT in in-vitro models, but not in tissue samples. However, the ratio between ESRP1 or ESRP2 and RBFOX2 significantly decreased during EMT and positively correlated with the EMT-specific phenotype in cell models. Low ESRP1/RBFOX2 ratio value was associated with a higher risk of metastasis in early breast cancer patients. (PMID:27911856)
• The authors report that a subset of cell cycle-related genes including retinoblastoma 1 is the target of Rbfox2 in cytoplasmic stress granules, and Rbfox2 regulates the retinoblastoma 1 mRNA and protein expression levels during and following stress exposure. (PMID:28894257)
• Rbfox2 modulates the functions of vascular CaV1.2 calcium channel by dynamically regulating the expressions of alternative exons 9* and 33, which in turn affects the vascular myogenic tone. (PMID:28993448)
• Results provide evidence that RBFOX2 expression in epithelial ovarian cancer is regulated by MALAT1 which its alternative splicing. (PMID:30294913)
• Data show that exon 10, responsible for nuclear localization, of RBFOX2. was absent in calcific tendons. (PMID:31128090)
• Aberrant Expression of a Non-muscle RBFOX2 Isoform Triggers Cardiac Conduction Defects in Myotonic Dystrophy. (PMID:32109384)
• Trophoblast lineage specific expression of the alternative splicing factor RBFOX2 suggests a role in placental development. (PMID:32762877)
• Concentration-dependent splicing is enabled by Rbfox motifs of intermediate affinity. (PMID:32807990)
• ERG transcription factors have a splicing regulatory function involving RBFOX2 that is altered in the EWS-FLI1 oncogenic fusion. (PMID:34009296)
• RBFOX2/GOLIM4 Splicing Axis Activates Vesicular Transport Pathway to Promote Nasopharyngeal Carcinogenesis. (PMID:34180133)
• RBFOX2 alters splicing outcome in distinct binding modes with multiple protein partners. (PMID:34244793)
• Alternative microexon splicing by RBFOX2 and PTBP1 is associated with metastasis in colorectal cancer. (PMID:34346508)
• SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity. (PMID:34548489)
• The Splicing of the Mitochondrial Calcium Uniporter Genuine Activator MICU1 Is Driven by RBFOX2 Splicing Factor during Myogenic Differentiation. (PMID:35269658)
• Alternative Splicing of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) Is Regulated by RBFOX2 in Lymphoid Malignancies. (PMID:35404107)
• The Role of Alternative Splicing Factors hnRNP G and Fox-2 in the Progression and Prognosis of Esophageal Cancer. (PMID:36466711)
• RBFOX2 modulates a metastatic signature of alternative splicing in pancreatic cancer. (PMID:36949200)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rbfox2	ENSDARG00000052182
mus_musculus	Rbfox2	ENSMUSG00000033565
rattus_norvegicus	Rbfox2	ENSRNOG00000004688
drosophila_melanogaster	Rbfox1	FBGN0052062
caenorhabditis_elegans		WBGENE00001484

Paralogs (2): RBFOX1 (ENSG00000078328), RBFOX3 (ENSG00000167281)

Protein

Protein identifiers

RNA binding protein fox-1 homolog 2 — O43251 (reviewed: O43251)

Alternative names: Fox-1 homolog B, Hexaribonucleotide-binding protein 2, RNA-binding motif protein 9, RNA-binding protein 9, Repressor of tamoxifen transcriptional activity

All UniProt accessions (13): O43251, A0A8Q3SI19, A0A8Q3SI20, A0A8Q3SI31, A0A8Q3SI58, A0A8Q3SI75, A0A8Q3WKT3, B0QYV1, B0QYY4, B0QYY6, B0QYY7, S4R3K7, S4R469

UniProt curated annotations — full annotation on UniProt →

Function. RNA-binding protein that regulates alternative splicing events by binding to 5’-UGCAUGU-3’ elements. Prevents binding of U2AF2 to the 3’-splice site. Regulates alternative splicing of tissue-specific exons and of differentially spliced exons during erythropoiesis. RNA-binding protein that seems to act as a coregulatory factor of ER-alpha. Together with RNA binding proteins RBPMS and MBNL1/2, activates vascular smooth muscle cells alternative splicing events.

Subunit / interactions. Interacts with ER-alpha N-terminal activation domain. Interacts with RBPMS; the interaction allows cooperative assembly of stable cell-specific alternative splicing regulatory complexes.

Subcellular location. Nucleus. Cytoplasm.

Isoforms (10)

UniProt ID	Names	Canonical?
O43251-1	1	yes
O43251-2	2
O43251-3	3
O43251-4	4
O43251-5	5
O43251-6	6
O43251-7	7
O43251-8	8
O43251-9	9
O43251-10	10

RefSeq proteins (26): NP_001026865, NP_001076045, NP_001076046, NP_001076047, NP_001076048, NP_001336911, NP_001336912, NP_001336918, NP_001336919, NP_001336920, NP_001336921, NP_001336923, NP_001336924, NP_001336925, NP_001336926, NP_001336927, NP_001336928, NP_001381037, NP_001381038, NP_001381039, NP_001381040, NP_001381041, NP_001381042, NP_001381043, NP_001381044, NP_055124 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR017325	RBFOX1-3	Family
IPR025670	Fox-1_C_dom	Domain
IPR034237	FOX1_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR047131	RBFOX1-like	Family

Pfam: PF00076, PF12414

UniProt features (47 total): modified residue 13, site 8, splice variant 7, sequence conflict 5, strand 4, compositionally biased region 3, helix 3, chain 1, domain 1, region of interest 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2CQ3	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43251-F1	55.86	0.21

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (8): 160 (interaction with rna); 164 (interaction with rna); 188 (interaction with rna); 198 (interaction with rna); 122 (interaction with rna); 130 (interaction with rna); 131 (interaction with rna); 155 (interaction with rna)

Post-translational modifications (13): 281, 297, 329, 381, 381, 386, 386, 249, 267, 67, 277, 67, 268

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6803529	FGFR2 alternative splicing

MSigDB gene sets: 285 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_CELLULAR_RESPONSE_TO_LIPID, ATACCTC_MIR202, GOBP_ALTERNATIVE_MRNA_SPLICING_VIA_SPLICEOSOME, REACTOME_SIGNALING_BY_FGFR, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, CAGCTG_AP4_Q5, PATIL_LIVER_CANCER, MARTINEZ_RB1_TARGETS_UP, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, ONKEN_UVEAL_MELANOMA_UP, SOX9_B1, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, ROZANOV_MMP14_TARGETS_UP

GO Biological Process (25): regulation of alternative mRNA splicing, via spliceosome (GO:0000381), mRNA processing (GO:0006397), nervous system development (GO:0007399), RNA splicing (GO:0008380), RNA metabolic process (GO:0016070), estrogen receptor signaling pathway (GO:0030520), regulation of cell population proliferation (GO:0042127), negative regulation of DNA-templated transcription (GO:0045892), heart development (GO:0007507), positive regulation of gene expression (GO:0010628), regulation of definitive erythrocyte differentiation (GO:0010724), radial glia guided migration of Purkinje cell (GO:0021942), negative regulation of apoptotic process (GO:0043066), regulation of RNA splicing (GO:0043484), positive regulation of vasoconstriction (GO:0045907), dendrite morphogenesis (GO:0048813), neuromuscular process controlling balance (GO:0050885), negative regulation of mitochondrial depolarization (GO:0051902), regulation of mitochondrial gene expression (GO:0062125), cellular response to hydrogen peroxide (GO:0070301), cellular response to retinoic acid (GO:0071300), mRNA alternative polyadenylation (GO:0110104), negative regulation of membrane hyperpolarization (GO:1902631), cellular response to angiotensin (GO:1904385), cellular response to endothelin (GO:1990859)

GO Molecular Function (7): transcription corepressor activity (GO:0003714), RNA binding (GO:0003723), mRNA binding (GO:0003729), DNA-binding transcription factor binding (GO:0140297), nucleic acid binding (GO:0003676), single-stranded RNA binding (GO:0003727), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by FGFR2	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of gene expression	3
RNA processing	2
RNA binding	2
binding	2
cellular anatomical structure	2
alternative mRNA splicing, via spliceosome	1
regulation of mRNA splicing, via spliceosome	1
mRNA metabolic process	1
system development	1
nucleic acid metabolic process	1
nuclear receptor-mediated steroid hormone signaling pathway	1
cell population proliferation	1
regulation of cellular process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
animal organ development	1
circulatory system development	1
gene expression	1
positive regulation of macromolecule biosynthetic process	1
regulation of erythrocyte differentiation	1
definitive erythrocyte differentiation	1
hindbrain radial glia guided cell migration	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
RNA splicing	1
regulation of primary metabolic process	1
regulation of vasoconstriction	1
vasoconstriction	1
positive regulation of multicellular organismal process	1
dendrite development	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
musculoskeletal movement	1
neuromuscular process	1
mitochondrial depolarization	1
regulation of mitochondrial depolarization	1
negative regulation of membrane depolarization	1
mitochondrial gene expression	1

Protein interactions and networks

STRING

1674 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RBFOX2	ATXN1	P54253	843
RBFOX2	QKI	Q96PU8	837
RBFOX2	HNRNPH1	P31943	815
RBFOX2	RBPMS	Q93062	809
RBFOX2	EPB41	P11171	741
RBFOX2	MBNL1	Q9NR56	721
RBFOX2	PUM1	Q14671	712
RBFOX2	HNRNPH2	P55795	692
RBFOX2	HNRNPC	P07910	680
RBFOX2	NOVA1	P51513	677
RBFOX2	ESR1	P03372	674
RBFOX2	ATP5F1C	P36542	671
RBFOX2	NOVA2	Q9UNW9	670
RBFOX2	PTBP1	P26599	670
RBFOX2	PUM2	Q8TB72	668

IntAct

156 interactions, top by confidence:

A	B	Type	Score
RBFOX2	ATXN1	psi-mi:“MI:0915”(physical association)	0.790
ATXN1	RBFOX2	psi-mi:“MI:0915”(physical association)	0.790
DAZAP2	RBFOX2	psi-mi:“MI:0915”(physical association)	0.740
RBFOX2	DAZAP2	psi-mi:“MI:0915”(physical association)	0.740
QKI	RBFOX2	psi-mi:“MI:0914”(association)	0.720
QKI	RBFOX2	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PKN3	ARHGAP10	psi-mi:“MI:0914”(association)	0.680
RBFOX2	VAC14	psi-mi:“MI:0915”(physical association)	0.670
RBFOX2	BOLL	psi-mi:“MI:0915”(physical association)	0.670
RBFOX2	HNRNPF	psi-mi:“MI:0915”(physical association)	0.670
VAC14	RBFOX2	psi-mi:“MI:0915”(physical association)	0.670
HNRNPF	RBFOX2	psi-mi:“MI:0915”(physical association)	0.670
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
FAM136A	RBFOX3	psi-mi:“MI:0914”(association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640

BioGRID (444): RBFOX2 (Two-hybrid), RBFOX2 (Two-hybrid), RBFOX2 (Two-hybrid), RBFOX2 (Two-hybrid), RBFOX2 (Two-hybrid), RBFOX2 (Two-hybrid), RBFOX2 (Two-hybrid), RBFOX2 (Two-hybrid), VAC14 (Two-hybrid), BOLL (Two-hybrid), C1orf94 (Two-hybrid), NAF1 (Two-hybrid), MAPK1IP1L (Two-hybrid), RBFOX2 (Affinity Capture-MS), RBFOX2 (Affinity Capture-MS)

ESM2 similar proteins: A1A5R1, A2YXQ1, A4F5G6, A6NFN3, A6QPR6, E3WDQ9, O42366, O43251, O65034, O80416, P24344, P35453, P46609, P55316, P56260, P70217, Q00939, Q02962, Q0VD23, Q14671, Q17QD3, Q1A1A1, Q1A1A2, Q1A1A3, Q1A1A4, Q1A1A5, Q1A1A6, Q1KKX5, Q27002, Q2VB19, Q5NVN8, Q5R5X3, Q60987, Q642J5, Q66JB7, Q66KI6, Q6YHU8, Q6ZBH6, Q6ZK57, Q7TN99

Diamond homologs: A0A0D1C8Z4, A1A5R1, A2A5N3, A3LXL0, A4F5G6, A5A6M3, A5DW14, A6NFN3, A6QPR6, F1QB54, F4HT49, O04319, O13845, O35698, O43251, O93235, P0CB38, P11940, P19682, P19683, P19684, P20965, P28644, P29341, P38159, P42731, P49313, P49314, P60824, P60825, P60826, P61286, P62995, P62996, P62997, Q04836, Q08935, Q08937, Q09511, Q0VD23

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
IKBKB	“up-regulates activity”	RBFOX2	phosphorylation
MAPK1	unknown	RBFOX2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 113 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA Polyadenylation	9	11.1×	2e-05
mRNA Splicing - Major Pathway	11	8.5×	2e-05
Processing of Capped Intron-Containing Pre-mRNA	7	8.1×	3e-03
Dengue Virus-Host Interactions	12	7.7×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
regulation of alternative mRNA splicing, via spliceosome	6	15.8×	6e-04
RNA processing	5	11.8×	7e-03
regulation of RNA splicing	5	11.8×	7e-03
mRNA splicing, via spliceosome	10	9.8×	4e-05
mRNA processing	9	7.6×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	70
Likely benign	38
Benign	11

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
4151401	NM_001349999.2(RBFOX2):c.1218C>G (p.Tyr406Ter)	Pathogenic
521760	NM_001349999.2(RBFOX2):c.523dup (p.Ser175fs)	Pathogenic
1699029	NM_001349999.2(RBFOX2):c.352C>T (p.Gln118Ter)	Likely pathogenic
4531845	NM_001349999.2(RBFOX2):c.754G>T (p.Glu252Ter)	Likely pathogenic

SpliceAI

2797 predictions. Top by Δscore:

Variant	Effect	Δscore
22:35745917:ACTT:A	donor_loss	1.0000
22:35745918:CTT:C	donor_loss	1.0000
22:35745920:TAC:T	donor_loss	1.0000
22:35745921:A:AC	donor_gain	1.0000
22:35745921:ACCAC:A	donor_loss	1.0000
22:35745922:C:CC	donor_gain	1.0000
22:35745922:CCA:C	donor_gain	1.0000
22:35745991:CATAA:C	acceptor_gain	1.0000
22:35745993:TAA:T	acceptor_gain	1.0000
22:35745994:AA:A	acceptor_gain	1.0000
22:35745994:AAC:A	acceptor_loss	1.0000
22:35745996:C:CC	acceptor_gain	1.0000
22:35745997:T:C	acceptor_loss	1.0000
22:35746467:ACAT:A	donor_loss	1.0000
22:35746468:CATA:C	donor_loss	1.0000
22:35746470:TACC:T	donor_loss	1.0000
22:35746557:CCACC:C	acceptor_gain	1.0000
22:35746558:CACC:C	acceptor_gain	1.0000
22:35746558:CACCC:C	acceptor_gain	1.0000
22:35746559:ACC:A	acceptor_gain	1.0000
22:35746560:CC:C	acceptor_gain	1.0000
22:35746560:CCC:C	acceptor_gain	1.0000
22:35746561:CC:C	acceptor_gain	1.0000
22:35746562:C:A	acceptor_loss	1.0000
22:35746562:C:CC	acceptor_gain	1.0000
22:35746563:T:A	acceptor_loss	1.0000
22:35749107:T:TA	donor_gain	1.0000
22:35765419:TTAC:T	donor_loss	1.0000
22:35765421:A:AC	donor_gain	1.0000
22:35765422:C:CC	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000010794 (22:35993520 T>A,C), RS1000020491 (22:36011912 C>G), RS1000022278 (22:35786623 C>T), RS1000028250 (22:35857579 C>T), RS1000028657 (22:35770577 C>A,T), RS1000037716 (22:35739475 A>G), RS1000046766 (22:35961265 T>C), RS1000083273 (22:35754023 T>C), RS1000100367 (22:35943495 C>G,T), RS1000101502 (22:35874240 A>G), RS1000122114 (22:35986696 G>A), RS1000135423 (22:35892854 C>T), RS1000137494 (22:35848246 C>T), RS1000145120 (22:35815193 A>G), RS1000154235 (22:35943848 T>A,C)

Disease associations

OMIM: gene MIM:612149 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart defects, multiple types	Strong	Autosomal dominant
congenital heart disease	Strong	Autosomal dominant
RBFOX2-related congenital heart disorder	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Strong	AD

Mondo (3): RBFOX2-related congenital heart disorder (MONDO:0100557), congenital heart disease (MONDO:0005453), congenital heart defects, multiple types (MONDO:0000119)

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004401_4	Reading disability or specific language impairment (pleiotropy)	5.000000e-07
GCST005958_13	Waist-to-hip ratio adjusted for BMI (age >50)	1.000000e-06
GCST005962_33	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	6.000000e-06
GCST010989_164	Body size at age 10	4.000000e-08
GCST90002390_319	Mean corpuscular hemoglobin	9.000000e-17
GCST90002392_136	Mean corpuscular volume	1.000000e-18
GCST90002404_402	Red cell distribution width	4.000000e-17

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004527	mean corpuscular hemoglobin
EFO:0009188	Red cell distribution width

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	4
bisphenol A	affects methylation, increases expression	2
Benzo(a)pyrene	decreases expression	2
alpha-pinene	increases abundance, affects cotreatment, increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
butyraldehyde	decreases expression	1
nickel chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
torcetrapib	increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Vorinostat	decreases expression	1
Acrolein	increases expression, increases abundance, affects cotreatment	1
Air Pollutants	affects cotreatment, increases abundance, increases expression	1
Arsenic	decreases expression, increases abundance, affects cotreatment	1
Vehicle Emissions	increases abundance, increases expression	1
Caffeine	increases phosphorylation	1
Cisplatin	affects response to substance	1
Coumestrol	decreases expression, affects cotreatment	1
Dexamethasone	affects cotreatment, decreases expression	1
Diuron	decreases expression	1
Gallic Acid	increases expression	1
Indomethacin	affects cotreatment, decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7HB	Ubigene HEK293T RBFOX2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE