RBFOX1

Summary

RBFOX1 (RNA binding fox-1 homolog 1, HGNC:18222) is a protein-coding gene on chromosome 16p13.3, encoding RNA binding protein fox-1 homolog 1 (Q9NWB1). RNA-binding protein that regulates alternative splicing events by binding to 5’-UGCAUGU-3’ elements.

The Fox-1 family of RNA-binding proteins is evolutionarily conserved, and regulates tissue-specific alternative splicing in metazoa. Fox-1 recognizes a (U)GCAUG stretch in regulated exons or in flanking introns. The protein binds to the C-terminus of ataxin-2 and may contribute to the restricted pathology of spinocerebellar ataxia type 2 (SCA2). Ataxin-2 is the product of the SCA2 gene which causes familial neurodegenerative diseases. Fox-1 and ataxin-2 are both localized in the trans-Golgi network. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 54715 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 100
• Clinical variants (ClinVar): 612 total — 4 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 2
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_018723

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18222
Approved symbol	RBFOX1
Name	RNA binding fox-1 homolog 1
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	A2BP1, FOX-1, HRNBP1
Ensembl gene	ENSG00000078328
Ensembl biotype	protein_coding
OMIM	605104
Entrez	54715

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 27 protein_coding, 10 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000311745, ENST00000355637, ENST00000422070, ENST00000436368, ENST00000535565, ENST00000547338, ENST00000547372, ENST00000547427, ENST00000547605, ENST00000548749, ENST00000550418, ENST00000551752, ENST00000552089, ENST00000553186, ENST00000564850, ENST00000567470, ENST00000569889, ENST00000569895, ENST00000570188, ENST00000570626, ENST00000585867, ENST00000620507, ENST00000641259, ENST00000674626, ENST00000674792, ENST00000674859, ENST00000675077, ENST00000675140, ENST00000675242, ENST00000675459, ENST00000675562, ENST00000675653, ENST00000675725, ENST00000675842, ENST00000675904, ENST00000676218, ENST00000676253, ENST00000682918, ENST00000683326, ENST00000705321

RefSeq mRNA: 40 — MANE Select: NM_018723 NM_001142333, NM_001142334, NM_001308117, NM_001364800, NM_001411047, NM_001415887, NM_001415888, NM_001415889, NM_001415890, NM_001415891, NM_001415892, NM_001415893, NM_001415894, NM_001415895, NM_001415896, NM_001415897, NM_001415898, NM_001415899, NM_001415900, NM_001415901, NM_001415902, NM_001415903, NM_001415904, NM_001415905, NM_001415906, NM_001415907, NM_001415908, NM_001415909, NM_001415910, NM_001415911, NM_001415912, NM_001415913, NM_001415914, NM_001415915, NM_001415916, NM_001415917, NM_018723, NM_145891, NM_145892, NM_145893

CCDS: CCDS10531, CCDS10532, CCDS45405, CCDS55983, CCDS55984, CCDS76818, CCDS92100, CCDS92101

Canonical transcript exons

ENST00000550418 — 16 exons

Exon	Start	End
ENSE00000667533	7579777	7579920
ENSE00000667546	7587247	7587300
ENSE00001010795	7664929	7664968
ENSE00001594633	7653815	7653947
ENSE00001620899	7597371	7597431
ENSE00002174063	7630603	7630683
ENSE00003503620	7052057	7052098
ENSE00003534387	7518147	7518389
ENSE00003581405	7709056	7709131
ENSE00003681903	7607285	7607338
ENSE00003691282	7676774	7676838
ENSE00003790298	7595549	7595641
ENSE00003813330	6654603	6654650
ENSE00003813425	6316995	6317057
ENSE00003889106	6019024	6019992
ENSE00003895214	7710623	7713340

Expression profiles

Bgee: expression breadth ubiquitous, 220 present calls, max score 99.15.

FANTOM5 (CAGE): breadth broad, TPM avg 13.6896 / max 1507.1295, expressed in 364 samples.

FANTOM5 promoters (45 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152523	2.2110	146
152546	1.4810	111
152609	0.9806	98
152531	0.8899	135
152615	0.8402	72
152537	0.8301	143
152522	0.7023	132
152521	0.6166	117
152534	0.6039	106
152543	0.4907	89

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	99.15	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.96	gold quality
cortical plate	UBERON:0005343	98.46	gold quality
primary visual cortex	UBERON:0002436	98.30	gold quality
occipital lobe	UBERON:0002021	97.93	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.60	gold quality
gluteal muscle	UBERON:0002000	97.59	gold quality
pons	UBERON:0000988	97.42	gold quality
superior frontal gyrus	UBERON:0002661	97.40	gold quality
tibialis anterior	UBERON:0001385	97.39	gold quality
parietal lobe	UBERON:0001872	97.39	gold quality
cerebellar vermis	UBERON:0004720	97.35	gold quality
postcentral gyrus	UBERON:0002581	97.18	gold quality
deltoid	UBERON:0001476	97.14	gold quality
quadriceps femoris	UBERON:0001377	96.67	gold quality
orbitofrontal cortex	UBERON:0004167	96.64	gold quality
vastus lateralis	UBERON:0001379	96.46	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.30	gold quality
skeletal muscle tissue	UBERON:0001134	96.19	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.14	gold quality
entorhinal cortex	UBERON:0002728	96.09	gold quality
prefrontal cortex	UBERON:0000451	96.01	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.01	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.98	gold quality
triceps brachii	UBERON:0001509	95.92	gold quality
frontal cortex	UBERON:0001870	95.79	gold quality
diaphragm	UBERON:0001103	95.73	silver quality
gastrocnemius	UBERON:0001388	95.69	gold quality
body of tongue	UBERON:0011876	95.42	gold quality
biceps brachii	UBERON:0001507	95.36	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-30	yes	48844.28
E-GEOD-180759	yes	46226.38
E-HCAD-35	yes	11691.20
E-MTAB-7316	yes	1299.12
E-GEOD-75140	yes	320.60
E-GEOD-93593	yes	212.11
E-HCAD-25	yes	77.04
E-ANND-3	yes	6.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MECP2

miRNA regulators (miRDB)

196 targeting RBFOX1, 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-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-1277-5P	100.00	73.95	5056
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-3662	99.99	73.82	5684
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
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

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)
• These results demonstrate the unusual molecular mechanism of sequence-specific RNA recognition by Fox-1, which is exceptional in its high affinity for a defined but short sequence element. (PMID:16362037)
• Fox-1 and Fox-2 splicing factors have roles in alternative splicing of protein 4.1R (PMID:16537540)
• These results define a critical role for Fox-1 and Fox-2 proteins in exon 4 inclusion of calcitonin/CGRP pre-mRNA and establish a regulatory network that controls the fate of exon 4. (PMID:17101796)
• A2BP1 may affect susceptibility or cause autism in a subset of patients (PMID:17503474)
• Fox-1/Fox-2 proteins block prespliceosome complex formation at two distinct steps through binding to two functionally important UGCAUG elements. (PMID:18573872)
• 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)
• Five single-nucleotide polymorphisms (SNPs) of ataxin 2 binding protein 1 had a likelihood of association with hand osteoarthritis. (PMID:19508968)
• Studies indicate that the Fox-1 family specifically recognizes the (U)GCAUG stretch in regulated exons or in flanking introns, and either promotes or represses target exons. (PMID:19688295)
• the A2BP1 gene might play a pivotal role for susceptibility to Primary biliary cirrhosis (PMID:20153395)
• hnRNP H1 and TFG modulate the splicing activity of RBFOX1/2. (PMID:22184459)
• RBFOX1 regulates RNA splicing and transcriptional networks in human neuronal development. (PMID:22730494)
• Loss of RBFOX1 may explain the anomalous splicing activity associated with colorectal cancer. (PMID:23286373)
• Variable expressivity, incomplete penetrance, and heterogeneous cosegregation patterns suggest that RBFOX1 deletions act as susceptibility factor in a genetically complex etiology of idiopathic generalized epilepsy (PMID:23350840)
• Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error. (PMID:23474815)
• Data indicate that reintroduction of A2BP1 or Myt1L in glioblastoma multiforme (GBM) cell lines and glioma stem cells profoundly inhibited tumorigenesis. (PMID:23918370)
• Exome sequencing of 242 rolandic epilepsy patients revealed two novel probably deleterious variants in RBFOX1, a frameshift mutation (p.A233Vfs*74) and a hexanucleotide deletion (p.A299_A300del), and a novel nonsense mutation in RBFOX3 (p.Y287*). (PMID:24039908)
• RBFOX1 regulates expression of large genetic networks during early neuronal development, and haploinsufficiency causes severe neurodevelopmental phenotypes including autism spectrum disorder (ASD), intellectual disability, and epilepsy. (PMID:24290388)
• Our results support the earlier findings of A2BP1 and TGFB1 being osteoarthritis susceptibility genes and provide evidence of a possible gene-gene interaction in the genetic influence on hand OA predisposition. (PMID:24825461)
• Data indicate that RNA binding protein RBFOX1 gene expression was detected in lymphoblastoid cell lines but not in lymphocytes. (PMID:24938762)
• Aberrantly expressed FOX genes and their downstream targets are involved in the pathogenesis of HL via deregulation of B-cell differentiation and may represent useful diagnostic markers and/or therapeutic targets. (PMID:25043849)
• RBFOX1 promotes the skipping of APP exon 7, but not the inclusion of exon 8. (PMID:25125370)
• Reduced RBFOX1 activity in myotonic dystrophy type 1 tissues may amplify several of the splicing alterations caused by the deficiency in MBNL1. (PMID:25211016)
• 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)
• The SNP rs1478697 in A2BP1 may be associated with antipsychotic induced weight gain induced by 8-week treatment with olanzapine. (PMID:26092620)
• This study underlines that tightly regulated splicing is necessary for unconstrained cardiac function and renders the splicing regulator rbfox1 an interesting target for investigation in human heart failure and cardiomyopathy. (PMID:26116573)
• This study suggested that exonic RBFOX1 deletions are involved in the broad spectrum of focal and generalized epilepsies. (PMID:26174448)
• Copy Number Variations in CTNNA3 and RBFOX1 Associate with Pediatric Food Allergy (PMID:26188062)
• The Genome-wide association study showed a significant association for a variant within the RBFOX1 gene with generalized anxiety disorder. (PMID:26274327)
• study identifies regulation of RNA splicing by RBFox1 as an important player in transcriptome reprogramming during heart failure that influence pathogenesis of the disease (PMID:26619120)
• Cytoplasmic Rbfox1 target mRNAs were enriched in genes involved in cortical development and autism (PMID:26687839)
• 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)
• We present a joint atomistic molecular dynamics (MD) and experimental study of two RRM-containing proteins bound with their single-stranded target RNAs, namely the Fox-1 and SRSF1 complexes.The simulations predict unanticipated specific participation of Arg142 at the protein-RNA interface of the SRFS1 complex, which is subsequently confirmed by NMR and ITC measurements (PMID:27193998)
• Copy-number variations are enriched for RBFOX1 and other neurodevelopmental genes in children with developmental coordination disorder. (PMID:27489308)
• FGF12, RBFOX1, and MIR302F could be important in human heterotaxy, because they were noted in multiple cases. Further investigation into genes involved in the NODAL, BMP, and WNT body patterning pathways and into the dosage effects of FGF12, RBFOX1, and MIR302F is warranted. (PMID:27637763)
• Our findings suggested rs17648524 (intronic RBFOX1 gene) and rs7084402 (7.5kb 5’ of the BICC1 gene) showed gender-specific associations with high myopia in the Han Chinese. (PMID:28085524)
• Data indicate that multiple rare, coding variants in RBFOX1 protein associated with reduced systolic blood pressure (SBP). (PMID:28346479)
• Report a 1.8 A X-ray structure of the free Fox-1 containing six distinct monomers. We use this and the nuclear magnetic resonance (NMR) structure of the Fox-1 protein/RNA complex for molecular dynamics (MD) analyses of the structured hydration. The individual monomers of the X-ray structure show diverse hydration patterns, however, MD excellently reproduces the most occupied hydration sites. (PMID:28505313)
• Low RBFOX1 expression is associated with aberrant splicing in Type 1 diabetes. (PMID:28512194)
• RBFOX1 - strong candidate gene, associated with clinical features of Depression (e.g., earlier age at onset and recurrent and more severe forms of Depression). Gene expression patterns in the prefrontal and anterior cingulate cortex most closely matched the genetic findings. (PMID:28969442)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rbfox1	ENSDARG00000014746
mus_musculus	Rbfox1	ENSMUSG00000008658
rattus_norvegicus	Rbfox1	ENSRNOG00000002827
drosophila_melanogaster	Rbfox1	FBGN0052062
caenorhabditis_elegans		WBGENE00001484

Paralogs (2): RBFOX2 (ENSG00000100320), RBFOX3 (ENSG00000167281)

Protein

Protein identifiers

RNA binding protein fox-1 homolog 1 — Q9NWB1 (reviewed: Q9NWB1)

Alternative names: Ataxin-2-binding protein 1, Fox-1 homolog A, Hexaribonucleotide-binding protein 1

All UniProt accessions (19): Q9NWB1, A0A087X2B1, A0A286YEU2, A0A286YFF2, A0A6Q8PFM4, A0A6Q8PGE0, A0A6Q8PH77, A0A6Q8PHA3, A0A804HJM2, A0A804HKG7, A0A994J531, B7Z1U7, F5H0M1, F8VR27, F8VRS4, F8VZG9, F8VZY7, H3BM62, I3L1D4

UniProt curated annotations — full annotation on UniProt →

Function. RNA-binding protein that regulates alternative splicing events by binding to 5’-UGCAUGU-3’ elements. Regulates alternative splicing of tissue-specific exons and of differentially spliced exons during erythropoiesis.

Subunit / interactions. Binds to the C-terminus of ATXN2.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Predominantly expressed in muscle and brain.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9NWB1-1	1	yes
Q9NWB1-2	2, Gamma
Q9NWB1-3	3, 1
Q9NWB1-4	4, Alpha
Q9NWB1-5	5, Beta

RefSeq proteins (40): NP_001135805, NP_001135806, NP_001295046, NP_001351729, NP_001397976, NP_001402816, NP_001402817, NP_001402818, NP_001402819, NP_001402820, NP_001402821, NP_001402822, NP_001402823, NP_001402824, NP_001402825, NP_001402826, NP_001402827, NP_001402828, NP_001402829, NP_001402830, NP_001402831, NP_001402832, NP_001402833, NP_001402834, NP_001402835, NP_001402836, NP_001402837, NP_001402838, NP_001402839, NP_001402840, NP_001402841, NP_001402842, NP_001402843, NP_001402844, NP_001402845, NP_001402846, NP_061193, NP_665898, NP_665899, NP_665900 (=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 (36 total): site 8, mutagenesis site 6, splice variant 5, strand 4, compositionally biased region 3, helix 3, modified residue 2, chain 1, domain 1, region of interest 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4ZKA	X-RAY DIFFRACTION	1.8
2ERR	SOLUTION NMR
2N82	SOLUTION NMR
7VRL	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NWB1-F1	56.23	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): 156 (interaction with rna); 160 (interaction with rna); 184 (interaction with rna); 194 (interaction with rna); 118 (interaction with rna); 126 (interaction with rna); 127 (interaction with rna); 151 (interaction with rna)

Post-translational modifications (2): 317, 388

Mutagenesis-validated functional residues (6):

Position	Phenotype
120	reduces rna-binding affinity 160-fold.
126	reduces rna-binding affinity 1500-fold.
126	reduces rna-binding affinity 15-fold.
126	no effect on rna-binding.
158	reduces rna-binding affinity 700-fold.
160	reduces rna-binding affinity 30'000-fold.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9022707	MECP2 regulates transcription factors

MSigDB gene sets: 279 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, AGGAAGC_MIR5163P, WWTAAGGC_UNKNOWN, TGCGCANK_UNKNOWN, RORA1_01, GCANCTGNY_MYOD_Q6, ATACCTC_MIR202, GOBP_ALTERNATIVE_MRNA_SPLICING_VIA_SPLICEOSOME, TGACCTY_ERR1_Q2, TAKADA_GASTRIC_CANCER_COPY_NUMBER_DN, MEF2_02, ATGCAGT_MIR217, LHX3_01, FOXO1_01, CAGCTG_AP4_Q5

GO Biological Process (6): regulation of alternative mRNA splicing, via spliceosome (GO:0000381), mRNA processing (GO:0006397), nervous system development (GO:0007399), RNA splicing (GO:0008380), RNA transport (GO:0050658), regulation of RNA splicing (GO:0043484)

GO Molecular Function (4): RNA binding (GO:0003723), mRNA binding (GO:0003729), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), trans-Golgi network (GO:0005802), cytoplasmic stress granule (GO:0010494), nuclear stress granule (GO:0097165)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transcriptional Regulation by MECP2	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
binding	2
alternative mRNA splicing, via spliceosome	1
regulation of mRNA splicing, via spliceosome	1
mRNA metabolic process	1
system development	1
nucleic acid transport	1
establishment of RNA localization	1
RNA splicing	1
regulation of gene expression	1
regulation of primary metabolic process	1
nucleic acid binding	1
RNA binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
Golgi apparatus subcompartment	1
cytoplasmic ribonucleoprotein granule	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

2810 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RBFOX1	ATXN2	Q99700	995
RBFOX1	RBPMS	Q93062	715
RBFOX1	NOVA1	P51513	685
RBFOX1	MBNL1	Q9NR56	678
RBFOX1	NOVA2	Q9UNW9	665
RBFOX1	ATXN1	P54253	656
RBFOX1	HNRNPAB	Q99729	629
RBFOX1	PTBP2	Q9UKA9	620
RBFOX1	TARDBP	Q13148	617
RBFOX1	ATP5F1C	P36542	607
RBFOX1	PTBP1	P26599	606
RBFOX1	CELF1	Q92879	600
RBFOX1	HNRNPM	P52272	599
RBFOX1	SRRM4	A7MD48	593
RBFOX1	MBNL2	Q5VZF2	576

IntAct

65 interactions, top by confidence:

A	B	Type	Score
C1orf94	RBFOX1	psi-mi:“MI:0915”(physical association)	0.560
RBFOX1	RBPMS	psi-mi:“MI:0915”(physical association)	0.560
RBPMS	RBFOX1	psi-mi:“MI:0915”(physical association)	0.560
RBFOX1	C1orf94	psi-mi:“MI:0915”(physical association)	0.560
BBS2	PCK2	psi-mi:“MI:0914”(association)	0.510
RBFOX1	PSMF1	psi-mi:“MI:0915”(physical association)	0.510
RBFOX1	NUMBL	psi-mi:“MI:0915”(physical association)	0.510
PLEKHA5	RBFOX1	psi-mi:“MI:0915”(physical association)	0.510
RBFOX1	ATN1	psi-mi:“MI:0915”(physical association)	0.510
RBFOX1	ATXN1	psi-mi:“MI:0915”(physical association)	0.510
RBFOX1	QKI	psi-mi:“MI:0915”(physical association)	0.510
RBFOX1	RBFOX2	psi-mi:“MI:0915”(physical association)	0.510
RBFOX1	CFAP418	psi-mi:“MI:0915”(physical association)	0.370
PB1	HAX1	psi-mi:“MI:0914”(association)	0.350
PB2	HAX1	psi-mi:“MI:0914”(association)	0.350
PB2	ESYT2	psi-mi:“MI:0914”(association)	0.350
NS1	HAX1	psi-mi:“MI:0914”(association)	0.350
NS1	ESYT2	psi-mi:“MI:0914”(association)	0.350
PB1	ESYT2	psi-mi:“MI:0914”(association)	0.350
PB2	PIK3R2	psi-mi:“MI:0914”(association)	0.350
PB2	SEC16A	psi-mi:“MI:0914”(association)	0.350
PB2	CDIPT	psi-mi:“MI:0914”(association)	0.350
PB1		psi-mi:“MI:0914”(association)	0.350

BioGRID (115): RBFOX1 (Two-hybrid), C1orf94 (Two-hybrid), RBFOX1 (Affinity Capture-MS), RBFOX1 (Affinity Capture-MS), RBFOX1 (Affinity Capture-MS), RBFOX1 (Affinity Capture-MS), RBFOX1 (Affinity Capture-MS), RNF25 (Affinity Capture-MS), MKRN1 (Affinity Capture-MS), PRMT5 (Affinity Capture-MS), COPRS (Affinity Capture-MS), SDR9C7 (Affinity Capture-MS), CAPNS2 (Affinity Capture-MS), RIOK1 (Affinity Capture-MS), IMPA2 (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

1 interactions.

A	Effect	B	Mechanism
MECP2	“down-regulates quantity by repression”	RBFOX1	“transcriptional regulation”

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — PRAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	14
Uncertain significance	348
Likely benign	211
Benign	20

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
146927	GRCh38/hg38 16p13.3(chr16:6786909-6996218)x1	Pathogenic
57015	GRCh38/hg38 16p13.3(chr16:6735606-6996218)x1	Pathogenic
59460	GRCh38/hg38 16p13.3(chr16:6245158-6327302)x1	Pathogenic
59461	GRCh38/hg38 16p13.3(chr16:6305477-6373270)x1	Pathogenic
1013115	GRCh37/hg19 16p13.3(chr16:7354384-7383089)x3	Likely pathogenic
1176675	GRCh37/hg19 16p13.3(chr16:7354384-7383089)x1	Likely pathogenic
2580160	NM_018723.4(RBFOX1):c.1189T>G (p.Tyr397Asp)	Likely pathogenic
3152109	NM_018723.4(RBFOX1):c.548G>T (p.Gly183Val)	Likely pathogenic
420861	NM_145893.3(RBFOX1):c.79C>G (p.Leu27Val)	Likely pathogenic
495280	NC_000016.10:g.(?6316970)(6317082_?)del	Likely pathogenic
495281	NC_000016.10:g.(?6654578)(6654675_?)del	Likely pathogenic
545206	NC_000016.10:g.(?6355716)(6937802_?)del	Likely pathogenic
545207	NC_000016.10:g.(?6360351)(6582207_?)del	Likely pathogenic
545208	NC_000016.10:g.(?6622570)(6720408_?)del	Likely pathogenic
545210	NC_000016.10:g.(?6759006)(6789572_?)del	Likely pathogenic
545211	NC_000016.10:g.(?6773909)(6978067_?)del	Likely pathogenic
545212	NC_000016.10:g.(?7029167)(7099643_?)del	Likely pathogenic
997088	GRCh37/hg19 16p13.3(chr16:6042083-6237086)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2570 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:7579857:G:C	K117N	1.000
16:7579857:G:T	K117N	1.000
16:7579858:C:G	R118G	1.000
16:7579862:T:A	L119Q	1.000
16:7579862:T:C	L119P	1.000
16:7579862:T:G	L119R	1.000
16:7579864:C:A	H120N	1.000
16:7579864:C:G	H120D	1.000
16:7579865:A:G	H120R	1.000
16:7579866:T:A	H120Q	1.000
16:7579866:T:G	H120Q	1.000
16:7579868:T:A	V121D	1.000
16:7579870:T:C	S122P	1.000
16:7579871:C:A	S122Y	1.000
16:7579871:C:T	S122F	1.000
16:7579873:A:G	N123D	1.000
16:7579874:A:T	N123I	1.000
16:7579875:T:A	N123K	1.000
16:7579875:T:G	N123K	1.000
16:7579877:T:A	I124N	1.000
16:7579877:T:C	I124T	1.000
16:7579877:T:G	I124S	1.000
16:7579879:C:A	P125T	1.000
16:7579880:C:A	P125H	1.000
16:7579880:C:G	P125R	1.000
16:7579882:T:A	F126I	1.000
16:7579882:T:C	F126L	1.000
16:7579882:T:G	F126V	1.000
16:7579883:T:C	F126S	1.000
16:7579883:T:G	F126C	1.000

dbSNP variants (sampled 300 via entrez): RS1000000925 (16:5746579 T>A), RS1000001573 (16:6732069 C>G,T), RS1000001954 (16:5435809 C>G,T), RS1000003427 (16:5260330 C>G,T), RS1000004394 (16:5868487 T>A,C), RS1000004556 (16:5553111 A>G), RS1000004805 (16:7428761 T>C), RS1000005105 (16:6829888 C>G,T), RS1000005786 (16:5575844 C>G), RS1000007032 (16:7098243 C>G,T), RS1000007711 (16:7583136 C>A,G,T), RS1000008822 (16:7625968 G>A), RS1000009380 (16:6071760 C>T), RS1000009627 (16:7155504 G>C), RS1000010090 (16:6853182 G>A,C,T)

Disease associations

OMIM: gene MIM:605104 | disease phenotypes: MIM:600669, MIM:117100, MIM:181500, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant
epilepsy	Limited	Autosomal dominant
autism susceptibility 1	Limited	Unknown

Mondo (11): idiopathic generalized epilepsy (MONDO:0005579), autism spectrum disorder (MONDO:0005258), intellectual disability (MONDO:0001071), self-limited epilepsy with centrotemporal spikes (MONDO:0007295), undetermined early-onset epileptic encephalopathy (MONDO:0018614), schizophrenia (MONDO:0005090), autism (MONDO:0005260), hearing loss disorder (MONDO:0005365), epilepsy (MONDO:0005027), (MONDO:0020643), neurodevelopmental disorder (MONDO:0700092)

Orphanet (5): Self-limited epilepsy with centrotemporal spikes (Orphanet:1945), Non-specific early-onset epileptic encephalopathy (Orphanet:442835), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0100753	Schizophrenia
HP:0000717	Autism

GWAS associations

100 associations (top):

Study	Trait	p-value
GCST000245_15	Conduct disorder (maternal expressed emotions interaction)	3.000000e-06
GCST000253_16	Attention deficit hyperactivity disorder and conduct disorder	9.000000e-06
GCST000274_10	Metabolite levels	5.000000e-07
GCST000514_16	Response to antipsychotic therapy (extrapyramidal side effects)	2.000000e-06
GCST001017_9	Diabetic retinopathy	6.000000e-07
GCST001356_12	Gout	1.000000e-07
GCST001523_26	Visceral adipose tissue adjusted for BMI	2.000000e-07
GCST001762_176	Obesity-related traits	9.000000e-06
GCST001762_379	Obesity-related traits	2.000000e-06
GCST001762_546	Obesity-related traits	2.000000e-06
GCST001858_25	Refractive error	6.000000e-10
GCST001898_1	Refractive error	4.000000e-09
GCST001969_22	Heart rate	2.000000e-07
GCST002136_11	Periodontitis (PAL4Q3)	5.000000e-06
GCST002168_8	Intraocular pressure	4.000000e-06
GCST002358_1	Pit-and-Fissure caries	2.000000e-06
GCST002529_1	Glaucoma	1.000000e-08
GCST002529_8	Glaucoma	4.000000e-08
GCST002550_21	Allergic rhinitis	5.000000e-07
GCST002615_4	Myopia	2.000000e-06
GCST002617_5	Hyperopia	5.000000e-07
GCST002783_216	Body mass index	3.000000e-06
GCST002928_19	Nickel levels	3.000000e-06
GCST003075_56	Cognitive decline rate in late mild cognitive impairment	2.000000e-09
GCST003075_83	Cognitive decline rate in late mild cognitive impairment	5.000000e-09
GCST003455_13	Spherical equivalent (joint analysis main effects and education interaction)	3.000000e-09
GCST003455_36	Spherical equivalent (joint analysis main effects and education interaction)	3.000000e-08
GCST003992_36	Photic sneeze reflex	3.000000e-21
GCST003997_50	Myopia	2.000000e-63
GCST004015_5	Extraversion	2.000000e-06

EFO canonical traits (40, from GWAS)

EFO ID	Trait name
EFO:0008342	parental emotion expression measurmement
EFO:0004340	body mass index
EFO:0005106	body composition measurement
EFO:0004338	body weight
EFO:0004695	intraocular pressure measurement
EFO:0007710	cognitive decline measurement
EFO:0004784	self reported educational attainment
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome
EFO:0004317	extraversion
EFO:0007660	neuroticism measurement
EFO:0004337	intelligence
EFO:0005128	albumin:globulin ratio measurement
EFO:0000482	event free survival time
EFO:0004866	autoantibody measurement
EFO:0004847	age at onset
EFO:0006335	systolic blood pressure
EFO:0009589	worry measurement
EFO:0007620	volumetric bone mineral density
EFO:0008579	risk-taking behaviour
EFO:0007876	insomnia measurement
EFO:0008328	chronotype measurement
EFO:0009603	stroke outcome severity measurement
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0010093	bitter non-alcoholic beverage consumption measurement
EFO:0010130	health study participation
EFO:0006797	neurofibrillary tangles measurement
EFO:0010221	systemising measurement
EFO:1001243	wheat allergic reaction
EFO:0008320	white matter volume measurement
EFO:0010118	sphingomyelin measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D004827	Epilepsy	C10.228.140.490
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C562694	Epilepsy, Idiopathic Generalized (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs6500843	Efficacy	3	antineoplastic agents	Breast Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6500843	RBFOX1	3	1.75	1	antineoplastic agents

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
trichostatin A	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	decreases methylation, affects response to substance	2
bisphenol A	decreases methylation	1
sodium arsenite	affects methylation	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Poly(amidoamine)	decreases expression	1
incobotulinumtoxinA	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cadmium	decreases expression, increases abundance	1
Copper	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases methylation	1
Tretinoin	decreases expression	1
Asbestos, Serpentine	increases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	PHASE4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	PHASE4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy