RBFOX3

Summary

RBFOX3 (RNA binding fox-1 homolog 3, HGNC:27097) is a protein-coding gene on chromosome 17q25.3, encoding RNA binding protein fox-1 homolog 3 (A6NFN3). Pre-mRNA alternative splicing regulator.

This gene encodes a member of the RNA-binding FOX protein family which is involved in the regulation of alternative splicing of pre-mRNA. The protein has an N-terminal proline-rich region, an RNA recognition motif (RRM) domain, and a C-terminal alanine-rich region. This gene produces the neuronal nuclei (NeuN) antigen that has been widely used as a marker for post-mitotic neurons. This gene has its highest expression in the central nervous system and plays a prominent role in neural tissue development and regulation of adult brain function. Mutations in this gene have been associated with numerous neurological disorders. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 146713 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 12
• Clinical variants (ClinVar): 341 total — 1 pathogenic
• MANE Select transcript: NM_001350451

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27097
Approved symbol	RBFOX3
Name	RNA binding fox-1 homolog 3
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	FOX-3, NeuN, HRNBP3
Ensembl gene	ENSG00000167281
Ensembl biotype	protein_coding
OMIM	616999
Entrez	146713

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 35 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000578887, ENST00000578998, ENST00000580155, ENST00000580508, ENST00000581393, ENST00000582043, ENST00000582139, ENST00000582344, ENST00000582880, ENST00000582894, ENST00000583458, ENST00000584778, ENST00000648001, ENST00000693108, ENST00000857744, ENST00000857745, ENST00000857746, ENST00000857747, ENST00000857748, ENST00000857749, ENST00000857750, ENST00000857751, ENST00000857752, ENST00000857753, ENST00000857754, ENST00000857755, ENST00000857756, ENST00000857757, ENST00000857758, ENST00000917331, ENST00000917333, ENST00000954784, ENST00000954785, ENST00000954786, ENST00000954787, ENST00000954788, ENST00000954789, ENST00000954790, ENST00000954791

RefSeq mRNA: 47 — MANE Select: NM_001350451 NM_001082575, NM_001350451, NM_001350453, NM_001385804, NM_001385805, NM_001385806, NM_001385807, NM_001385808, NM_001385809, NM_001385810, NM_001385811, NM_001385812, NM_001385813, NM_001385814, NM_001385815, NM_001385816, NM_001385817, NM_001385818, NM_001385819, NM_001385820, NM_001385821, NM_001385822, NM_001385823, NM_001385824, NM_001385825, NM_001385826, NM_001385827, NM_001385828, NM_001385829, NM_001385830, NM_001385831, NM_001385832, NM_001385833, NM_001385834, NM_001385835, NM_001385836, NM_001385837, NM_001385838, NM_001385839, NM_001385840, NM_001385841, NM_001385842, NM_001385843, NM_001385844, NM_001385845, NM_001385846, NM_001385847

CCDS: CCDS45805, CCDS92408, CCDS92409, CCDS92410

Canonical transcript exons

ENST00000693108 — 15 exons

Exon	Start	End
ENSE00001193327	79103162	79103254
ENSE00001193353	79104073	79104126
ENSE00001331989	79101584	79101644
ENSE00001529235	79115494	79115748
ENSE00001529237	79235766	79235805
ENSE00001529239	79482454	79482598
ENSE00001645179	79097692	79097745
ENSE00001783045	79307724	79307824
ENSE00001803126	79106651	79106788
ENSE00002703054	79089345	79090885
ENSE00002723678	79096653	79096833
ENSE00003608062	79094451	79094529
ENSE00003613944	79095513	79095574
ENSE00003615536	79097292	79097424
ENSE00003929945	79610826	79611051

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 99.39.

FANTOM5 (CAGE): breadth broad, TPM avg 7.8253 / max 1066.2571, expressed in 256 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
208428	4.3487	151
208429	1.3640	120
208431	0.9455	113
208430	0.3755	77
168547	0.2778	85
208427	0.2616	74
168546	0.1661	83
168545	0.0594	26
168548	0.0266	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.39	gold quality
cerebellar cortex	UBERON:0002129	99.35	gold quality
cerebellar hemisphere	UBERON:0002245	99.35	gold quality
cerebellum	UBERON:0002037	99.24	gold quality
cerebellar vermis	UBERON:0004720	99.11	gold quality
right frontal lobe	UBERON:0002810	97.28	gold quality
postcentral gyrus	UBERON:0002581	96.94	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.54	gold quality
superior frontal gyrus	UBERON:0002661	96.41	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.28	gold quality
frontal cortex	UBERON:0001870	96.19	gold quality
parietal lobe	UBERON:0001872	96.11	gold quality
prefrontal cortex	UBERON:0000451	95.92	gold quality
primary visual cortex	UBERON:0002436	95.75	gold quality
neocortex	UBERON:0001950	95.45	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.87	gold quality
anterior cingulate cortex	UBERON:0009835	94.78	gold quality
entorhinal cortex	UBERON:0002728	94.73	gold quality
cerebral cortex	UBERON:0000956	94.55	gold quality
occipital lobe	UBERON:0002021	94.21	gold quality
temporal lobe	UBERON:0001871	93.02	gold quality
middle temporal gyrus	UBERON:0002771	92.84	gold quality
putamen	UBERON:0001874	92.69	gold quality
amygdala	UBERON:0001876	92.42	gold quality
Brodmann (1909) area 46	UBERON:0006483	92.35	gold quality
nucleus accumbens	UBERON:0001882	92.09	gold quality
caudate nucleus	UBERON:0001873	92.04	gold quality
cortical plate	UBERON:0005343	91.90	gold quality
Ammon’s horn	UBERON:0001954	91.49	gold quality
Brodmann (1909) area 23	UBERON:0013554	91.29	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	3041.53
E-HCAD-25	yes	78.82
E-HCAD-35	yes	58.98
E-HCAD-30	no	433.06
E-MTAB-7303	no	42.45
E-ANND-3	no	5.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MSC, NFIA, NFIB, NFIX, NPAS4, TAL1

miRNA regulators (miRDB)

72 targeting RBFOX3, 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-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-1252-5P	100.00	69.80	2774
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-128-1-5P	99.33	60.46	332
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-4505	99.27	67.81	2678

Literature-anchored findings (GeneRIF, showing 17)

• NeuN (neuronal nuclei) is a neuron-specific nuclear protein identified by anti-NeuN antibody, and widely used as the postmitotic neuron marker. NeuN is identified as the Fox-3 gene product by mass spectrometry, immunoblotting, RNAi, and immunostaining. (PMID:19713214)
• High NeuN levels are associated with supratentorial ependymomas. (PMID:23371454)
• In addition, eight genes classified as ‘second tier’ hits in the original study (PAX7, THADA, COL8A1/FILIP1L, DCAF4L2, GADD45G, NTN1, RBFOX3 and FOXE1) showed evidence of linkage and association in this replication sample. (PMID:23512105)
• NeuN immunocytochemical reaction in neurons of human substantia nigra was expressed much weaker than in the nucleus rubrum neurons located in the same sections. (PMID:23898728)
• 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)
• RNA splicing occurs in the nucleus hence, the altered localization of RbFox3 to the cytoplasm may lead to the downregulation of neuronal gene expression. (PMID:24215932)
• 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)
• NeuN was recently eventually identified as an epitope of Rbfox3. NeuN is highly conserved among species and is stably expressed during specific stages of development. NeuN has been considered to be a reliable marker of mature neurons, however, this role has been challenged by recent studies indicating that NeuN staining is variable and even absent during certain diseases and states. Review. (PMID:25680637)
• SNPs (rs9900428, rs9907432 and rs7211029) in RBFOX3 associate with sleep latency. (PMID:27142678)
• this study show that TGF-beta-induced RBFOX3 inhibition plays an important role in epithelial-mesenchymal transition and lung cancer progression (PMID:27432190)
• In human lung tissue, Claudin-1 is higher in RBFOX3-positive cells than in RBFOX3-negative cells. Immunostaining and mRNA quantification revealed that protein levels, but not mRNA levels, of Claudin-1 are increased by RBFOX3. (PMID:28126724)
• RBFOX3 knockdown synergized with 5-FU to inhibit the growth and invasion of HCC cells through PI3K/AKT and epithelial-mesenchymal transition (EMT) signaling, and promote apoptosis by activating the cytochrome-c/caspase signaling pathway. (PMID:29689552)
• Differential Clinical Features in Colombian Patients With Rolandic Epilepsy and Suggestion of Unlikely Association With GRIN2A, RBFOX1, or RBFOX3 Gene Variants. (PMID:34039076)
• Genetic variants in splicing factor genes and susceptibility to bladder cancer. (PMID:34673209)
• Altered temporal sequence of transcriptional regulators in the generation of human cerebellar granule cells. (PMID:34842137)
• NeuN, a DNA-binding neuron-specific protein expressed by Merkel cell carcinoma: analysis of 15 cases. (PMID:34974547)
• Paclitaxel-induced inhibition of NSCLC invasion and migration via RBFOX3-mediated circIGF1R biogenesis. (PMID:38191906)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rbfox3a	ENSDARG00000010083
danio_rerio	rbfox3b	ENSDARG00000074310
mus_musculus	Rbfox3	ENSMUSG00000025576
rattus_norvegicus	Rbfox3	ENSRNOG00000003386
drosophila_melanogaster	Rbfox1	FBGN0052062
caenorhabditis_elegans		WBGENE00001484

Paralogs (2): RBFOX1 (ENSG00000078328), RBFOX2 (ENSG00000100320)

Protein

Protein identifiers

RNA binding protein fox-1 homolog 3 — A6NFN3 (reviewed: A6NFN3)

Alternative names: Fox-1 homolog C, Neuronal nuclei antigen

All UniProt accessions (8): A0A3B3ITL7, A0A8I5KWJ3, A6NFN3, J3QQZ2, J3QRF4, K7EJX6, K7EQK7, K7ESF7

UniProt curated annotations — full annotation on UniProt →

Function. Pre-mRNA alternative splicing regulator. Regulates alternative splicing of RBFOX2 to enhance the production of mRNA species that are targeted for nonsense-mediated decay (NMD).

Subcellular location. Nucleus. Cytoplasm.

Isoforms (2)

UniProt ID	Names	Canonical?
A6NFN3-1	1	yes
A6NFN3-2	2

RefSeq proteins (47): NP_001076044, NP_001337380, NP_001337382, NP_001372733, NP_001372734, NP_001372735, NP_001372736, NP_001372737, NP_001372738, NP_001372739, NP_001372740, NP_001372741, NP_001372742, NP_001372743, NP_001372744, NP_001372745, NP_001372746, NP_001372747, NP_001372748, NP_001372749, NP_001372750, NP_001372751, NP_001372752, NP_001372753, NP_001372754, NP_001372755, NP_001372756, NP_001372757, NP_001372758, NP_001372759, NP_001372760, NP_001372761, NP_001372762, NP_001372763, NP_001372764, NP_001372765, NP_001372766, NP_001372767, NP_001372768, NP_001372769, NP_001372770, NP_001372771, NP_001372772, NP_001372773, NP_001372774, NP_001372775, NP_001372776 (=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 (17 total): site 8, modified residue 3, compositionally biased region 2, chain 1, domain 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NFN3-F1	62.27	0.26

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): 142 (interaction with rna); 166 (interaction with rna); 176 (interaction with rna); 100 (interaction with rna); 108 (interaction with rna); 109 (interaction with rna); 133 (interaction with rna); 138 (interaction with rna)

Post-translational modifications (3): 223, 223, 272

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9768919	NPAS4 regulates expression of target genes

MSigDB gene sets: 61 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_ALTERNATIVE_MRNA_SPLICING_VIA_SPLICEOSOME, IVANOVA_HEMATOPOIESIS_MATURE_CELL, CHANDRAN_METASTASIS_DN, GOBP_RNA_SPLICING, GOBP_REGULATION_OF_MRNA_SPLICING_VIA_SPLICEOSOME, CUI_TCF21_TARGETS_2_UP, GOBP_REGULATION_OF_RNA_SPLICING, GOMF_MRNA_BINDING, MEISSNER_NPC_HCP_WITH_H3K4ME2_AND_H3K27ME3, MIKKELSEN_MCV6_HCP_WITH_H3K27ME3, MIKKELSEN_NPC_HCP_WITH_H3K27ME3, MIKKELSEN_MEF_HCP_WITH_H3K27ME3, GOBP_REGULATION_OF_MRNA_PROCESSING, GOBP_MRNA_PROCESSING

GO Biological Process (5): regulation of alternative mRNA splicing, via spliceosome (GO:0000381), mRNA processing (GO:0006397), nervous system development (GO:0007399), RNA splicing (GO:0008380), regulation of RNA splicing (GO:0043484)

GO Molecular Function (4): mRNA binding (GO:0003729), nucleic acid binding (GO:0003676), DNA binding (GO:0003677), RNA binding (GO:0003723)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), neuronal cell body (GO:0043025), perikaryon (GO:0043204)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transcriptional Regulation by NPAS4	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
nucleic acid 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
RNA splicing	1
regulation of gene expression	1
regulation of primary metabolic process	1
RNA binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
somatodendritic compartment	1
cell body	1
neuronal cell body	1

Protein interactions and networks

STRING

4380 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RBFOX3	NES	P48681	932
RBFOX3	GFAP	P14136	918
RBFOX3	AIF1	P55008	905
RBFOX3	RBM45	Q8IUH3	892
RBFOX3	DCX	O43602	885
RBFOX3	IQSEC3	Q9UPP2	825
RBFOX3	OLIG2	Q13516	812
RBFOX3	NKAIN1	Q4KMZ8	810
RBFOX3	MAP2	P11137	789
RBFOX3	CALB1	P05937	786
RBFOX3	SYP	P08247	774
RBFOX3	PVALB	P20472	773
RBFOX3	BDNF	P23560	769
RBFOX3	GAD1	Q99259	766
RBFOX3	S100B	P04271	765

IntAct

21 interactions, top by confidence:

A	B	Type	Score
FAM136A	RBFOX3	psi-mi:“MI:0914”(association)	0.640
SLC2A5	RBFOX3	psi-mi:“MI:0914”(association)	0.530
PRKAR1A	RBFOX3	psi-mi:“MI:0914”(association)	0.350
SH3GL3	RBFOX3	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
MSI1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
SIGLECL1	RBFOX3	psi-mi:“MI:0914”(association)	0.350
CLEC4A	RBFOX3	psi-mi:“MI:0914”(association)	0.350
SPDYC	RBFOX3	psi-mi:“MI:0914”(association)	0.350
TCF7	RBFOX3	psi-mi:“MI:0914”(association)	0.350
OR5H1	RBFOX3	psi-mi:“MI:0914”(association)	0.350
LIMK1	RBFOX3	psi-mi:“MI:0914”(association)	0.350
FAM83F	RBFOX3	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
RBM11	RBFOX3	psi-mi:“MI:0915”(physical association)	0.000
RUNX1	RBFOX3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (41): RBFOX3 (Affinity Capture-MS), RBFOX3 (Affinity Capture-MS), RBFOX3 (Affinity Capture-MS), RBFOX3 (Affinity Capture-MS), RBFOX3 (Affinity Capture-MS), RBFOX3 (Affinity Capture-MS), TLR4 (Co-localization), HMGB1 (Co-localization), RBFOX3 (Affinity Capture-MS), RBFOX3 (Affinity Capture-MS), RBFOX2 (Affinity Capture-Western), RBFOX1 (Affinity Capture-Western), RBFOX2 (Reconstituted Complex), RBFOX1 (Reconstituted Complex), RBFOX3 (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

3 interactions.

A	Effect	B	Mechanism
NFIA	“up-regulates quantity”	RBFOX3	“transcriptional regulation”
NFIB	“up-regulates quantity”	RBFOX3	“transcriptional regulation”
NFIX	“up-regulates quantity”	RBFOX3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	150
Likely benign	167
Benign	14

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
433136	NM_001350451.2(RBFOX3):c.1002C>A (p.Tyr334Ter)	Pathogenic

SpliceAI

7914 predictions. Top by Δscore:

Variant	Effect	Δscore
17:79094445:CCTTA:C	donor_loss	1.0000
17:79094446:CTTA:C	donor_loss	1.0000
17:79094447:TTACC:T	donor_loss	1.0000
17:79094448:TAC:T	donor_loss	1.0000
17:79094449:A:AC	donor_gain	1.0000
17:79094449:A:C	donor_loss	1.0000
17:79094450:C:CC	donor_gain	1.0000
17:79094525:CGTAA:C	acceptor_gain	1.0000
17:79094527:TAA:T	acceptor_gain	1.0000
17:79094527:TAAC:T	acceptor_loss	1.0000
17:79094528:AA:A	acceptor_gain	1.0000
17:79094528:AAC:A	acceptor_loss	1.0000
17:79094529:ACTA:A	acceptor_loss	1.0000
17:79094530:C:CC	acceptor_gain	1.0000
17:79094530:CTAGG:C	acceptor_loss	1.0000
17:79094531:T:C	acceptor_loss	1.0000
17:79094541:CG:C	acceptor_gain	1.0000
17:79094542:G:C	acceptor_gain	1.0000
17:79095508:CTCA:C	donor_loss	1.0000
17:79095509:TCA:T	donor_loss	1.0000
17:79095510:CA:C	donor_loss	1.0000
17:79095511:A:AC	donor_gain	1.0000
17:79095511:A:AT	donor_loss	1.0000
17:79095512:C:CC	donor_gain	1.0000
17:79095571:CTCC:C	acceptor_gain	1.0000
17:79095572:TCCC:T	acceptor_loss	1.0000
17:79095573:CC:C	acceptor_gain	1.0000
17:79095574:CC:C	acceptor_gain	1.0000
17:79095574:CCTG:C	acceptor_loss	1.0000
17:79095575:C:CC	acceptor_gain	1.0000

AlphaMissense

2300 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:79101628:G:T	A175D	1.000
17:79101634:G:T	A173D	1.000
17:79101639:A:C	N171K	1.000
17:79101639:A:T	N171K	1.000
17:79101643:A:T	V170D	1.000
17:79103162:C:A	E169D	1.000
17:79103162:C:G	E169D	1.000
17:79103164:C:T	E169K	1.000
17:79103166:A:C	I168S	1.000
17:79103166:A:T	I168N	1.000
17:79103172:C:G	R166P	1.000
17:79103173:G:C	R166G	1.000
17:79103175:C:A	G165V	1.000
17:79103175:C:T	G165E	1.000
17:79103176:C:G	G165R	1.000
17:79103176:C:T	G165R	1.000
17:79103196:A:G	L158P	1.000
17:79103205:C:G	R155P	1.000
17:79103208:G:T	A154D	1.000
17:79103209:C:G	A154P	1.000
17:79103217:G:T	A151D	1.000
17:79103234:A:C	F145L	1.000
17:79103234:A:T	F145L	1.000
17:79103235:A:G	F145S	1.000
17:79103236:A:G	F145L	1.000
17:79103241:A:T	V143E	1.000
17:79103243:A:C	F142L	1.000
17:79103243:A:T	F142L	1.000
17:79103244:A:C	F142C	1.000
17:79103244:A:G	F142S	1.000

dbSNP variants (sampled 300 via entrez): RS1000004102 (17:79415742 A>C,G), RS1000009313 (17:79196650 G>A), RS1000013001 (17:79621214 G>C,T), RS1000017090 (17:79181462 G>A), RS1000017532 (17:79210111 A>G), RS1000017765 (17:79587238 C>T), RS1000018666 (17:79258324 C>T), RS1000024480 (17:79384994 A>T), RS1000029779 (17:79228599 C>A), RS1000029910 (17:79101145 T>C), RS1000037074 (17:79321896 G>T), RS1000038975 (17:79113378 C>A,T), RS1000039919 (17:79389858 A>G), RS1000042802 (17:79385170 G>A), RS1000047913 (17:79099532 C>G)

Disease associations

OMIM: gene MIM:616999 | disease phenotypes: MIM:600669, MIM:189800, MIM:117100

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Moderate	Autosomal dominant
epilepsy	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
epilepsy	Disputed	AD

Mondo (5): idiopathic generalized epilepsy (MONDO:0005579), preeclampsia (MONDO:0005081), self-limited epilepsy with centrotemporal spikes (MONDO:0007295), epilepsy (MONDO:0005027), neurodevelopmental disorder (MONDO:0700092)

Orphanet (2): Preeclampsia (Orphanet:275555), Self-limited epilepsy with centrotemporal spikes (Orphanet:1945)

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002783_19	Body mass index	4.000000e-06
GCST002826_7	Urate levels (BMI interaction)	2.000000e-06
GCST002827_5	Urate levels (BMI interaction)	3.000000e-08
GCST002828_19	Urate levels in obese individuals	4.000000e-07
GCST003481_1	Sleep latency	1.000000e-07
GCST003992_11	Photic sneeze reflex	2.000000e-09
GCST004029_22	Angiotensin-converting enzyme inhibitor intolerance	6.000000e-09
GCST004493_1	Lower body strength	7.000000e-06
GCST008642_4	Annualised percent change of cerebrospinal fluid AB1-42 levels	8.000000e-06
GCST008927_3	Phosphatidylcholine levels	3.000000e-08
GCST011741_45	LDL cholesterol levels in HIV infection	4.000000e-06
GCST011826_9	Computer vision syndrome	9.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004531	urate measurement
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0007999	lower body strength measurement
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D065886	Neurodevelopmental Disorders	F03.625
D011225	Pre-Eclampsia	C12.050.703.395.249
C562694	Epilepsy, Idiopathic Generalized (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2061538	RBFOX3		0.00	0
rs56209714	RBFOX3		0.00	0
rs62063838	RBFOX3		0.00	0
rs56044629	RBFOX3		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	affects cotreatment, increases expression	3
Valproic Acid	increases expression, increases methylation, affects expression	3
sodium arsenite	affects expression, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	affects cotreatment, increases expression	2
belinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation	2
Lead	affects expression, affects methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases methylation	1
bis(2,3,3,3-tetrachloropropyl) ether	affects cotreatment, increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
diethyl phosphate	increases expression, affects cotreatment	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
abrine	decreases expression	1
dorsomorphin	increases expression, affects cotreatment, decreases expression	1
licochalcone B	increases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Aripiprazole	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Alitretinoin	increases expression	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