U2AF2

Summary

U2AF2 (U2 small nuclear RNA auxiliary factor 2, HGNC:23156) is a protein-coding gene on chromosome 19q13.42, encoding Splicing factor U2AF 65 kDa subunit (P26368). Plays a role in pre-mRNA splicing and 3’-end processing. It is a common-essential gene (DepMap: required in 99.4% of cancer cell lines).

U2 auxiliary factor (U2AF), comprised of a large and a small subunit, is a non-snRNP protein required for the binding of U2 snRNP to the pre-mRNA branch site. This gene encodes the U2AF large subunit which contains a sequence-specific RNA-binding region with 3 RNA recognition motifs and an Arg/Ser-rich domain necessary for splicing. The large subunit binds to the polypyrimidine tract of introns early during spliceosome assembly. Multiple transcript variants have been detected for this gene, but the full-length natures of only two have been determined to date.

Source: NCBI Gene 11338 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental delay, dysmorphic facies, and brain anomalies (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 97 total — 5 pathogenic, 6 likely-pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Cancer dependency (DepMap): dependent in 99.4% of screened cell lines (common-essential)
• MANE Select transcript: NM_007279

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23156
Approved symbol	U2AF2
Name	U2 small nuclear RNA auxiliary factor 2
Location	19q13.42
Locus type	gene with protein product
Status	Approved
Aliases	U2AF65
Ensembl gene	ENSG00000063244
Ensembl biotype	protein_coding
OMIM	191318
Entrez	11338

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 10 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000308924, ENST00000450554, ENST00000587196, ENST00000587275, ENST00000588850, ENST00000592867, ENST00000592874, ENST00000890134, ENST00000890135, ENST00000890136, ENST00000890137, ENST00000890138, ENST00000890139, ENST00000913861, ENST00000913862

RefSeq mRNA: 2 — MANE Select: NM_007279 NM_001012478, NM_007279

CCDS: CCDS12933, CCDS46197

Canonical transcript exons

ENST00000308924 — 12 exons

Exon	Start	End
ENSE00001172923	55669083	55669181
ENSE00001172954	55662502	55662618
ENSE00001178717	55669444	55669692
ENSE00001178763	55668670	55668792
ENSE00002748119	55655035	55655153
ENSE00002748418	55673934	55674716
ENSE00003502130	55668507	55668586
ENSE00003536533	55659210	55659345
ENSE00003631183	55661038	55661189
ENSE00003652336	55660177	55660221
ENSE00003668399	55660516	55660619
ENSE00003683702	55663606	55663744

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 98.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 128.4156 / max 559.5577, expressed in 1827 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177673	99.2344	1827
177669	22.8665	1804
177671	2.8741	1468
177670	1.3918	902
177678	0.7664	244
177672	0.5457	304
177680	0.3450	182
177675	0.3340	146
177679	0.0577	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	98.72	gold quality
endocervix	UBERON:0000458	98.64	gold quality
granulocyte	CL:0000094	98.63	gold quality
adenohypophysis	UBERON:0002196	98.62	gold quality
right ovary	UBERON:0002118	98.53	gold quality
body of uterus	UBERON:0009853	98.52	gold quality
right lobe of thyroid gland	UBERON:0001119	98.51	gold quality
left ovary	UBERON:0002119	98.49	gold quality
left lobe of thyroid gland	UBERON:0001120	98.38	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.37	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.37	gold quality
left uterine tube	UBERON:0001303	98.33	gold quality
right testis	UBERON:0004534	98.29	gold quality
metanephros cortex	UBERON:0010533	98.29	gold quality
ectocervix	UBERON:0012249	98.26	gold quality
body of stomach	UBERON:0001161	98.21	gold quality
transverse colon	UBERON:0001157	98.19	gold quality
left testis	UBERON:0004533	98.16	gold quality
ganglionic eminence	UBERON:0004023	98.13	gold quality
right adrenal gland	UBERON:0001233	98.12	gold quality
ventricular zone	UBERON:0003053	98.12	gold quality
lower esophagus	UBERON:0013473	98.12	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.12	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.12	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.10	gold quality
right adrenal gland cortex	UBERON:0035827	98.10	gold quality
right coronary artery	UBERON:0001625	98.08	gold quality
mucosa of transverse colon	UBERON:0004991	98.07	gold quality
cerebellar hemisphere	UBERON:0002245	98.04	gold quality
spleen	UBERON:0002106	98.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.55

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SF1, WT1

miRNA regulators (miRDB)

27 targeting U2AF2, 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-6748-5P	100.00	65.81	1057
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-4738-3P	98.98	67.98	1846
HSA-MIR-6871-5P	98.90	66.67	671
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-3187-3P	97.38	65.80	904
HSA-MIR-4288	97.11	67.23	1636
HSA-MIR-2276-5P	96.27	65.85	937

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• U2AF 65 promotes 3’-end processing, which contributes to 3’-terminal exon definition in RNA splicing (PMID:12189174)
• U2AF35 RRM is unstructured in solution but its tertiary structure is induced upon binding to U2AF65. (PMID:12297299)
• U2AF65 modulates the function of the PLE (poly(A)-limiting element) (PMID:14576315)
• two members of the U2AF65 family of proteins, hCC1.3, which we call CAPERalpha, and a related protein, CAPERbeta, regulate both steroid hormone receptor-mediated transcription and alternative splicing (PMID:15694343)
• identified and spatially localized sites of direct interaction between U2AF35 and U2AF65 in vivo in live cell nuclei. (PMID:16043505)
• Multiple U2AF65 binding sites within SF3b155 regulate conformational rearrangements during spliceosome assembly. (PMID:16376933)
• Cocrystals of a U2AF65 variant with a deoxyuridine dodecamer diffract X-rays to 2.9 angstroms resolution and contain one complex per asymmetric unit. (PMID:16682775)
• DEK enforces 3’ splice site discrimination by U2AF; DEK phosphorylated at serines 19 and 32 associates with U2AF35, facilitates the U2AF35-AG interaction and prevents binding of U2AF65 to pyrimidine tracts not followed by AG (PMID:16809543)
• Results describe the roles of the two subunits of U2AF, U2AF65 and 35, in the selection between alternative 3’ splice sites associated with polypyrimidine tracts of different strengths. (PMID:16940179)
• a direct role of the U2AF 65/CF I(m) 59 interaction in the functional coordination of splicing and 3’ end processing. (PMID:17024186)
• U2AF65 associates with specific subsets of spliced mRNAs, strongly suggesting that it is involved in novel cellular functions in addition to splicing. (PMID:17137510)
• This rare, high-resolution view of an important member of the RNA recognition motifs class of RNA-binding domains highlights the role of alternative side-chain conformations in RNA recognition. (PMID:17188295)
• SF1 and U2AF form extraspliceosomal complexes before and after taking part in the assembly of catalytic spliceosomes. (PMID:18285458)
• there is a functional link among apoptosis induction, U2AF65 cleavage, and the regulation of Fas alternative splicing (PMID:18508922)
• Solution conformation and thermodynamic characteristics of RNA binding by the splicing factor U2AF65. (PMID:18842594)
• Puf60-UHM binds to ULM sequences in the splicing factors SF1, U2AF65, and SF3b155. (PMID:18974054)
• Collectively, the results suggest that both U2AF binding and other steps of U2 snRNP recruitment can be control points in SMN splicing regulation. (PMID:19244360)
• study reveals the splicing factor U2AF65 undergoes posttranslational lysyl-5-hydroxylation catalyzed by Jmjd6 (PMID:19574390)
• the conformational changes that are induced by assembly of the SF1/U2AF(65)/RNA complex serve to position the pre-mRNA splice site optimally for subsequent stages of splicing. (PMID:21146534)
• U2AF65 binds directly to the phosphorylated C-terminal domain, and that this interaction results in increased recruitment of U2AF65 and PRP19C to the pre-mRNA (PMID:21536736)
• The U2AF65 protein served as an adaptor to link expanded CAG RNA to NXF1 for RNA export. (PMID:21725067)
• the molecular mechanisms of the recognition of the 3’-splice-site-associated polypyrimidine tract RNA by the large subunit of the human U2 snRNP auxiliary factor (U2AF65) as a key early step in pre-mRNA splicing (PMID:21753750)
• dephosphorylation of pS776-ATXN1 by PP2A regulates the interaction of ATXN1 with the splicing factors RBM17 and U2AF65 (PMID:21835928)
• hnRNP A1 forms a ternary complex with the U2AF heterodimer on AG-containing/uridine-rich RNAs, while it displaces U2AF from non-AG-containing/uridine-rich RNAs, an activity that requires the glycine-rich domain of hnRNP A1 (PMID:22325350)
• These complementary structural methods demonstrate that diverse splice sites have the opportunity to select compact or extended inter-RRM proximities from the U2AF65 conformational pool (PMID:22702716)
• The REST N exon is a very versatile sequence with a complex array of splicing signals, and its activation in H69 cells depends on the relative amounts of hnRNP H and U2AF65. (PMID:22792276)
• RBM5 promotes exon 4 skipping of AID pre-mRNA by competing with the binding of U2AF65 to the polypyrimidine tract. (PMID:23017209)
• The conserved SPSP motif phosphorylation and the SF1/U2AF interface are essential in vivo. (PMID:23273425)
• By preventing U2AF65 binding to Alu elements, hnRNP C plays a critical role as a genome-wide sentinel protecting the transcriptome. (PMID:23374342)
• The results highlight both local and global conformational selection as a means for universal 3’ splice site recognition by U2AF65. (PMID:23376934)
• U2AF65 represents a new route for modulating TRF1 function at telomeres. (PMID:24389012)
• The spatial distribution of U2AF65 conformations is found to be highly anisotropic, comprising significantly populated interdomain contacts that appear to be electrostatic in origin. (PMID:24734879)
• U2AF has the capacity to directly define ~88% of functional 3’ splice sites in the human genome; numerous U2AF binding events also occur in intronic locations. (PMID:25326705)
• reduced U2AF(65) binding is a molecular consequence of disease-relevant mutations, and a structure-guided U2AF(65) variant is capable of manipulating gene expression in eukaryotic cells (PMID:25422459)
• We demonstrated that PRPF40B interacts directly with SF1 and associates with U2AF(65 (PMID:25605964)
• U2AF(65) possesses a splicing Inhibitory function that leads to alternative exon skipping. (PMID:26216990)
• Nuclear retention of full-length HTT RNA is mediated by splicing factors MBNL1 and U2AF65 (PMID:26218986)
• Serum RNU2-1f may serve as a biomarker for lung cancer detection, prognosis prediction and treatment monitoring. (PMID:26687686)
• The U2AF(65) linker residues between the dual RNA recognition motifs (RRMs) recognize the central nucleotide, whereas the N- and C-terminal RRM extensions recognize the 3’ terminus and third nucleotide. (PMID:26952537)
• These findings uncovered a hitherto unappreciated function of CD82 in severing the linkage between U2AF2-mediated CD44 alternative splicing and cancer aggressiveness, with potential prognostic and therapeutic implications in melanoma (PMID:27041584)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	u2af2b	ENSDARG00000011740
danio_rerio	u2af2a	ENSDARG00000012505
mus_musculus	U2af2	ENSMUSG00000030435
rattus_norvegicus	U2af2	ENSRNOG00000015914
drosophila_melanogaster	U2af50	FBGN0005411
drosophila_melanogaster	LS2	FBGN0034834
caenorhabditis_elegans		WBGENE00006697

Paralogs (5): CSTF2 (ENSG00000101811), RBMX2 (ENSG00000134597), ZCRB1 (ENSG00000139168), UHMK1 (ENSG00000152332), CSTF2T (ENSG00000177613)

Protein

Protein identifiers

Splicing factor U2AF 65 kDa subunit — P26368 (reviewed: P26368)

Alternative names: U2 auxiliary factor 65 kDa subunit, U2 snRNP auxiliary factor large subunit

All UniProt accessions (3): P26368, K7ELP8, M0QYQ9

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in pre-mRNA splicing and 3’-end processing. By recruiting PRPF19 and the PRP19C/Prp19 complex/NTC/Nineteen complex to the RNA polymerase II C-terminal domain (CTD), and thereby pre-mRNA, may couple transcription to splicing. Induces cardiac troponin-T (TNNT2) pre-mRNA exon inclusion in muscle. Regulates the TNNT2 exon 5 inclusion through competition with MBNL1. Binds preferentially to a single-stranded structure within the polypyrimidine tract of TNNT2 intron 4 during spliceosome assembly. Required for the export of mRNA out of the nucleus, even if the mRNA is encoded by an intron-less gene. Represses the splicing of MAPT/Tau exon 10. Positively regulates pre-mRNA 3’-end processing by recruiting the CFIm complex to cleavage and polyadenylation signals.

Subunit / interactions. Interacts with U2AF1L4. Heterodimer with U2AF1. Binds unphosphorylated SF1. Interacts with SCAF11 and SNW1. Interacts with ZRSR2/U2AF1-RS2. Interacts with RBM17. Interacts with PRPF19; the interaction is direct. Interacts with POLR2A (via the C-terminal domain); recruits PRPF19 and the Prp19 complex to the pre-mRNA. Interacts with KHDC4 (Isoform 2). Interacts with ZRSR2. Interacts with the SF3B complex composed of SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6 and PHF5A. Interacts (via N-terminus) with CPSF7 (via C-terminus); this interaction stimulates pre-mRNA 3’-end processing by promoting the recruitment of the CFIm complex to cleavage and polyadenylation signals. Interacts with ARGLU1; interaction may be involved in ARGLU1-mediated modulation of alternative splicing.

Subcellular location. Nucleus.

Post-translational modifications. Lysyl-hydroxylation at Lys-15 and Lys-276 affects the mRNA splicing activity of the protein, leading to regulate some, but not all, alternative splicing events.

Disease relevance. Developmental delay, dysmorphic facies, and brain anomalies (DEVDFB) [MIM:620535] An autosomal dominant disorder characterized by global developmental delay with intellectual disability and speech delay, epilepsy, hypotonia, short stature, microcephaly, intermittent exotropia, and non-specific facial dysmorphism. Brain imaging shows a thin corpus callosum and/or delayed myelination. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the splicing factor SR family.

Isoforms (2)

UniProt ID	Names	Canonical?
P26368-1	1	yes
P26368-2	2

RefSeq proteins (2): NP_001012496, NP_009210* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR006529	U2AF_lg	Family
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR035979	RBD_domain_sf	Homologous_superfamily

Pfam: PF00076

UniProt features (71 total): strand 21, helix 12, mutagenesis site 10, modified residue 7, turn 5, compositionally biased region 4, domain 3, region of interest 3, cross-link 2, initiator methionine 1, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

40 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5W0G	X-RAY DIFFRACTION	1.07
5W0H	X-RAY DIFFRACTION	1.11
6XLV	X-RAY DIFFRACTION	1.4
9C7A	X-RAY DIFFRACTION	1.4
9C7B	X-RAY DIFFRACTION	1.4
2HZC	X-RAY DIFFRACTION	1.47
7S3A	X-RAY DIFFRACTION	1.48
5EV3	X-RAY DIFFRACTION	1.5
6XLW	X-RAY DIFFRACTION	1.5
7S3C	X-RAY DIFFRACTION	1.51
5EV4	X-RAY DIFFRACTION	1.57
6XLX	X-RAY DIFFRACTION	1.7
7SN6	X-RAY DIFFRACTION	1.8
5EV2	X-RAY DIFFRACTION	1.86
7S3B	X-RAY DIFFRACTION	1.89
3VAJ	X-RAY DIFFRACTION	1.9
4TU8	X-RAY DIFFRACTION	1.92
4TU9	X-RAY DIFFRACTION	1.99
5EV1	X-RAY DIFFRACTION	2.04
4TU7	X-RAY DIFFRACTION	2.09
3VAK	X-RAY DIFFRACTION	2.17
3VAG	X-RAY DIFFRACTION	2.19
1JMT	X-RAY DIFFRACTION	2.2
3VAI	X-RAY DIFFRACTION	2.2
4FXW	X-RAY DIFFRACTION	2.29
3VAM	X-RAY DIFFRACTION	2.4
3VAF	X-RAY DIFFRACTION	2.49
2G4B	X-RAY DIFFRACTION	2.5
3VAH	X-RAY DIFFRACTION	2.5
3VAL	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P26368-F1	73.24	0.31

Functional residue map

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

Post-translational modifications (9): 2, 2, 15, 70, 79, 276, 294, 15, 70

Mutagenesis-validated functional residues (10):

Position	Phenotype
92	decreases affinity for uaf1 by 3 orders of magnitude.
96	decreases affinity for uaf1 by 2 orders of magnitude.
104	decreases affinity for uaf1 by 2 orders of magnitude.
387–388	reduces interaction with sf1.
391–394	reduces interaction with sf1.
396–397	no effect.
396–397	reduces interaction with sf1.
454	reduces interaction with sf1.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-159236	Transport of Mature mRNA derived from an Intron-Containing Transcript
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-72187	mRNA 3’-end processing
R-HSA-9629569	Protein hydroxylation
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-73856	RNA Polymerase II Transcription Termination

MSigDB gene sets: 234 (showing top): TGCGCANK_UNKNOWN, GOBP_POSITIVE_REGULATION_OF_RNA_SPLICING, PAL_PRMT5_TARGETS_UP, GOBP_NEGATIVE_REGULATION_OF_RNA_SPLICING, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, CHX10_01, MYCMAX_01, GGAANCGGAANY_UNKNOWN, BLALOCK_ALZHEIMERS_DISEASE_UP, REACTOME_MRNA_3_END_PROCESSING, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, USF_01, GOBP_PROTEIN_RNA_COMPLEX_ORGANIZATION, GOBP_RNA_SPLICING, HOSHIDA_LIVER_CANCER_LATE_RECURRENCE_DN

GO Biological Process (7): spliceosomal complex assembly (GO:0000245), mRNA splicing, via spliceosome (GO:0000398), mRNA processing (GO:0006397), negative regulation of protein ubiquitination (GO:0031397), positive regulation of RNA splicing (GO:0033120), negative regulation of mRNA splicing, via spliceosome (GO:0048025), RNA splicing (GO:0008380)

GO Molecular Function (8): RNA binding (GO:0003723), poly-pyrimidine tract binding (GO:0008187), enzyme binding (GO:0019899), pre-mRNA 3’-splice site binding (GO:0030628), C2H2 zinc finger domain binding (GO:0070742), molecular function inhibitor activity (GO:0140678), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (8): commitment complex (GO:0000243), nucleus (GO:0005634), nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), nuclear speck (GO:0016607), U2-type prespliceosome (GO:0071004), U2AF complex (GO:0089701), Prp19 complex (GO:0000974)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Transport of Mature Transcript to Cytoplasm	1
mRNA Splicing	1
Processing of Capped Intron-Containing Pre-mRNA	1
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1
mRNA 3’-end processing	1
Dengue Virus Infection	1
RNA Polymerase II Transcription	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mRNA splicing, via spliceosome	2
RNA processing	2
binding	2
U2-type spliceosomal complex	2
U1 snRNP	2
nuclear protein-containing complex	2
protein-RNA complex assembly	1
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
mRNA metabolic process	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
RNA splicing	1
positive regulation of gene expression	1
regulation of RNA splicing	1
negative regulation of RNA splicing	1
regulation of mRNA splicing, via spliceosome	1
negative regulation of mRNA processing	1
nucleic acid binding	1
single-stranded RNA binding	1
protein binding	1
pre-mRNA binding	1
protein domain specific binding	1
molecular function regulator activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
ribonucleoprotein complex	1
nuclear ribonucleoprotein granule	1
U2 snRNP	1
prespliceosome	1
protein-containing complex	1

Protein interactions and networks

STRING

3490 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
U2AF2	U2AF1	Q01081	999
U2AF2	SF1	Q15637	993
U2AF2	SF3B1	O75533	980
U2AF2	JMJD6	Q6NYC1	975
U2AF2	DDX39B	Q13838	974
U2AF2	SRSF2	Q01130	973
U2AF2	CPSF6	Q16630	970
U2AF2	ZRSR2	Q15696	969
U2AF2	SRSF1	Q07955	942
U2AF2	CPSF7	Q8N684	939
U2AF2	SNRPA	P09012	933
U2AF2	PAPOLG	Q9BWT3	920
U2AF2	PAPOLA	P51003	873
U2AF2	PAPOLB	Q9NRJ5	869
U2AF2	PNISR	Q8TF01	848

IntAct

374 interactions, top by confidence:

A	B	Type	Score
U2AF2	U2AF1	psi-mi:“MI:0915”(physical association)	0.950
U2AF2	U2AF1	psi-mi:“MI:0407”(direct interaction)	0.950
U2AF1	U2AF2	psi-mi:“MI:0915”(physical association)	0.950
SF1	U2AF2	psi-mi:“MI:0914”(association)	0.950
U2AF2	SF1	psi-mi:“MI:0407”(direct interaction)	0.950
SF1	U2AF2	psi-mi:“MI:0915”(physical association)	0.950
SF1	U2AF2	psi-mi:“MI:0407”(direct interaction)	0.950
U2AF2	U2AF1	psi-mi:“MI:0914”(association)	0.950
PUF60	U2AF2	psi-mi:“MI:0915”(physical association)	0.850
SUGP1	U2AF2	psi-mi:“MI:0915”(physical association)	0.820
U2AF2	SUGP1	psi-mi:“MI:0915”(physical association)	0.820
U2AF2	SUGP1	psi-mi:“MI:0407”(direct interaction)	0.820
SRPK2	U2AF2	psi-mi:“MI:0915”(physical association)	0.800

BioGRID (1139): U2AF2 (Two-hybrid), U2AF2 (Two-hybrid), U2AF2 (Two-hybrid), U2AF2 (Two-hybrid), PUF60 (Two-hybrid), THAP1 (Two-hybrid), U2AF2 (Affinity Capture-RNA), U2AF2 (Affinity Capture-MS), U2AF2 (Affinity Capture-MS), U2AF2 (Affinity Capture-MS), U2AF2 (Affinity Capture-MS), U2AF2 (Affinity Capture-MS), U2AF2 (Affinity Capture-MS), U2AF2 (Affinity Capture-MS), U2AF2 (Affinity Capture-MS)

ESM2 similar proteins: A2Y0J7, B5DF91, B8AM21, O22922, O95758, P09012, P17225, P26368, P26369, P26599, P43332, P45429, P70372, Q00438, Q06AA4, Q08E07, Q0DKM4, Q10MR0, Q12926, Q14576, Q15717, Q24562, Q28FX0, Q29099, Q2KIR1, Q39244, Q54J05, Q5R9Z6, Q5SZQ8, Q60899, Q60900, Q62189, Q66H20, Q6GLB5, Q8BHD7, Q8BHN5, Q8CFD1, Q8CH84, Q8CIN6, Q8H1S6

Diamond homologs: A0A0A0LLY1, A0A0D1C8Z4, A0A0R4IEW8, A7EWN6, B0BN49, B5DF91, C0HFE5, D3Z4I3, M0R7T6, O09032, O22703, O23212, O35698, O43040, O74978, O94290, P19684, P25299, P26368, P26369, P26378, P33240, P48810, P49311, P70372, P90727, P90978, P97343, P98179, Q00916, Q03250, Q03878, Q05966, Q08473, Q08935, Q08E07, Q10B98, Q12926, Q13595, Q14576

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
U2AF2	“form complex”	U2AF1/U2AF2	binding
U2AF2	“form complex”	ZRSR2/U2AF2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 155 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
Transport of Mature Transcript to Cytoplasm	6	20.8×	2e-05
mRNA 3’-end processing	10	17.9×	1e-08
mRNA Splicing	16	16.0×	4e-13
Processing of Capped Intron-Containing Pre-mRNA	21	15.7×	3e-17
RNA Polymerase II Transcription Termination	7	14.0×	3e-05
mRNA Polyadenylation	17	13.6×	7e-13
Transport of Mature mRNA derived from an Intron-Containing Transcript	9	12.5×	3e-06
mRNA Splicing - Major Pathway	25	12.4×	4e-18

GO biological processes:

GO term	Partners	Fold	FDR
regulation of mRNA splicing, via spliceosome	5	31.4×	6e-05
spliceosomal complex assembly	7	29.9×	6e-07
alternative mRNA splicing, via spliceosome	5	23.9×	2e-04
RNA splicing, via transesterification reactions	5	22.1×	3e-04
regulation of alternative mRNA splicing, via spliceosome	8	13.9×	2e-05
mRNA splicing, via spliceosome	21	13.6×	3e-15
mRNA stabilization	5	13.0×	3e-03
mitophagy	5	11.3×	5e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — AML.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	6
Uncertain significance	55
Likely benign	9
Benign	2

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1470385	NM_007279.3(U2AF2):c.445C>T (p.Arg149Trp)	Pathogenic
1510756	NM_007279.3(U2AF2):c.457G>A (p.Val153Met)	Pathogenic
2582779	NM_007279.3(U2AF2):c.603G>T (p.Glu201Asp)	Pathogenic
3893333	NM_007279.3(U2AF2):c.587A>C (p.Asn196Thr)	Pathogenic
57219	GRCh38/hg38 19q13.33-13.43(chr19:50191219-58535818)x3	Pathogenic
1685470	NM_007279.3(U2AF2):c.746T>A (p.Val249Asp)	Likely pathogenic
2412811	NM_007279.3(U2AF2):c.470C>T (p.Pro157Leu)	Likely pathogenic
3573511	NM_007279.3(U2AF2):c.530G>T (p.Gly177Val)	Likely pathogenic
3769848	NM_007279.3(U2AF2):c.368C>T (p.Pro123Leu)	Likely pathogenic
4278035	NM_007279.3(U2AF2):c.794G>A (p.Gly265Asp)	Likely pathogenic
4532818	NM_007279.3(U2AF2):c.694T>C (p.Tyr232His)	Likely pathogenic

SpliceAI

1961 predictions. Top by Δscore:

Variant	Effect	Δscore
19:55655150:CAAG:C	donor_gain	1.0000
19:55655152:AG:A	donor_gain	1.0000
19:55655153:GG:G	donor_gain	1.0000
19:55655153:GGTGA:G	donor_loss	1.0000
19:55655154:GTGAG:G	donor_loss	1.0000
19:55659198:A:AG	acceptor_gain	1.0000
19:55659199:C:G	acceptor_gain	1.0000
19:55659203:T:TA	acceptor_gain	1.0000
19:55659205:CCCAG:C	acceptor_gain	1.0000
19:55659206:CCAG:C	acceptor_gain	1.0000
19:55659207:CAG:C	acceptor_gain	1.0000
19:55659208:A:AG	acceptor_gain	1.0000
19:55659208:A:AT	acceptor_loss	1.0000
19:55659208:AGA:A	acceptor_gain	1.0000
19:55659208:AGAGC:A	acceptor_gain	1.0000
19:55659209:G:GA	acceptor_gain	1.0000
19:55659209:GA:G	acceptor_gain	1.0000
19:55659209:GAG:G	acceptor_gain	1.0000
19:55659209:GAGC:G	acceptor_gain	1.0000
19:55659209:GAGCG:G	acceptor_gain	1.0000
19:55659342:GCAG:G	donor_gain	1.0000
19:55659343:CAG:C	donor_loss	1.0000
19:55659344:AGGT:A	donor_loss	1.0000
19:55659345:GG:G	donor_loss	1.0000
19:55659346:G:C	donor_loss	1.0000
19:55659346:G:GG	donor_gain	1.0000
19:55660505:A:AG	acceptor_gain	1.0000
19:55660506:C:G	acceptor_gain	1.0000
19:55660514:A:AG	acceptor_gain	1.0000
19:55660515:G:GG	acceptor_gain	1.0000

AlphaMissense

3131 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:55660559:T:A	W92R	1.000
19:55660559:T:C	W92R	1.000
19:55660561:G:C	W92C	1.000
19:55660561:G:T	W92C	1.000
19:55660562:G:C	D93H	1.000
19:55660580:T:C	F99L	1.000
19:55660582:T:A	F99L	1.000
19:55660582:T:G	F99L	1.000
19:55660604:T:G	Y107D	1.000
19:55660609:G:C	K108N	1.000
19:55660609:G:T	K108N	1.000
19:55660610:G:C	A109P	1.000
19:55661145:G:C	A148P	1.000
19:55661146:C:A	A148D	1.000
19:55661148:C:T	R149W	1.000
19:55661149:G:C	R149P	1.000
19:55661151:C:A	R150S	1.000
19:55661151:C:G	R150G	1.000
19:55661152:G:C	R150P	1.000
19:55661155:T:A	L151H	1.000
19:55661155:T:C	L151P	1.000
19:55661155:T:G	L151R	1.000
19:55661157:T:A	Y152N	1.000
19:55661157:T:C	Y152H	1.000
19:55661157:T:G	Y152D	1.000
19:55661161:T:A	V153E	1.000
19:55661163:G:C	G154R	1.000
19:55661163:G:T	G154C	1.000
19:55661164:G:A	G154D	1.000
19:55661164:G:T	G154V	1.000

dbSNP variants (sampled 300 via entrez): RS1000012144 (19:55653544 A>G,T), RS1000053761 (19:55659645 TTCTCTG>T), RS1000064367 (19:55665214 C>T), RS1000095014 (19:55665451 C>G), RS1000123815 (19:55657878 A>C,G), RS1000178374 (19:55657398 T>C), RS1000230174 (19:55669917 G>C), RS1000247817 (19:55661250 C>A,G,T), RS1000369126 (19:55653732 C>G,T), RS1000386636 (19:55674841 G>A), RS1000419532 (19:55657549 C>T), RS1000581054 (19:55658307 A>C), RS1000602451 (19:55660775 C>G,T), RS1000722436 (19:55661477 G>C), RS1000729814 (19:55673982 G>C,T)

Disease associations

OMIM: gene MIM:191318 | disease phenotypes: MIM:620535, MIM:312080

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental delay, dysmorphic facies, and brain anomalies	Strong	Autosomal dominant

Mondo (3): developmental delay, dysmorphic facies, and brain anomalies (MONDO:0957810), neurodevelopmental disorder (MONDO:0700092), leukodystrophy (MONDO:0019046)

Orphanet (1): Leukodystrophy (Orphanet:68356)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005312_14	Menopause (age at onset)	6.000000e-85
GCST005312_15	Menopause (age at onset)	3.000000e-13
GCST005312_16	Menopause (age at onset)	8.000000e-16
GCST010242_109	HDL cholesterol levels	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724607 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.94	Kd	115	nM	MOLIBRESIB
6.51	IC50	310	nM	MOLIBRESIB
6.30	Kd	501	nM	CHEMBL5653589
6.30	ED50	501	nM	CHEMBL5653589

PubChem BioAssay actives

3 with measured affinity, of 9 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179148: Binding affinity against U2AF2 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.1150	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149698: Binding affinity to human U2AF2 incubated for 45 mins by Kinobead based pull down assay	kd	0.5010	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Air Pollutants	affects expression, increases abundance, increases expression	2
Benzo(a)pyrene	increases expression, affects cotreatment	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization, increases expression	1
quercitrin	increases expression	1
trichostatin A	affects expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	decreases expression, increases abundance	1
cyclic 3’,5’-uridine monophosphate	affects binding	1
chromium hexavalent ion	increases abundance, decreases expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Bortezomib	decreases expression	1
Resveratrol	affects cotreatment, decreases expression, increases expression	1
Vorinostat	decreases expression	1
Arsenic	affects methylation	1
Benztropine	decreases expression	1
Caffeine	decreases phosphorylation	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652740	Binding	Binding affinity to human U2AF2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice