U2AF1

Summary

U2AF1 (U2 small nuclear RNA auxiliary factor 1, HGNC:12453) is a protein-coding gene on chromosome 21q22.3, encoding Splicing factor U2AF 35 kDa subunit (Q01081). Plays a critical role in both constitutive and enhancer-dependent splicing by mediating protein-protein interactions and protein-RNA interactions required for accurate 3’-splice site selection. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

This gene belongs to the splicing factor SR family of genes. U2 auxiliary factor, comprising 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 small subunit which plays a critical role in both constitutive and enhancer-dependent RNA splicing by directly mediating interactions between the large subunit and proteins bound to the enhancers. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 7307 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 23 total — 1 likely-pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 9 cancer types
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_006758

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12453
Approved symbol	U2AF1
Name	U2 small nuclear RNA auxiliary factor 1
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Aliases	U2AF35, RNU2AF1, RN
Ensembl gene	ENSG00000160201
Ensembl biotype	protein_coding
OMIM	191317
Entrez	7307

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 14 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay

ENST00000291552, ENST00000380276, ENST00000459639, ENST00000463599, ENST00000464750, ENST00000468039, ENST00000471250, ENST00000475639, ENST00000478282, ENST00000486519, ENST00000496462, ENST00000887978, ENST00000887979, ENST00000887980, ENST00000887981, ENST00000887982, ENST00000887983, ENST00000887984, ENST00000921413, ENST00000921414, ENST00000921415, ENST00000921416

RefSeq mRNA: 3 — MANE Select: NM_006758 NM_001025203, NM_001025204, NM_006758

CCDS: CCDS13694, CCDS33574, CCDS42948

Canonical transcript exons

ENST00000291552 — 8 exons

Exon	Start	End
ENSE00001902995	43107451	43107570
ENSE00003477404	43094655	43094788
ENSE00003493768	43092956	43093249
ENSE00003537947	43095694	43095743
ENSE00003622010	43094471	43094563
ENSE00003653463	43104315	43104402
ENSE00003673252	43100453	43100519
ENSE00003694524	43095438	43095536

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 96.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.5651 / max 148.0827, expressed in 1619 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190682	9.5651	1619
209222	3.3186	1082

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	96.18	gold quality
left uterine tube	UBERON:0001303	96.11	gold quality
bone marrow	UBERON:0002371	95.96	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.81	gold quality
mucosa of transverse colon	UBERON:0004991	95.30	gold quality
vermiform appendix	UBERON:0001154	95.25	gold quality
stromal cell of endometrium	CL:0002255	95.05	gold quality
right lung	UBERON:0002167	95.03	gold quality
monocyte	CL:0000576	94.89	gold quality
granulocyte	CL:0000094	94.88	gold quality
primary visual cortex	UBERON:0002436	94.44	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.44	gold quality
leukocyte	CL:0000738	94.43	gold quality
bone marrow cell	CL:0002092	94.11	gold quality
metanephros cortex	UBERON:0010533	94.05	gold quality
placenta	UBERON:0001987	94.04	gold quality
cortex of kidney	UBERON:0001225	93.99	gold quality
ventricular zone	UBERON:0003053	93.95	gold quality
right uterine tube	UBERON:0001302	93.73	gold quality
endometrium	UBERON:0001295	93.68	gold quality
lymph node	UBERON:0000029	93.55	gold quality
islet of Langerhans	UBERON:0000006	93.38	gold quality
blood	UBERON:0000178	93.17	gold quality
pituitary gland	UBERON:0000007	93.12	gold quality
gall bladder	UBERON:0002110	92.68	gold quality
sural nerve	UBERON:0015488	92.44	gold quality
left ovary	UBERON:0002119	92.34	gold quality
left lobe of thyroid gland	UBERON:0001120	92.32	gold quality
ganglionic eminence	UBERON:0004023	92.25	gold quality
thyroid gland	UBERON:0002046	92.19	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	10.99
E-ANND-3	yes	4.66
E-MTAB-6142	no	84.36

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
TP53	Repression

Upstream regulators (CollecTRI, top): CEBPB, CEBPD, CEBPG, ESR1, NFKB, RBPJ, ZNF362

miRNA regulators (miRDB)

14 targeting U2AF1, 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-6844	99.82	70.69	2423
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-548AI	99.69	69.24	1494
HSA-MIR-548BA	99.69	69.14	1514
HSA-MIR-570-5P	99.69	69.24	1494
HSA-MIR-567	99.63	68.57	1219
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-4999-3P	99.11	65.55	424
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-3166	98.24	66.63	1223
HSA-MIR-34C-3P	98.11	65.60	858
HSA-MIR-582-3P	96.69	67.38	1019

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• A misspliced form of the cholecystokinin-B/gastrin receptor in pancreatic carcinoma: role of reduced sellular U2AF35 and a suboptimal 3’-splicing site leading to retention of the fourth intron. (PMID:11830556)
• U2AF35 RRM is unstructured in solution but its tertiary structure is induced upon binding to U2AF65. (PMID:12297299)
• U2AF1 gene expression may provide a mechanism by which the relative cellular concentration and availability of U2AF(35) protein isoforms are modulated, thus contributing to the finely tuned control of splicing events in different tissues. (PMID:15096518)
• U2AF35 appears to be completely dispensable for splicing in nuclear extracts prepared from adenovirus late-infected cells (PMID:15899895)
• Binding assays revealed that IpaH9.8 has a specific affinity to U2AF(35), a mammalian splicing factor, which interferes with U2AF(35)-dependent splicing as assayed for IgM pre-mRNA (PMID:15950937)
• identified and spatially localized sites of direct interaction between U2AF35 and U2AF65 in vivo in live cell nuclei. (PMID:16043505)
• 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)
• Taken together our results demonstrate that U2AF35a is essential for HeLa cell division and suggest a novel role for both U2AF35 protein isoforms as regulators of alternative splicing of a specific subset of genes. (PMID:16855028)
• 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)
• U2AF35 and hPrp3 interactions with SPF30 can occur simultaneously, thereby potentially linking 3’ splice site recognition with tri-small nuclear ribonucleoprotein addition (PMID:18211889)
• SF1 and U2AF form extraspliceosomal complexes before and after taking part in the assembly of catalytic spliceosomes. (PMID:18285458)
• Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML (PMID:22158538)
• U2AF1 and SRSF2 mutations are frequent in chronic myelomonocytic leukemia and advanced forms of MDS. U2AF1 and SRSF2 mutations are predictive for shorter survival. (PMID:22323480)
• 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)
• In univariate analysis, mutated SRSF2 predicted shorter overall survival and more frequent acute myeloid leukemia progression compared with wild-type SRSF2, whereas mutated U2AF1, ZRSR2 had no impact on patient outcome. (PMID:22389253)
• U2AF1 mutation is a recurrent event at a low frequency in acute myeloid leukemia and myelodysplastic syndrome and influences overall survival. (PMID:23029227)
• data suggest that SF3B1, U2AF1 and SRSF2 mutations occur not only in myeloid lineage tumors but also in lymphoid lineage tumors; data suggest that the splicing gene mutations play important roles in the pathogenesis of hematologic tumors, but rarely in solid tumors (PMID:23280334)
• SRSF2 is the most frequently mutated spliceosome gene in chronic myelomonocytic leukemia, but neither it nor SF3B1 or U2AF35 mutations are prognostically relevant. (PMID:23335386)
• U2AF1 mutations play a significant role in myeloid leukemogenesis due to selective missplicing of tumor-associated genes (PMID:23775717)
• genetic association studies in a population in Taiwan: Data suggest that U2AF1 mutations are associated with poor prognosis/survival in patients with myelodysplastic syndrome and shorter time-to-leukemia transformation in young patients. (PMID:23861105)
• study describes incidence and phenotypic and prognostic relevance of U2AF1 mutations in primary myelofibrosis(PMF); U2AF1 mutations cluster with JAK2V617F, ASXL1 mutations and normal karyotype; U2AF1 mutations are strongly and inter-independently associated with anemia and thrombocytopenia (PMID:24097336)
• Data indicate somatic mutations in the splicing factor U2AF1 across 12 cancer types. (PMID:24498085)
• Molecular monitoring of patients having undergone AHSCT for PMF should not be restricted to JAK2, MPL or CALR, but all mutations present in primary fibrotic neoplastic myeloproliferation should be included to interpret abnormal blood values after AHSCT (PMID:25231745)
• mutations influence the similarity of splicing programs in leukemias, but do not give rise to widespread splicing failure. (PMID:25267526)
• A mutant U2AF1 (S34F) found in a variety of cancer types results in delayed splicing and disruption of kinetic competition during transcription. (PMID:25271374)
• The S34F mutation alters U2AF1 function in the context of specific RNA sequences, leading to aberrant alternative splicing of target genes, some of which may be relevant for myelodysplastic syndromes pathogenesis. (PMID:25311244)
• 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)
• In multivariate analysis, U2AF1 and TP53 mutations retained independent prognostic significance across 93 cases of acute myeloid leukemia (PMID:25412851)
• The mutational status of the SRSF2, U2AF1 and ZRSR2 did not affect the response rate or survival in MDS patients who had received first-line decitabine treatment. (PMID:25964599)
• Mutations in ASXL1, U2AF1, and SF3B1 are common in Chinese patients with myelodysplastic syndromes. (PMID:26508027)
• in primary myelofibrosis, anemia was significantly associated with U2AF1 mutation; study confirms previous observation regarding the association of mutant U2AF1 with anemia supporting its role in hematopoiesis and in the pathogenesis of PMF-associated anemia (PMID:27058230)
• The U2AF35(S34F) mutation alters interaction with CFIm59, leading to increased use of a distal cleavage and polyadenylation site in the ATG7 pre-mRNA, decreasing levels of ATG7 protein and defective autophagy, ultimately leading to transformation. (PMID:27184077)
• data confirm MLL-PTD and, to a lesser extent, FLT3-ITD as common events in +11 AML.6, 7, 8 However, the high mutation frequencies of U2AF1 and genes involved in methylation (DNMT3A, IDH2) have hitherto not been reported in +11 AML (PMID:27435003)
• Alternative splicing of U2AF1 reveals a shared repression mechanism for duplicated exons controlled by SRF3. (PMID:27566151)
• this study characterized novel candidate pediatric T-cell acute lymphoblastic leukemia driver mutation in splicesome factor U2AF1 (PMID:27602765)
• The aberrantly spliced target genes and deregulated cellular pathways associated with the commonly mutated splicing factor genes in myelodysplastic syndromes (SF3B1, SRSF2 and U2AF1) are being identified, illuminating the molecular mechanisms underlying the disease. (Review) (PMID:27639445)
• Our results provide mechanistic explanations of the magnitude of splicing changes observed in U2AF1-mutant cells and why tumors harboring U2AF1 mutations always retain an expressed copy of the wild-type allele (PMID:27776121)
• In summary, we provide insight into the underlying molecular mechanism of U2AF binding to 3’ splice sites. (PMID:27799531)
• The splicing effects of sudemycin and U2AF1 can be cumulative in cells exposed to both perturbations-drug and mutation, as compared with cells exposed to either alone. (PMID:28067246)
• The frequently mutated SF3B1 residues contact the pre-mRNA splice site. Based on structural homology with other spliceosome subunits, and recent findings of altered RNA binding by mutant U2AF1 proteins, we suggest that affected U2AF1 residues also contact pre-mRNA. (PMID:28372848)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	u2af1	ENSDARG00000015325
mus_musculus	U2af1	ENSMUSG00000061613
rattus_norvegicus	U2af1	ENSRNOG00000045860
drosophila_melanogaster	U2af38	FBGN0017457
caenorhabditis_elegans		WBGENE00006698

Paralogs (2): U2AF1L4 (ENSG00000161265), ZRSR2 (ENSG00000169249)

Protein

Protein identifiers

Splicing factor U2AF 35 kDa subunit — Q01081 (reviewed: Q01081)

Alternative names: U2 auxiliary factor 35 kDa subunit, U2 small nuclear RNA auxiliary factor 1, U2 snRNP auxiliary factor small subunit

All UniProt accessions (2): Q01081, A0A1B0GW87

UniProt curated annotations — full annotation on UniProt →

Function. Plays a critical role in both constitutive and enhancer-dependent splicing by mediating protein-protein interactions and protein-RNA interactions required for accurate 3’-splice site selection. Recruits U2 snRNP to the branch point. Directly mediates interactions between U2AF2 and proteins bound to the enhancers and thus may function as a bridge between U2AF2 and the enhancer complex to recruit it to the adjacent intron.

Subunit / interactions. Identified in the spliceosome C complex. Heterodimer with U2AF2. Interacts (via RS domain) with PHF5A (via N-terminus). Interacts with ZRANB2. Interacts with SDE2. Interacts with SF3B1.

Subcellular location. Nucleus. Nucleus speckle.

Disease relevance. Myelodysplastic syndrome (MDS) [MIM:614286] A heterogeneous group of closely related clonal hematopoietic disorders. All are characterized by a hypercellular or hypocellular bone marrow with impaired morphology and maturation, dysplasia of the myeloid, megakaryocytic and/or erythroid lineages, and peripheral blood cytopenias resulting from ineffective blood cell production. Included diseases are: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS); chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative disease. MDS is considered a premalignant condition in a subgroup of patients that often progresses to acute myeloid leukemia (AML). The gene represented in this entry may be involved in disease pathogenesis. Mutation altering U2AF1 function in the context of specific RNA sequences can lead to aberrant alternative splicing of target genes, some of which may be relevant for MDS pathogenesis.

Domain organisation. The C-terminal SR-rich domain is required for interactions with SR proteins and the splicing regulators TRA and TRA2, and the N-terminal domain is required for formation of the U2AF1/U2AF2 heterodimer.

Miscellaneous. Interacts with U2AF2 and stimulates U2AF splicing activity in vitro. Less efficient than isoform 1. Produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the splicing factor SR family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q01081-1	1, U2AF35a	yes
Q01081-2	2, U2AF35b
Q01081-3	3, U2AF35c
Q01081-4	4

RefSeq proteins (6): NP_001020374, NP_001020375, NP_001307575, NP_001307577, NP_001307580, NP_006749* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR000571	Znf_CCCH	Domain
IPR003954	RRM_euk-type	Domain
IPR009145	U2AF_small	Family
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR035979	RBD_domain_sf	Homologous_superfamily

Pfam: PF00076, PF00642

UniProt features (30 total): modified residue 7, splice variant 4, strand 4, sequence variant 3, compositionally biased region 3, helix 2, zinc finger region 2, initiator methionine 1, chain 1, domain 1, mutagenesis site 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1JMT	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q01081-F1	79.96	0.61

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 (7): 39, 61, 145, 165, 39, 39, 2

Mutagenesis-validated functional residues (1):

Position	Phenotype
134	decreases affinity for uaf2 by 3 orders of magnitude.

Function

Pathways and Gene Ontology

Reactome pathways

6 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-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-73856	RNA Polymerase II Transcription Termination

MSigDB gene sets: 175 (showing top): TTTGTAG_MIR520D, MORF_SNRP70, MORF_UBE2I, MORF_HDAC1, MORF_UBE2N, MORF_RAD21, MORF_CDK2, MORF_HDAC2, PUJANA_CHEK2_PCC_NETWORK, MORF_TERF1, MORF_SKP1A, MUELLER_PLURINET, WANG_LMO4_TARGETS_DN, MORF_CCNI, MORF_CTBP1

GO Biological Process (3): mRNA splicing, via spliceosome (GO:0000398), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (7): RNA binding (GO:0003723), zinc ion binding (GO:0008270), pre-mRNA 3’-splice site binding (GO:0030628), RS domain binding (GO:0050733), nucleic acid binding (GO:0003676), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), Cajal body (GO:0015030), nuclear speck (GO:0016607), catalytic step 2 spliceosome (GO:0071013), U2AF complex (GO:0089701), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Transport of Mature Transcript to Cytoplasm	1
mRNA Splicing	1
Processing of Capped Intron-Containing Pre-mRNA	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
RNA processing	2
binding	2
nuclear protein-containing complex	2
nuclear ribonucleoprotein granule	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
mRNA metabolic process	1
nucleic acid binding	1
transition metal ion binding	1
pre-mRNA binding	1
protein domain specific binding	1
cation binding	1
nuclear lumen	1
cellular anatomical structure	1
ribonucleoprotein complex	1
Prp19 complex	1
spliceosomal complex	1
U5 snRNP	1
catalytic complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2238 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
U2AF1	U2AF2	P26368	999
U2AF1	SRSF2	Q01130	997
U2AF1	SRSF1	Q07955	938
U2AF1	SF1	Q15637	912
U2AF1	DEK	P35659	898
U2AF1	RBM39	Q14498	896
U2AF1	ASXL1	Q8IXJ9	881
U2AF1	SF3A1	Q15459	848
U2AF1	RSRC1	Q96IZ7	846
U2AF1	SF3B1	O75533	843
U2AF1	SRSF5	Q13243	819
U2AF1	TET2	Q6N021	800
U2AF1	SETBP1	Q9Y6X0	778
U2AF1	DNMT3A	Q9Y6K1	773
U2AF1	IDH1	O75874	763

IntAct

216 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
U2AF2	U2AF1	psi-mi:“MI:0914”(association)	0.950
U2AF1	SRPK2	psi-mi:“MI:0915”(physical association)	0.830
SRPK2	U2AF1	psi-mi:“MI:0915”(physical association)	0.830
U2AF1	CARNMT1	psi-mi:“MI:0915”(physical association)	0.740
U2AF1	SRSF3	psi-mi:“MI:2364”(proximity)	0.730
U2AF1	SRSF3	psi-mi:“MI:0915”(physical association)	0.730
SNW1	U2AF2	psi-mi:“MI:0914”(association)	0.730
HNRNPK	U2AF1	psi-mi:“MI:0915”(physical association)	0.670
U2AF1	HNRNPK	psi-mi:“MI:0915”(physical association)	0.670
U2AF1	U2AF2	psi-mi:“MI:0914”(association)	0.670
U2AF1	U2AF2	psi-mi:“MI:0915”(physical association)	0.670
ATXN1	U2AF1	psi-mi:“MI:0915”(physical association)	0.670
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640

BioGRID (399): U2AF1 (Two-hybrid), U2AF1 (Two-hybrid), U2AF1 (Two-hybrid), U2AF1 (Two-hybrid), RNPS1 (Two-hybrid), U2AF2 (Two-hybrid), U2AF1 (Affinity Capture-MS), U2AF1 (Affinity Capture-MS), U2AF1 (Affinity Capture-MS), U2AF1 (Affinity Capture-MS), U2AF1 (Affinity Capture-MS), U2AF2 (Two-hybrid), FTSJ3 (Co-fractionation), U2AF2 (Affinity Capture-Western), U2AF1 (Co-fractionation)

ESM2 similar proteins: A1A4K8, A1Z9L3, A2A4P0, B5DGI7, E0X9N4, O01159, O23212, O48534, P17133, P90727, P90978, Q01081, Q08C72, Q09176, Q09217, Q14498, Q21832, Q27W01, Q28BZ1, Q2QKB3, Q2QKB4, Q2QZL4, Q2R0Q1, Q3T127, Q3ZCE8, Q52KN9, Q5D018, Q5RC80, Q5ZKA3, Q6AUG0, Q6IDS6, Q6P616, Q6PH90, Q7TP17, Q7ZXB5, Q8BGJ9, Q8L716, Q8VH51, Q8WU68, Q94535

Diamond homologs: A1A4K8, O13845, Q01081, Q09176, Q15695, Q15696, Q29350, Q3T127, Q62377, Q64707, Q6AUG0, Q6YVX9, Q7TP17, Q8BGJ9, Q8WU68, Q94535, Q9D883, Q9FMY5, Q9S709, Q9SY74, Q9ZQW8, A1A5R1, A6NDE4, A6NEQ0, A6NFN3, A6QPR6, B0BNE4, O14369, O43251, O89086, P04147, P0C7P1, P0CB38, P0DJD3, P0DJD4, P19339, P41891, P42696, P57052, P60047

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
U2AF1	“down-regulates quantity by repression”	TP53	“transcriptional regulation”
U2AF1	“form complex”	U2AF1/U2AF2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 127 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	7	27.2×	3e-07
mRNA 3’-end processing	11	22.1×	2e-10
mRNA Splicing - Minor Pathway	9	20.6×	3e-08
mRNA Splicing	17	19.1×	2e-15
Processing of Capped Intron-Containing Pre-mRNA	22	18.4×	1e-19
Transport of Mature mRNA derived from an Intron-Containing Transcript	11	17.1×	3e-09
mRNA Polyadenylation	19	17.0×	3e-16
mRNA Splicing - Major Pathway	30	16.7×	3e-26

GO biological processes:

GO term	Partners	Fold	FDR
regulation of mRNA splicing, via spliceosome	7	53.1×	1e-08
spliceosomal complex assembly	9	46.3×	7e-11
negative regulation of mRNA splicing, via spliceosome	6	39.3×	1e-06
U2-type prespliceosome assembly	5	26.7×	2e-04
mRNA splicing, via spliceosome	25	19.6×	2e-22
regulation of alternative mRNA splicing, via spliceosome	8	16.7×	4e-06
RNA splicing	19	14.3×	4e-14
mRNA export from nucleus	5	12.6×	4e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

U2AF1 is one of several spliceosome complex genes frequently mutated in a variety of hematologic malignancies, particularly de novo myelodysplastic syndromes (MDS), as well as solid tumors such as lung and pancreatic cancers. Two hotspot mutations (S34 and Q157) occur within the two zinc-finger domains of the U2AF1 protein. These mutations have been associated with altered splicing patterns in vitro and in vivo. U2AF1 mutations in MDS have been associated with an increased risk of transformation to secondary acute myeloid leukemia, however, the impact of these mutations on overall survival has been an area of debate.

From intOGen — cancer-driver classification: activating (oncogene-like) across 9 cancer types — AML, CHOL, LUAD, NSCLC, PAAD, PRAD, STAD, UCEC, UCS.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	6
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
376024	NM_006758.3(U2AF1):c.470A>C (p.Gln157Pro)	Likely pathogenic

SpliceAI

1775 predictions. Top by Δscore:

Variant	Effect	Δscore
21:43094465:A:AC	donor_gain	1.0000
21:43094466:C:CC	donor_gain	1.0000
21:43094466:CTCA:C	donor_gain	1.0000
21:43094467:TCA:T	donor_loss	1.0000
21:43094468:CACTT:C	donor_loss	1.0000
21:43094469:A:AC	donor_gain	1.0000
21:43094469:AC:A	donor_loss	1.0000
21:43094469:ACTT:A	donor_gain	1.0000
21:43094470:C:CA	donor_gain	1.0000
21:43094470:CT:C	donor_gain	1.0000
21:43094470:CTT:C	donor_gain	1.0000
21:43094470:CTTC:C	donor_gain	1.0000
21:43094470:CTTCT:C	donor_gain	1.0000
21:43094472:T:TA	donor_gain	1.0000
21:43094559:ATTCT:A	acceptor_gain	1.0000
21:43094560:TTCT:T	acceptor_gain	1.0000
21:43094560:TTCTC:T	acceptor_loss	1.0000
21:43094562:CT:C	acceptor_gain	1.0000
21:43094563:TC:T	acceptor_loss	1.0000
21:43094564:C:CA	acceptor_loss	1.0000
21:43094564:C:CC	acceptor_gain	1.0000
21:43094565:T:G	acceptor_loss	1.0000
21:43094651:TCACC:T	donor_loss	1.0000
21:43094652:C:CG	donor_loss	1.0000
21:43094652:CACC:C	donor_loss	1.0000
21:43094653:A:AC	donor_gain	1.0000
21:43094653:AC:A	donor_gain	1.0000
21:43094653:ACC:A	donor_gain	1.0000
21:43094653:ACCC:A	donor_gain	1.0000
21:43094654:C:CC	donor_gain	1.0000

AlphaMissense

1571 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:43094513:G:A	S178F	1.000
21:43094521:C:A	K175N	1.000
21:43094521:C:G	K175N	1.000
21:43094527:A:C	H173Q	1.000
21:43094527:A:T	H173Q	1.000
21:43094528:T:C	H173R	1.000
21:43094529:G:C	H173D	1.000
21:43094529:G:T	H173N	1.000
21:43094531:A:C	M172R	1.000
21:43094531:A:G	M172T	1.000
21:43094531:A:T	M172K	1.000
21:43094533:G:C	F171L	1.000
21:43094533:G:T	F171L	1.000
21:43094534:A:C	F171C	1.000
21:43094534:A:G	F171S	1.000
21:43094535:A:C	F171V	1.000
21:43094535:A:G	F171L	1.000
21:43094535:A:T	F171I	1.000
21:43094536:G:C	N170K	1.000
21:43094536:G:T	N170K	1.000
21:43094537:T:A	N170I	1.000
21:43094538:T:C	N170D	1.000
21:43094538:T:G	N170H	1.000
21:43094539:G:C	C169W	1.000
21:43094540:C:A	C169F	1.000
21:43094540:C:G	C169S	1.000
21:43094540:C:T	C169Y	1.000
21:43094541:A:C	C169G	1.000
21:43094541:A:G	C169R	1.000
21:43094541:A:T	C169S	1.000

dbSNP variants (sampled 300 via entrez): RS1000371308 (21:43106997 A>G), RS1001817932 (21:43096098 C>A), RS1002945584 (21:43098306 T>C), RS1003261434 (21:43107799 C>T), RS1003387260 (21:43103551 G>A,C), RS1003540651 (21:43097070 A>T), RS1003945250 (21:43094192 C>T), RS1004757101 (21:43104039 G>T), RS1004837729 (21:43092804 G>A), RS1004892284 (21:43097889 C>T), RS1005560446 (21:43100417 C>G), RS1005858603 (21:43100115 G>A), RS1006276467 (21:43104987 G>A), RS1006433932 (21:43105309 AT>A,ATT), RS1007001246 (21:43106828 C>G)

Disease associations

OMIM: gene MIM:191317 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002670_11	Blood and toenail selenium levels	3.000000e-08
GCST002670_12	Blood and toenail selenium levels	5.000000e-09
GCST002670_4	Blood and toenail selenium levels	4.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725064 (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

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

pChembl	Type	Value	Unit	Molecule
9.28	Kd	0.531	nM	CHEMBL3752910
9.28	ED50	0.531	nM	CHEMBL3752910
6.95	Kd	112	nM	MOLIBRESIB
6.86	Kd	137.4	nM	CHEMBL5653589
6.86	ED50	137.4	nM	CHEMBL5653589
6.70	IC50	200	nM	MOLIBRESIB

PubChem BioAssay actives

4 with measured affinity, of 11 total; 3 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149697: Binding affinity to human U2AF1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0005	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179137: Binding affinity against U2AF1 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.1120	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149697: Binding affinity to human U2AF1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1374	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression, increases expression	2
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
bisphenol A	decreases expression	1
methylparaben	increases expression	1
methacrylaldehyde	decreases expression, increases abundance, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
qinghuang	affects response to substance	1
NSC668394	increases expression	1
Temozolomide	increases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cytarabine	decreases expression	1
Enzyme Inhibitors	increases O-linked glycosylation, decreases activity	1
Lead	affects expression, affects splicing	1
Methotrexate	increases expression	1
Ozone	affects cotreatment, decreases expression, increases abundance	1
Paraquat	increases expression	1
Ribonucleotides	affects binding	1
Selenium	increases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Vitamin E	increases expression	1
Cyclosporine	increases expression	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
CHEMBL5652739	Binding	Binding affinity to human U2AF1 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

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8A7	Abcam Raji U2AF1 KO	Cancer cell line	Male
CVCL_C0B1	Abcam THP-1 U2AF1 KO	Cancer cell line	Male
CVCL_C7CP	Abcam PC-3 U2AF1 KO	Cancer cell line	Male
CVCL_S607	SKK-1	Cancer cell line	Male

Clinical trials (associated diseases)

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