U2AF1L4

Summary

U2AF1L4 (U2 small nuclear RNA auxiliary factor 1 like 4, HGNC:23020) is a protein-coding gene on chromosome 19q13.12, encoding Splicing factor U2AF 26 kDa subunit (Q8WU68). RNA-binding protein that function as a pre-mRNA splicing factor.

Predicted to enable pre-mRNA 3’-splice site binding activity. Predicted to be involved in mRNA splicing, via spliceosome. Predicted to be located in nucleoplasm. Predicted to be part of U2AF complex and spliceosomal complex.

Source: NCBI Gene 199746 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 50 total
• MANE Select transcript: NM_001040425

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23020
Approved symbol	U2AF1L4
Name	U2 small nuclear RNA auxiliary factor 1 like 4
Location	19q13.12
Locus type	gene with protein product
Status	Approved
Aliases	MGC33901, U2af26
Ensembl gene	ENSG00000161265
Ensembl biotype	protein_coding
OMIM	601080
Entrez	199746

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 9 retained_intron, 7 nonsense_mediated_decay, 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000292879, ENST00000378975, ENST00000412391, ENST00000585554, ENST00000585771, ENST00000586476, ENST00000587886, ENST00000587987, ENST00000588100, ENST00000588892, ENST00000588980, ENST00000589429, ENST00000590135, ENST00000590650, ENST00000591057, ENST00000591084, ENST00000591855, ENST00000592913, ENST00000594792, ENST00000600296, ENST00000601236

RefSeq mRNA: 3 — MANE Select: NM_001040425 NM_001040425, NM_001369824, NM_144987

CCDS: CCDS12473, CCDS42551

Canonical transcript exons

ENST00000378975 — 6 exons

Exon	Start	End
ENSE00002903742	35745348	35745418
ENSE00003534024	35745125	35745212
ENSE00003578226	35743809	35743904
ENSE00003596292	35744012	35744145
ENSE00003638307	35744323	35744421
ENSE00003643844	35742527	35742803

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 95.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.4293 / max 122.9063, expressed in 1765 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180551	7.4833	1736
180549	2.6447	490
180550	0.3013	149

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left lobe of thyroid gland	UBERON:0001120	95.06	gold quality
right lobe of thyroid gland	UBERON:0001119	94.98	gold quality
thyroid gland	UBERON:0002046	94.85	gold quality
pituitary gland	UBERON:0000007	94.33	gold quality
adenohypophysis	UBERON:0002196	94.29	gold quality
right uterine tube	UBERON:0001302	93.98	gold quality
right adrenal gland cortex	UBERON:0035827	93.81	gold quality
metanephros cortex	UBERON:0010533	93.26	gold quality
right adrenal gland	UBERON:0001233	93.24	gold quality
right lobe of liver	UBERON:0001114	93.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.82	gold quality
apex of heart	UBERON:0002098	92.75	gold quality
left adrenal gland cortex	UBERON:0035825	92.72	gold quality
spleen	UBERON:0002106	92.66	gold quality
primary visual cortex	UBERON:0002436	92.64	gold quality
granulocyte	CL:0000094	92.61	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.54	gold quality
left adrenal gland	UBERON:0001234	92.52	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.44	gold quality
lower esophagus	UBERON:0013473	92.41	gold quality
mucosa of stomach	UBERON:0001199	92.09	gold quality
right testis	UBERON:0004534	92.06	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.99	gold quality
left testis	UBERON:0004533	91.92	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.80	gold quality
tibial artery	UBERON:0007610	91.76	gold quality
popliteal artery	UBERON:0002250	91.75	gold quality
left uterine tube	UBERON:0001303	91.70	gold quality
body of stomach	UBERON:0001161	91.60	gold quality
fundus of stomach	UBERON:0001160	91.49	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.54

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 5)

• Differential isoform expression and interaction with the P32 regulatory protein controls the subcellular localization of the splicing factor U2AF26 (PMID:18460468)
• One of the conservative regions is responsible for the enhancer activity and is able to interact with proteins of HeLa cell nuclear extract. (PMID:22022969)
• a 269 bp region located between the PSENEN and U2AF1L4 human genes is a genuine bidirectional promoter regulating a concerted divergent transcription of these genes. (PMID:23246698)
• U2AF1L4 gene expression is regulated by cytokines in activated T cells. (PMID:27143377)
• The zinc finger domains in U2AF26 and U2AF35 have diverse functionalities including a role in controlling translation. (PMID:32116123)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	U2af1l4	ENSMUSG00000078765
rattus_norvegicus	U2af1l4	ENSRNOG00000024497
drosophila_melanogaster	U2af38	FBGN0017457
caenorhabditis_elegans		WBGENE00006698

Paralogs (2): U2AF1 (ENSG00000160201), ZRSR2 (ENSG00000169249)

Protein

Protein identifiers

Splicing factor U2AF 26 kDa subunit — Q8WU68 (reviewed: Q8WU68)

Alternative names: U2 auxiliary factor 26, U2 small nuclear RNA auxiliary factor 1-like protein 4, U2(RNU2) small nuclear RNA auxiliary factor 1-like protein 3

All UniProt accessions (9): A0A1D5RMU4, Q8WU68, K7EJH3, K7EJM7, M0QYK5, M0R1E1, S4R353, S4R3L8, S4R443

UniProt curated annotations — full annotation on UniProt →

Function. RNA-binding protein that function as a pre-mRNA splicing factor. 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. Acts by enhancing the binding of U2AF2 to weak pyrimidine tracts. Also participates in the regulation of alternative pre-mRNA splicing. Activates exon 5 skipping of PTPRC during T-cell activation; an event reversed by GFI1. Binds to RNA at the AG dinucleotide at the 3’-splice site. Shows a preference for AGC or AGA.

Subunit / interactions. Interacts with GFI1, U2AF2 and C1QBP.

Subcellular location. Nucleus. Nucleus speckle. Cytoplasm.

Tissue specificity. Isoform 2 is widely expressed. Isoform 3 is highly expressed in heart, brain and lung, lower expressed in thymus and much lower expressed in peripheral blood leukocytes.

Domain organisation. The second zinc finger in necessary for interaction with GFI1 and for alternative pre-mRNA splicing events. The region 162-220 is essential for the nuclear import of the protein in spite of the absence of a nuclear localization signal (NLS). This region is essential for the interaction with C1QBP, interaction which is required for the nuclear translocation. This region may be involved in the localization in nuclear dot-like structures and it also confers the ability of nucleo-cytoplasmic shuttling.

Similarity. Belongs to the splicing factor SR family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8WU68-1	1	yes
Q8WU68-2	2
Q8WU68-3	3

RefSeq proteins (3): NP_001035515, NP_001356753, NP_659424 (=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 (12 total): splice variant 2, zinc finger region 2, compositionally biased region 2, initiator methionine 1, chain 1, sequence conflict 1, domain 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WU68-F1	83.53	0.67

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 (1): 2

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: 87 (showing top): STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, AACYNNNNTTCCS_UNKNOWN, CREBP1_Q2, CREB_Q4, GATA3_01, ATF1_Q6, REACTOME_MRNA_3_END_PROCESSING, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, HNF4_DR1_Q3, E4F1_Q6, GOBP_RNA_SPLICING, REACTOME_MRNA_SPLICING, AACTTT_UNKNOWN

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

GO Molecular Function (5): zinc ion binding (GO:0008270), pre-mRNA 3’-splice site binding (GO:0030628), nucleic acid binding (GO:0003676), RNA binding (GO:0003723), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), cytoplasm (GO:0005737), nuclear speck (GO:0016607), 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
cellular anatomical structure	2
nuclear protein-containing complex	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
mRNA metabolic process	1
transition metal ion binding	1
pre-mRNA binding	1
binding	1
nucleic acid binding	1
cation binding	1
nuclear lumen	1
ribonucleoprotein complex	1
intracellular anatomical structure	1
nuclear ribonucleoprotein granule	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

12 interactions, top by confidence:

A	B	Type	Score
N	NOP56	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
GFI1	U2AF1L4	psi-mi:“MI:0915”(physical association)	0.400
Gfi1	U2AF1L4	psi-mi:“MI:0915”(physical association)	0.400
N	RBM47	psi-mi:“MI:0914”(association)	0.350
U2AF1	RGPD2	psi-mi:“MI:0914”(association)	0.350

BioGRID (18): U2AF1L4 (Affinity Capture-MS), U2AF1L4 (Affinity Capture-MS), U2AF1L4 (Affinity Capture-MS), U2AF1L4 (Affinity Capture-MS), U2AF1L4 (Affinity Capture-MS), U2AF1L4 (Affinity Capture-MS), U2AF1L4 (Affinity Capture-MS), U2AF1L4 (Affinity Capture-MS), U2AF1L4 (Affinity Capture-MS), U2AF1L4 (Affinity Capture-MS), U2AF1L4 (Affinity Capture-MS), U2AF1L4 (Affinity Capture-MS), U2AF1L4 (Affinity Capture-MS), U2AF1L4 (Affinity Capture-MS), U2AF1L4 (Affinity Capture-MS)

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, Q59LX5, Q8BGC0, O43719, Q5RB63, P90727, P90978, P97343, Q24562, Q5RCY1, Q63285, Q8TAS1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	12
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1785 predictions. Top by Δscore:

Variant	Effect	Δscore
19:35744022:A:AC	donor_gain	1.0000
19:35744023:C:CC	donor_gain	1.0000
19:35744040:C:CA	donor_gain	1.0000
19:35744146:C:CC	acceptor_gain	1.0000
19:35744318:AGCAC:A	donor_loss	1.0000
19:35744319:GCAC:G	donor_loss	1.0000
19:35744320:CACC:C	donor_loss	1.0000
19:35744321:ACCTT:A	donor_loss	1.0000
19:35744322:CCTT:C	donor_loss	1.0000
19:35744417:ACCTC:A	acceptor_gain	1.0000
19:35744418:CCTCC:C	acceptor_gain	1.0000
19:35744419:CTC:C	acceptor_gain	1.0000
19:35744420:TCCTG:T	acceptor_loss	1.0000
19:35744421:CCTG:C	acceptor_gain	1.0000
19:35744422:C:CC	acceptor_gain	1.0000
19:35744423:T:G	acceptor_loss	1.0000
19:35744620:A:AC	donor_gain	1.0000
19:35744621:C:CC	donor_gain	1.0000
19:35744624:A:AC	donor_gain	1.0000
19:35744625:C:CC	donor_gain	1.0000
19:35745120:CTCA:C	donor_loss	1.0000
19:35745121:TCAC:T	donor_loss	1.0000
19:35745122:CA:C	donor_loss	1.0000
19:35745123:ACCTG:A	donor_loss	1.0000
19:35745124:C:A	donor_loss	1.0000
19:35745124:CCTGG:C	donor_gain	1.0000
19:35745330:C:CA	donor_gain	1.0000
19:35745346:A:AC	donor_gain	1.0000
19:35745347:C:CC	donor_gain	1.0000
19:35743798:T:TA	donor_gain	0.9900

AlphaMissense

1200 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:35745197:A:C	F20L	0.981
19:35745197:A:T	F20L	0.981
19:35745199:A:G	F20L	0.981
19:35743874:G:C	F171L	0.978
19:35743874:G:T	F171L	0.978
19:35743876:A:G	F171L	0.978
19:35744143:G:C	F117L	0.974
19:35744143:G:T	F117L	0.974
19:35744145:A:G	F117L	0.974
19:35745365:G:C	F9L	0.969
19:35745365:G:T	F9L	0.969
19:35745367:A:G	F9L	0.969
19:35744413:G:C	F86L	0.966
19:35744413:G:T	F86L	0.966
19:35744415:A:G	F86L	0.966
19:35744044:G:C	F150L	0.965
19:35744044:G:T	F150L	0.965
19:35744046:A:G	F150L	0.965
19:35745131:G:C	F42L	0.955
19:35745131:G:T	F42L	0.955
19:35745133:A:G	F42L	0.955
19:35744144:A:G	F117S	0.954
19:35743883:G:C	F168L	0.945
19:35743883:G:T	F168L	0.945
19:35743885:A:G	F168L	0.945
19:35744089:G:C	F135L	0.943
19:35744089:G:T	F135L	0.943
19:35744091:A:G	F135L	0.943
19:35745128:G:C	S43R	0.936
19:35745128:G:T	S43R	0.936

dbSNP variants (sampled 300 via entrez): RS1001123270 (19:35746666 C>A), RS1001532039 (19:35746250 C>T), RS1002437820 (19:35746106 G>A), RS1003090496 (19:35743423 G>A), RS1003120808 (19:35744197 G>A,T), RS1003447402 (19:35744976 A>T), RS1003974626 (19:35745396 A>G), RS1004089174 (19:35745518 C>A,T), RS1005034610 (19:35744258 C>T), RS1006039121 (19:35742666 C>A,T), RS1006262926 (19:35746051 G>A), RS1007028135 (19:35744616 C>T), RS1007528852 (19:35745561 G>A,C,T), RS1008033533 (19:35743039 G>A,C), RS1008057979 (19:35745761 C>T)

Disease associations

OMIM: gene MIM:601080 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol S	decreases expression, affects cotreatment, increases expression	2
Air Pollutants	increases abundance, increases expression	2
Tunicamycin	increases expression	2
GSK-J4	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
pentabromodiphenyl ether	increases expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
Sunitinib	increases expression	1
Atrazine	increases expression	1
Coal	increases abundance, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diazinon	increases methylation	1
Diethylhexyl Phthalate	increases expression	1
Dimethyl Sulfoxide	affects expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Methyl Methanesulfonate	increases expression	1
Smoke	increases abundance, increases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Thiram	increases expression	1
Valproic Acid	affects expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cyclosporine	increases expression	1
Thapsigargin	increases expression	1

Clinical trials (associated diseases)

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