TRA2B

Summary

TRA2B (transformer 2 beta homolog, HGNC:10781) is a protein-coding gene on chromosome 3q27.2, encoding Transformer-2 protein homolog beta (P62995). Sequence-specific RNA-binding protein which participates in the control of pre-mRNA splicing. It is a selective cancer dependency (DepMap: 58.9% of cell lines).

This gene encodes a nuclear protein which functions as sequence-specific serine/arginine splicing factor which plays a role in mRNA processing, splicing patterns, and gene expression. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 6434 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 45 total — 6 pathogenic
• Phenotypes (HPO): 65
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 58.9% of screened cell lines
• MANE Select transcript: NM_004593

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10781
Approved symbol	TRA2B
Name	transformer 2 beta homolog
Location	3q27.2
Locus type	gene with protein product
Status	Approved
Aliases	Htra2-beta, PPP1R156
Ensembl gene	ENSG00000136527
Ensembl biotype	protein_coding
OMIM	602719
Entrez	6434

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 8 protein_coding, 8 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000259043, ENST00000382191, ENST00000414862, ENST00000453386, ENST00000456380, ENST00000463328, ENST00000465245, ENST00000466832, ENST00000471134, ENST00000477939, ENST00000480461, ENST00000485530, ENST00000487615, ENST00000492417, ENST00000493864, ENST00000867018, ENST00000867019, ENST00000939862, ENST00000939863

RefSeq mRNA: 2 — MANE Select: NM_004593 NM_001243879, NM_004593

CCDS: CCDS33905, CCDS58872

Canonical transcript exons

ENST00000453386 — 9 exons

Exon	Start	End
ENSE00001618549	185914558	185917725
ENSE00001674355	185937825	185938014
ENSE00003470018	185921104	185921187
ENSE00003479423	185918365	185918438
ENSE00003483374	185922011	185922126
ENSE00003484668	185926601	185926734
ENSE00003556786	185923796	185923984
ENSE00003606061	185919437	185919496
ENSE00003666696	185925464	185925626

Expression profiles

Bgee: expression breadth ubiquitous, 305 present calls, max score 99.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 128.4339 / max 1056.3810, expressed in 1827 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45944	69.5261	1825
45945	58.2665	1823
45942	0.4543	234
45943	0.1870	61

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	99.57	gold quality
parietal pleura	UBERON:0002400	99.42	gold quality
ventricular zone	UBERON:0003053	99.36	gold quality
pleura	UBERON:0000977	99.34	gold quality
embryo	UBERON:0000922	99.24	gold quality
visceral pleura	UBERON:0002401	99.23	gold quality
endothelial cell	CL:0000115	99.17	gold quality
ganglionic eminence	UBERON:0004023	99.16	gold quality
cervix squamous epithelium	UBERON:0006922	99.16	gold quality
amniotic fluid	UBERON:0000173	99.15	gold quality
tibia	UBERON:0000979	99.13	gold quality
esophagus squamous epithelium	UBERON:0006920	99.07	gold quality
squamous epithelium	UBERON:0006914	99.05	gold quality
epithelium of nasopharynx	UBERON:0001951	99.00	gold quality
nasopharynx	UBERON:0001728	98.98	gold quality
palpebral conjunctiva	UBERON:0001812	98.98	gold quality
gingival epithelium	UBERON:0001949	98.97	gold quality
hair follicle	UBERON:0002073	98.95	gold quality
eye	UBERON:0000970	98.90	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.84	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.79	gold quality
trabecular bone tissue	UBERON:0002483	98.69	gold quality
pigmented layer of retina	UBERON:0001782	98.68	gold quality
oral cavity	UBERON:0000167	98.67	gold quality
endometrium	UBERON:0001295	98.67	gold quality
corpus epididymis	UBERON:0004359	98.67	gold quality
pancreatic ductal cell	CL:0002079	98.65	gold quality
retina	UBERON:0000966	98.65	gold quality
tongue squamous epithelium	UBERON:0006919	98.64	gold quality
cauda epididymis	UBERON:0004360	98.62	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	42.12
E-CURD-88	yes	20.66
E-MTAB-7249	yes	10.87
E-MTAB-9154	no	555.02
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETS1, HES1, HEY1, HNRNPA1, TFAP4

miRNA regulators (miRDB)

164 targeting TRA2B, 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-3646	100.00	73.56	5283
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3910	99.95	71.13	2227
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 58.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 33)

• interacts with calcitonin/CGRP exon 4 exonic splice enhancer; required for calcitonin splicing in vitro (PMID:12531473)
• results implicate the human tau gene as a target gene for the alternative splicing regulator Tra2 beta protein, suggesting that Tra2 beta may play a role in aberrant tau exon 10 alternative splicing (PMID:12649279)
• Tra2beta1 transcript levels are developmentally regulated in a tissue- and temporal-specific pattern, although expression is ubiquitous. (PMID:12798777)
• Reduced SMN protein levels cause a reduction in the amount of its interacting proteins and of Htra2-beta1 in both discordant and non-discordant spinal muscular atrophy phenotypes. (PMID:14520560)
• hTra2-beta1 expression in cervical cancer. The observed shuttle process of this splicing factor with higher concentrations in the nucleus effects on the cellular function and tumor biology, leading to the worse patient outcome. (PMID:19037821)
• DARPP-32 changes the usage of tra2-beta1 dependent alternative exons in a concentration-dependent manner, suggesting that the DARPP-32:tra2-beta1 interaction is a molecular link between signaling pathways and pre-mRNA processing. (PMID:20074680)
• nuclear hnRNP G level as well as hTra2-beta1 level were independent prognostic factors for endometrial cancer progression-free survival (PMID:20607830)
• Results indicates that the Human Transformer2-beta RNA recognition motif recognizes two types of RNA sequences in different RNA binding modes. (PMID:20926394)
• reduced expression of SFRS10, as observed in tissues from obese humans, alters LPIN1 splicing, induces lipogenesis, and therefore contributes to metabolic phenotypes associated with obesity. (PMID:21803291)
• findings show the inclusion of both HIV-1 exon 3 and vpr mRNA processing is promoted by an exonic splicing enhancer (ESEvpr) localized between exonic splicing silencer ESSV and 5’ss D3; the ESEvpr sequence was found to be bound by members of the Tra2 protein family (PMID:23255807)
• Oxidative stress-responsive Transformer 2beta may play an important role in colon cancer growth. (PMID:23361474)
• analysis of mechanisms by which the subcellular and subnuclear localization of Tra2beta proteins are regulated (PMID:23396973)
• Specific induction of hTra2beta1 due to Alternative splicing is associated with epithelial ovarian cancer. (PMID:23748175)
• SFRS10 is not expressed in normal human retinae but is upregulated in Age-related macular degeneration retinae. (PMID:24098751)
• Facilitating Tra2beta-dependent inclusion of exons in target pre-mRNAs. (PMID:24865968)
• Results indicate that transformer 2beta (Tra2beta) was involved in the tumorigenesis of NSCLC and might be a potential therapeutic target of non-small cell lung cancer (NSCLC). (PMID:24952301)
• Simultaneous depletion of Tra2alpha and Tra2beta induces substantial shifts in splicing of endogenous Tra2beta target exons, and both constitutive and alternative target exons are under dual Tra2alpha-Tra2beta control. (PMID:25208576)
• findings suggest that Tra2beta regulates apoptosis by modulating Bcl-2 expression through its competition with miR-204. This novel function may have a crucial role in tumor growth. (PMID:25342468)
• Results showed that HNRNPG and HTRA2-BETA1 were specific antagonistic regulators of ERa exon7 splicing and increased HNRNPG levels were associated with improved clinical outcome of endometrial cancer through up-regulation of ERaD7 expression. (PMID:25884434)
• Overexpression of either Tra2alpha or Tra2beta results in a marked reduction in HIV-1 Gag/ Env expression. (PMID:25970345)
• SRPK1 is a regulator of Tra2beta1 splicing function and individual domains engage in considerable cross-talk, assuming novel functions with regard to RNA binding, splicing, and catalysis. (PMID:26013829)
• Tra2beta was significantly upregulated in prostate carcinoma, and multivariate analysis confirmed Tra2beta as an independent prognostic factor. (PMID:26261585)
• that TRA2beta promotes glioma cell growth and migration, and could be a candidate for molecular targeting during gene therapy treatments of glioma (PMID:26298634)
• It seems that a new signaling axis, SIRT1-SFRS10-LPIN1 axis, acting in the pathogenesis of alcoholic fatty liver disease exists. (PMID:28467182)
• Findings demonstrate that Tra2b is upregulated in non-small cell lung cancer (NSCLC) and is associated with poor prognosis. Furthermore, Tra2b was identified as a direct target of miR-335. These results indicate that the interaction between miR-335 and Tra2b may play a vital role in the pathogenesis of NSCLC. (PMID:29161765)
• HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells. (PMID:31311954)
• MicroRNA-330-3p represses the proliferation and invasion of laryngeal squamous cell carcinoma through downregulation of Tra2beta-mediated Akt signaling. (PMID:32289378)
• Bone marrow mesenchymal stem cell-derived exosomal miR-206 inhibits osteosarcoma progression by targeting TRA2B. (PMID:32682951)
• Tra2beta protects against the degeneration of chondrocytes by inhibiting chondrocyte apoptosis via activating the PI3K/Akt signaling pathway. (PMID:32964954)
• Clustered variants in the 5’ coding region of TRA2B cause a distinctive neurodevelopmental syndrome. (PMID:36549593)
• Tra2beta Enhances Cell Proliferation by Inducing the Expression of Transcription Factor SP1 in Cervical Cancer. (PMID:36861193)
• Bulk and single-cell alternative splicing analyses reveal roles of TRA2B in myogenic differentiation. (PMID:37705195)
• Autoregulated splicing of TRA2beta programs T cell fate in response to antigen-receptor stimulation. (PMID:39265028)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tra2b	ENSDARG00000002168
mus_musculus	Tra2b	ENSMUSG00000022858
rattus_norvegicus	Tra2b	ENSRNOG00000001783

Paralogs (1): TRA2A (ENSG00000164548)

Protein

Protein identifiers

Transformer-2 protein homolog beta — P62995 (reviewed: P62995)

Alternative names: Splicing factor, arginine/serine-rich 10, Transformer-2 protein homolog B

All UniProt accessions (3): P62995, H7BXF3, H7C2L4

UniProt curated annotations — full annotation on UniProt →

Function. Sequence-specific RNA-binding protein which participates in the control of pre-mRNA splicing. Can either activate or suppress exon inclusion. Acts additively with RBMX to promote exon 7 inclusion of the survival motor neuron SMN2. Activates the splicing of MAPT/Tau exon 10. Alters pre-mRNA splicing patterns by antagonizing the effects of splicing regulators, like RBMX. Binds to the AG-rich SE2 domain in the SMN exon 7 RNA. Binds to pre-mRNA.

Subunit / interactions. Found in a pre-mRNA exonic splicing enhancer (ESE) complex with TRA2B/SFRS10, SNRNP70, SNRPA1 and SRRM1. Binds to A3 enhancer proteins SFRS4, SFRS5, SFRS6 and SFRS9. Interacts with CPSF6, RBMY1A1, RBMX, RNPS1 and phosphorylated SFRS13A. Interacts with SAFB/SAFB1. Interacts with ILDR1 (via C-terminus) and ILDR2.

Subcellular location. Nucleus.

Tissue specificity. Highest expression in heart, skeletal muscle and pancreas. Less abundant in kidney, placenta and brain. Lowest expression in kidney and liver.

Post-translational modifications. Phosphorylated in the RS domains. Dimethylation at Arg-241 is probably asymmetric.

Similarity. Belongs to the splicing factor SR family.

Isoforms (3)

UniProt ID	Names	Canonical?
P62995-1	1, HTRA2-beta1	yes
P62995-2	2, HTRA2-beta2
P62995-3	3, HTRA2-beta3

RefSeq proteins (2): NP_001230808, NP_004584* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR050441	RBM	Family

Pfam: PF00076

UniProt features (43 total): modified residue 20, strand 6, region of interest 4, splice variant 3, helix 3, compositionally biased region 3, initiator methionine 1, chain 1, domain 1, cross-link 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2CQC	SOLUTION NMR
2KXN	SOLUTION NMR
2RRA	SOLUTION NMR
2RRB	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62995-F1	57.18	0.18

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 (21): 2, 2, 4, 14, 29, 33, 83, 85, 87, 95, 97, 99, 103, 201, 203, 215, 237, 241, 241, 241 …

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA
R-HSA-9013418	RHOBTB2 GTPase cycle
R-HSA-9013422	RHOBTB1 GTPase cycle
R-HSA-9770562	mRNA Polyadenylation

MSigDB gene sets: 339 (showing top): E2F_Q4, MORF_DNMT1, MORF_SMC1L1, E2F4DP1_01, GOBP_POSITIVE_REGULATION_OF_RNA_SPLICING, GOBP_POSITIVE_REGULATION_OF_MRNA_PROCESSING, MODULE_151, GOBP_ALTERNATIVE_MRNA_SPLICING_VIA_SPLICEOSOME, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, MORF_RRM1, MORF_HDAC1, MORF_UBE2N, CAGGTCC_MIR492, GNF2_MCM5

GO Biological Process (10): RNA splicing, via transesterification reactions (GO:0000375), regulation of alternative mRNA splicing, via spliceosome (GO:0000381), mRNA splicing, via spliceosome (GO:0000398), cerebral cortex regionalization (GO:0021796), regulation of RNA splicing (GO:0043484), positive regulation of mRNA splicing, via spliceosome (GO:0048026), cellular response to glucose stimulus (GO:0071333), embryonic brain development (GO:1990403), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (7): RNA binding (GO:0003723), mRNA binding (GO:0003729), protein domain specific binding (GO:0019904), pre-mRNA binding (GO:0036002), identical protein binding (GO:0042802), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nuclear inner membrane (GO:0005637), nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
RHOBTB GTPase Cycle	2
mRNA Splicing	1
Metabolism of RNA	1
mRNA 3’-end processing	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA splicing	2
regulation of mRNA splicing, via spliceosome	2
RNA processing	2
RNA binding	2
protein binding	2
binding	2
alternative mRNA splicing, via spliceosome	1
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
regionalization	1
telencephalon regionalization	1
cerebral cortex development	1
regulation of gene expression	1
regulation of primary metabolic process	1
mRNA splicing, via spliceosome	1
positive regulation of RNA splicing	1
positive regulation of mRNA processing	1
intracellular glucose homeostasis	1
response to glucose	1
cellular response to hexose stimulus	1
embryonic organ development	1
mRNA metabolic process	1
nucleic acid binding	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
nuclear membrane	1
nuclear lumen	1
cellular anatomical structure	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1
cellular_component	1

Protein interactions and networks

STRING

3165 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRA2B	SRSF9	Q13242	941
TRA2B	SRSF3	P23152	922
TRA2B	SRSF1	Q07955	902
TRA2B	SMN1	Q16637	862
TRA2B	PNN	Q9H307	816
TRA2B	HNRNPH1	P31943	803
TRA2B	SRSF11	Q05519	743
TRA2B	SRSF7	Q16629	742
TRA2B	HIPK3	Q9H422	737
TRA2B	SRRM1	Q8IYB3	733
TRA2B	HNRNPC	P07910	715
TRA2B	SRSF6	Q13247	707
TRA2B	KHDRBS1	Q07666	696
TRA2B	HTRA2	O43464	692
TRA2B	SRPK1	Q96SB4	669

IntAct

213 interactions, top by confidence:

A	B	Type	Score
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
TRA2B	CLK3	psi-mi:“MI:0915”(physical association)	0.800
TRA2B	SRPK2	psi-mi:“MI:0915”(physical association)	0.760
SRPK2	TRA2B	psi-mi:“MI:0217”(phosphorylation reaction)	0.760
YBX1	SSB	psi-mi:“MI:0914”(association)	0.710
SNRPD2	GEMIN2	psi-mi:“MI:0914”(association)	0.710
TRA2B	SRSF4	psi-mi:“MI:0915”(physical association)	0.670
RBMX	TRA2B	psi-mi:“MI:0915”(physical association)	0.670
TRA2B	YTHDC1	psi-mi:“MI:0915”(physical association)	0.670
SF3B1	SAP18	psi-mi:“MI:0914”(association)	0.640
THOC1	DDX39A	psi-mi:“MI:0914”(association)	0.640
TRA2B	EPM2AIP1	psi-mi:“MI:0915”(physical association)	0.560
TRA2B	RBMY1F	psi-mi:“MI:0915”(physical association)	0.560
CLK1	TRA2B	psi-mi:“MI:0915”(physical association)	0.560
TRA2B	SRSF8	psi-mi:“MI:0915”(physical association)	0.560
U2AF1	TRA2B	psi-mi:“MI:0915”(physical association)	0.560
TRA2B	MYPOP	psi-mi:“MI:0915”(physical association)	0.560
TRA2B	TRA2B	psi-mi:“MI:0915”(physical association)	0.560
TRA2B	MAGOHB	psi-mi:“MI:0915”(physical association)	0.560
TRA2B	PCDHB14	psi-mi:“MI:0915”(physical association)	0.560
TRA2B	SRSF9	psi-mi:“MI:0915”(physical association)	0.560
TRA2B	SRSF1	psi-mi:“MI:0915”(physical association)	0.560
SYNGAP1	SEC16A	psi-mi:“MI:0914”(association)	0.530
SNRNP70	GTPBP1	psi-mi:“MI:0914”(association)	0.530
ELAVL2	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
LUC7L2	CASC3	psi-mi:“MI:0914”(association)	0.530
SNIP1	CASC3	psi-mi:“MI:0914”(association)	0.530
ZC3H18	AQR	psi-mi:“MI:0914”(association)	0.530

BioGRID (513): TRA2B (Affinity Capture-MS), TRA2B (Affinity Capture-MS), TRA2B (Affinity Capture-MS), TRA2B (Affinity Capture-MS), TRA2B (Affinity Capture-MS), TRA2B (Affinity Capture-MS), TRA2B (Affinity Capture-RNA), TRA2B (Affinity Capture-MS), DDX47 (Co-fractionation), EIF3I (Co-fractionation), RNPS1 (Co-fractionation), SLC3A2 (Co-fractionation), TRA2B (Co-fractionation), TRA2B (Co-fractionation), TRA2B (Co-fractionation)

ESM2 similar proteins: A5A6M3, D4AE41, O22703, O75526, P30352, P35637, P38159, P56959, P60824, P60825, P60826, P62995, P62996, P62997, P78814, P84586, P92965, P92966, Q01560, Q01844, Q14011, Q24491, Q27294, Q28009, Q29RT0, Q3ZBT6, Q4P2Q5, Q4R7F0, Q4R813, Q4V898, Q54Y98, Q55FQ0, Q5RF83, Q61545, Q6IRQ4, Q7ZWA3, Q8L3X8, Q8RWN5, Q8VYA5, Q91VM5

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

2 interactions.

A	Effect	B	Mechanism
HNRNPA1	“up-regulates quantity by expression”	TRA2B	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 193 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	11	30.8×	1e-12
mRNA 3’-end processing	17	24.6×	7e-18
RNA Polymerase II Transcription Termination	15	24.2×	1e-15
mRNA Splicing	26	21.0×	1e-25
mRNA Polyadenylation	32	20.7×	1e-31
Processing of Capped Intron-Containing Pre-mRNA	34	20.5×	1e-33
Transport of Mature mRNA derived from an Intron-Containing Transcript	17	19.0×	8e-16
mRNA Splicing - Major Pathway	42	16.9×	5e-38

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of mRNA splicing, via spliceosome	10	45.1×	1e-12
regulation of mRNA splicing, via spliceosome	6	31.3×	3e-06
U2-type prespliceosome assembly	7	25.7×	1e-06
spliceosomal complex assembly	7	24.8×	1e-06
mRNA splice site recognition	5	23.6×	1e-04
regulation of alternative mRNA splicing, via spliceosome	15	21.6×	5e-14
spliceosomal snRNP assembly	6	20.5×	3e-05
RNA splicing, via transesterification reactions	5	18.4×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	0
Uncertain significance	22
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
2579119	NM_004593.3(TRA2B):c.170+1G>A	Pathogenic
4277369	NM_004593.3(TRA2B):c.19C>T (p.Gln7Ter)	Pathogenic
4531189	NM_004593.3(TRA2B):c.170+1del	Pathogenic
4531190	NM_004593.3(TRA2B):c.2T>G (p.Met1Arg)	Pathogenic
4531191	NM_004593.3(TRA2B):c.2_4del (p.Met1del)	Pathogenic
4531192	NM_004593.3(TRA2B):c.1A>G (p.Met1Val)	Pathogenic

SpliceAI

1283 predictions. Top by Δscore:

Variant	Effect	Δscore
3:185918363:A:AC	donor_gain	1.0000
3:185918364:C:CT	donor_gain	1.0000
3:185918364:CGA:C	donor_gain	1.0000
3:185918364:CGAG:C	donor_gain	1.0000
3:185918364:CGAGG:C	donor_gain	1.0000
3:185918435:CCTT:C	acceptor_loss	1.0000
3:185918436:CTT:C	acceptor_gain	1.0000
3:185918437:TT:T	acceptor_gain	1.0000
3:185918438:TCTA:T	acceptor_loss	1.0000
3:185918439:C:A	acceptor_loss	1.0000
3:185918439:C:CC	acceptor_gain	1.0000
3:185918440:T:G	acceptor_loss	1.0000
3:185921099:CTTA:C	donor_loss	1.0000
3:185921100:TTA:T	donor_loss	1.0000
3:185921102:A:AC	donor_gain	1.0000
3:185921102:A:AT	donor_loss	1.0000
3:185921103:C:CA	donor_loss	1.0000
3:185921103:C:CC	donor_gain	1.0000
3:185921103:CCT:C	donor_gain	1.0000
3:185921103:CCTGT:C	donor_gain	1.0000
3:185921183:TGCCA:T	acceptor_gain	1.0000
3:185921185:CCA:C	acceptor_gain	1.0000
3:185921186:CA:C	acceptor_gain	1.0000
3:185921186:CACTA:C	acceptor_gain	1.0000
3:185921188:C:CC	acceptor_gain	1.0000
3:185921190:A:AC	acceptor_gain	1.0000
3:185921190:A:C	acceptor_gain	1.0000
3:185922009:A:AC	donor_gain	1.0000
3:185922010:C:CC	donor_gain	1.0000
3:185923791:CTT:C	donor_loss	1.0000

AlphaMissense

1825 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:185922023:C:A	G209V	1.000
3:185922023:C:T	G209E	1.000
3:185922024:C:A	G209W	1.000
3:185922024:C:G	G209R	1.000
3:185922024:C:T	G209R	1.000
3:185922026:A:G	M208T	1.000
3:185922029:T:C	Y207C	1.000
3:185922030:A:C	Y207D	1.000
3:185922030:A:G	Y207H	1.000
3:185922030:A:T	Y207N	1.000
3:185922035:C:A	G205V	1.000
3:185922035:C:T	G205E	1.000
3:185922036:C:G	G205R	1.000
3:185922036:C:T	G205R	1.000
3:185922038:G:A	P204L	1.000
3:185922038:G:T	P204Q	1.000
3:185922039:G:A	P204S	1.000
3:185922041:G:A	T203I	1.000
3:185922044:G:T	P202Q	1.000
3:185922049:A:C	H200Q	1.000
3:185922049:A:T	H200Q	1.000
3:185922050:T:C	H200R	1.000
3:185922051:G:C	H200D	1.000
3:185922051:G:T	H200N	1.000
3:185922055:T:A	R198S	1.000
3:185922055:T:G	R198S	1.000
3:185922062:G:A	T196I	1.000
3:185922062:G:T	T196K	1.000
3:185922063:T:C	T196A	1.000
3:185922065:A:C	I195R	1.000

dbSNP variants (sampled 300 via entrez): RS1000040289 (3:185933651 A>AT), RS1000052374 (3:185922002 T>C), RS1000102064 (3:185916941 T>C), RS1000155967 (3:185916675 G>A,T), RS1000239069 (3:185915296 A>G), RS1000323777 (3:185937410 G>C,T), RS1000395502 (3:185927923 G>A,C), RS1000480775 (3:185924452 T>C), RS1000587988 (3:185937239 C>T), RS1000732846 (3:185931340 T>C), RS1000741467 (3:185924585 T>C,G), RS1000805779 (3:185926316 C>G,T), RS1000836986 (3:185926076 C>T), RS1001007446 (3:185921295 T>C), RS1001040024 (3:185929183 T>G)

Disease associations

OMIM: gene MIM:602719 | disease phenotypes: MIM:621421

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant
complex neurodevelopmental disorder	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic complex neurodevelopmental disorder	Definitive	AD

Mondo (3): Ramond-Elliott neurodevelopmental syndrome (MONDO:0980751), complex neurodevelopmental disorder (MONDO:0100038), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

65 total (30 of 65 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000121	Nephrocalcinosis
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000252	Microcephaly
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000483	Astigmatism
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000577	Exotropia
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000744	Low frustration tolerance
HP:0000750	Delayed speech and language development
HP:0000823	Delayed puberty
HP:0001156	Brachydactyly
HP:0001159	Syndactyly
HP:0001182	Tapered finger
HP:0001238	Slender finger
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001290	Generalized hypotonia
HP:0001321	Cerebellar hypoplasia
HP:0001513	Obesity
HP:0001562	Oligohydramnios
HP:0001642	Pulmonic stenosis
HP:0001643	Patent ductus arteriosus
HP:0001655	Patent foramen ovale

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000296_14	Body mass index	7.000000e-11
GCST000299_16	Weight	4.000000e-09
GCST000880_42	Menarche (age at onset)	1.000000e-09
GCST002541_7	Menarche (age at onset)	1.000000e-16
GCST003262_614	Post bronchodilator FEV1	1.000000e-06
GCST003264_437	Post bronchodilator FEV1/FVC ratio	6.000000e-07
GCST003993_16	Menarche (age at onset)	6.000000e-07
GCST008839_519	Height	7.000000e-11
GCST90000025_681	Appendicular lean mass	1.000000e-13

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004338	body weight
EFO:0004703	age at menarche
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0004980	appendicular lean mass

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): CHEMBL5725060 (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

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

pChembl	Type	Value	Unit	Molecule
7.92	Kd	12.12	nM	CHEMBL3752910
7.92	ED50	12.12	nM	CHEMBL3752910
6.64	IC50	230	nM	MOLIBRESIB
6.27	Kd	537.3	nM	CHEMBL5653589
6.27	ED50	537.3	nM	CHEMBL5653589

PubChem BioAssay actives

3 with measured affinity, of 10 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	2149650: Binding affinity to human TRA2B incubated for 45 mins by Kinobead based pull down assay	kd	0.0121	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	2178784: Inhibition of SFRS10 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.2300	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149650: Binding affinity to human TRA2B incubated for 45 mins by Kinobead based pull down assay	kd	0.5373	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases phosphorylation, increases reaction, decreases expression, affects binding, increases expression	3
bisphenol A	decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment, increases expression	2
bisphenol S	affects cotreatment, increases methylation, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression, increases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression, increases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	decreases expression	1
gossypol acetic acid	increases expression	1
coumarin	affects phosphorylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
chloropicrin	increases expression	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652692	Binding	Binding affinity to human TRA2B 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)

204 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
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
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