TRIB2

Summary

TRIB2 (tribbles pseudokinase 2, HGNC:30809) is a protein-coding gene on chromosome 2p24.3, encoding Tribbles homolog 2 (Q92519). Interacts with MAPK kinases and regulates activation of MAP kinases.

This gene encodes one of three members of the Tribbles family. The Tribbles members share a Trb domain, which is homologous to protein serine-threonine kinases, but lacks the active site lysine and probably lacks a catalytic function. The Tribbles proteins interact and modulate the activity of signal transduction pathways in a number of physiological and pathological processes. This Tribbles member induces apoptosis of cells mainly of the hematopoietic origin. It has been identified as a protein up-regulated by inflammatory stimuli in myeloid (THP-1) cells, and also as an oncogene that inactivates the transcription factor C/EBPalpha (CCAAT/enhancer-binding protein alpha) and causes acute myelogenous leukemia. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 28951 — RefSeq curated summary.

At a glance

• GWAS associations: 32
• Clinical variants (ClinVar): 37 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_021643

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30809
Approved symbol	TRIB2
Name	tribbles pseudokinase 2
Location	2p24.3
Locus type	gene with protein product
Status	Approved
Aliases	TRB2, GS3955
Ensembl gene	ENSG00000071575
Ensembl biotype	protein_coding
OMIM	609462
Entrez	28951

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000155926, ENST00000381465, ENST00000405331, ENST00000483034

RefSeq mRNA: 1 — MANE Select: NM_021643 NM_021643

CCDS: CCDS1683

Canonical transcript exons

ENST00000155926 — 3 exons

Exon	Start	End
ENSE00000804846	12716936	12718577
ENSE00001488678	12740326	12742734
ENSE00003631446	12723260	12723552

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 97.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.1975 / max 470.0070, expressed in 1600 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
18942	14.5951	1558
18952	1.3690	660
18941	1.1794	578
18944	1.1136	507
18953	0.9781	482
18955	0.8822	498
18954	0.7942	390
18947	0.4327	185
18945	0.3710	218
18946	0.2046	84

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	97.48	gold quality
ganglionic eminence	UBERON:0004023	97.18	gold quality
right ovary	UBERON:0002118	96.61	gold quality
nerve	UBERON:0001021	96.28	gold quality
tibial nerve	UBERON:0001323	96.28	gold quality
trigeminal ganglion	UBERON:0001675	96.21	gold quality
spleen	UBERON:0002106	95.79	gold quality
paraflocculus	UBERON:0005351	95.78	gold quality
renal medulla	UBERON:0000362	95.61	gold quality
left adrenal gland	UBERON:0001234	95.50	gold quality
ventricular zone	UBERON:0003053	95.47	gold quality
ovary	UBERON:0000992	95.28	gold quality
left adrenal gland cortex	UBERON:0035825	95.24	gold quality
right adrenal gland	UBERON:0001233	95.21	gold quality
adrenal cortex	UBERON:0001235	95.05	gold quality
lymph node	UBERON:0000029	95.02	gold quality
adrenal gland	UBERON:0002369	94.87	gold quality
metanephros cortex	UBERON:0010533	94.85	gold quality
right adrenal gland cortex	UBERON:0035827	94.81	gold quality
dorsal root ganglion	UBERON:0000044	94.75	gold quality
frontal pole	UBERON:0002795	94.57	gold quality
embryo	UBERON:0000922	94.12	gold quality
right lung	UBERON:0002167	94.00	gold quality
omental fat pad	UBERON:0010414	93.43	gold quality
peritoneum	UBERON:0002358	93.42	gold quality
sural nerve	UBERON:0015488	93.09	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.01	gold quality
adrenal tissue	UBERON:0018303	92.97	gold quality
body of stomach	UBERON:0001161	92.66	gold quality
cardia of stomach	UBERON:0001162	92.57	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-6	yes	318.78
E-HCAD-6	yes	42.93
E-ANND-3	yes	7.83
E-ENAD-27	yes	7.17
E-CURD-97	no	618.50
E-CURD-112	no	2.95

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, E2F1, GLI1, NR1I2, PITX1, TAL1, TCF12, TCF3

miRNA regulators (miRDB)

178 targeting TRIB2, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-590-3P	99.96	74.34	6478
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-767-5P	99.95	70.85	993

Literature-anchored findings (GeneRIF, showing 40)

• Anti-TRB2 antibody activities were detected in several autoimmune uveitis patients but not in control subjects, suggesting that TRB2 is a uveitis-associated candidate autoantigen. (PMID:15950723)
• TRB2-Mcl-1 axis plays an important role in survival factor withdrawal-induced apoptosis of TF-1 erythroleukemia cells. (PMID:17545167)
• Downregulation potentiates IL-8 production by human monocytes via enhanced activation of the ERKs and JNK/MAPK pathways (PMID:18952906)
• Data show that SNPs associated with TG in normolipidemic samples, including APOA5, TRIB1, TBL2, GCKR, GALNT2 and ANGPTL3 were significantly associated with HLP types 2B, 3, 4 and 5. (PMID:19656773)
• Trb-2 expression was reduced in acute myeloid leukaemia compared to healthy controls (PMID:20005259)
• Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. (PMID:20160349)
• Overexpression of TRIB2 is associated with malignant melanoma. (PMID:20208562)
• studies have found increased autoantibodies against Tribbles homolog 2 in narcolepsy (PMID:20614846)
• A study reported an increased prevalence of autoantibodies against Tribbles homolog 2 (TRIB2) in patients with narcolepsy (PMID:20614847)
• our data demonstrate that Trib2 can bind both COP1 and C/EBP-alpha, leading to degradation of C/EBP-alpha. (PMID:20805362)
• TRIB2 as a potential driver of lung tumorigenesis through a mechanism that involves downregulation of C/EBPalpha (PMID:21399661)
• Low Trib2 is associated with inflammatory bowel disease. (PMID:22271508)
• We have identified a SNP near the TRIB2 locus that is associated with pericardial fat but not with body mass index or visceral abdominal fat. (PMID:22589742)
• Our findings here support the ability of high TRIB2 expression to reveal a T cell profile in both T cell acute lymphoblastic leukaemias and acute myeloid leukaemias. (PMID:22775572)
• results illustrate that miR-511 and miR-1297 act as tumor suppressor genes, which could suppress A549 cell proliferation in vitro and in vivo by suppressing TRIB2 and further increasing C/EBPalpha expression (PMID:23071539)
• Positive natural selection of TRIB2, a novel gene that influences visceral fat accumulation, in East Asia. (PMID:23108367)
• We discuss the role of Tribs as central signaling mediators in different subtypes of acute leukemia and propose that inhibition of dysregulated Trib signaling may be therapeutically beneficial. (PMID:23550039)
• through regulating the expression of TRIB2 and its downstream factors, let-7c can effectively inhibit A549 cell proliferation in vitro and in vivo (PMID:23850892)
• impaired phosphorylation and ubiquitination by p70S6K and Smurf1 increase the protein stability of TRIB2 in liver cancer (PMID:24089522)
• this study reveals that the stability and ubiquitination of TRIB2 can be also controlled by Ubiquitin E3 ligase SCFb-TRCP. (PMID:24211582)
• we identify the contribution of dysregulated C/EBPalpha and E2F1 to elevated Trib2 expression and leukemic cell survival (PMID:24516045)
• TRIB2 negatively regulates Wnt activity through a reduction in protein stability of TCF4 and beta-Catenin (PMID:25311538)
• Data suggest that TRB2 exhibits metal-independent autophosphorylation activity, low affinity ATP binding/hydrolysis, and a conserved catalytic lysine residue in the active site (rather than the asparagine in many metal-dependent kinases). (PMID:25583260)
• The results suggest that TRIB2 is a meaningful biomarker reflecting diagnosis and progression of melanoma, as well as predicting clinical response to chemotherapy. (PMID:25586991)
• High TRIB2 reinforces the oncogenic transcriptional program controlled by the TAL1 complex in T-cell acute lymphoblastic leukemia. (PMID:26202930)
• Studies suggest that pseudo-kinase family of tribbles (TRIB) proteins TRIB1, TRIB2 and TRIB3 play roles in pathogenesis of rheumatoid arthritis (RA) and osteoarthritis. (PMID:26517922)
• Studies suggest that pseudo-kinase family of tribbles (TRIB) proteins TRIB1, TRIB2 and TRIB3 were involved in the pathogenesis of inflammation. (PMID:26517925)
• Studies suggest that tribbles homolog 2 (Drosophila) protein (TRIB2) as a meaningful biomarker to both diagnose and stage melanoma. (PMID:26517928)
• Studies indicate that the molecular interactions that take place between tribbles homolog 2 (Drosophila) protein (TRIB2) and factors involved in the ubiquitin proteasome system (UPS) are varied and have differential downstream effects. (PMID:26517929)
• Studies indicate that small molecules can reveal rate-limiting signalling outputs and functions of pseudo-kinase family of tribbles (TRIB) proteins TRIB1, TRIB2 and TRIB3 in cells and intact organisms, serving as guides for the development of new drugs. (PMID:26517930)
• Studies show that TRIB1 and TRIB2 are highly expressed in molecularly-defined sub-types of acute myeloid leukemia (AML). (PMID:26517933)
• Studies show a remarkable reduction in tribbles 2 protein (Trib2) expression during oocyte maturation whereas tribbles 1 protein (Trib1) and tribbles 3 protein (Trib3) expression was significantly increased during this process. (PMID:26517934)
• our data show that excess p30 cooperated with TRIB2 only in the presence of p42 to accelerate acute myeloid leukaemia (AML), and the direct interaction and degradation of C/EBPa p42 is required for TRIB2-mediated AML. (PMID:26996668)
• O-GlcNAcylation of TRIB2 might be critical for diabetes-associated liver cancer. (PMID:27515988)
• Data show that TRIB2-mediated degradation of CDC25C is associated with lysine-48-linked CDC25C polyubiquitination driven by the TRIB2 kinase-like domain. (PMID:27563873)
• miR-206 and miR-140, as tumor suppressors, induced lung adenocarcinoma cell death and inhibited cell proliferation by modifying oncogenic TRIB2 promoter activity through p-Smad3. (PMID:28005074)
• Studied effect of TRIB2 SNP on the expression of genes involved in adaptive thermogenesis using messenger RNAs prepared from adipose tissues of Japanese adults. Of the five thermogenic genes, DIO2, CIDEA, PPARGC1A, and PRDM16 showed significantly higher transcript levels in SAT of individuals with the AA genotype relative to those with the AT + TT genotype. (PMID:28212671)
• Tumors from resistant patients expressed the lowest levels of TRIB2. Downregulation of TRIB2 contributes to platin-resistance. (PMID:28670762)
• Trib2 is important for maintaining self-renewal in ES cells and for pluripotency induction during the reprogramming process. (PMID:29170476)
• Due to the downregulation of MDR1 and MRP1, the intracellular accumulation of ADM was increased in the transfected cells compared with that in the parental K562/ADM cells..Our research revealed that protein expression of the ERK signaling pathway was inhibited by downregulating TRIB2, indicating that the ERK pathway was involved in cell drug resistance and proliferation. (PMID:29436678)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	trib2	ENSDARG00000068179
mus_musculus	Trib2	ENSMUSG00000020601
rattus_norvegicus	Trib2	ENSRNOG00000004110
drosophila_melanogaster	trbl	FBGN0028978

Paralogs (3): TRIB3 (ENSG00000101255), TRIB1 (ENSG00000173334), STK40 (ENSG00000196182)

Protein

Protein identifiers

Tribbles homolog 2 — Q92519 (reviewed: Q92519)

All UniProt accessions (3): Q92519, B5MCX4, F8WA18

UniProt curated annotations — full annotation on UniProt →

Function. Interacts with MAPK kinases and regulates activation of MAP kinases. Does not display kinase activity.

Subunit / interactions. Interacts with COP1.

Subcellular location. Cytoplasm. Cytoskeleton.

Tissue specificity. Highly expressed in peripheral blood leukocytes.

Domain organisation. The protein kinase domain is predicted to be catalytically inactive.

Miscellaneous. Antibodies against TRIB2 are present in sera from patients with autoimmune uveitis.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. Tribbles subfamily.

RefSeq proteins (1): NP_067675* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR024104	Tribbles/Ser_Thr_kinase_40	Family

Pfam: PF00069

UniProt features (29 total): helix 10, strand 9, turn 5, chain 1, domain 1, region of interest 1, compositionally biased region 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7UPM	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92519-F1	80.93	0.68

Antibody-complex structures (SAbDab): 1 — 7UPM

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 490 (showing top): TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_6HR_DN, GCACCTT_MIR18A_MIR18B, TGGTGCT_MIR29A_MIR29B_MIR29C, VERHAAK_AML_WITH_NPM1_MUTATED_DN, CREL_01, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, MODULE_169, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, MODULE_45, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (5): positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), negative regulation of interleukin-10 production (GO:0032693), regulation of MAP kinase activity (GO:0043405), negative regulation of fat cell differentiation (GO:0045599), protein phosphorylation (GO:0006468)

GO Molecular Function (8): protein kinase inhibitor activity (GO:0004860), mitogen-activated protein kinase kinase binding (GO:0031434), ubiquitin protein ligase binding (GO:0031625), ubiquitin-protein transferase regulator activity (GO:0055106), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein kinase activity (GO:0004672), protein binding (GO:0005515), ATP binding (GO:0005524)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
negative regulation of cytokine production	1
interleukin-10 production	1
regulation of interleukin-10 production	1
MAP kinase activity	1
regulation of protein serine/threonine kinase activity	1
fat cell differentiation	1
negative regulation of cell differentiation	1
regulation of fat cell differentiation	1
phosphorylation	1
protein modification process	1
protein kinase activity	1
kinase inhibitor activity	1
protein kinase regulator activity	1
protein kinase binding	1
ubiquitin-like protein ligase binding	1
ubiquitin-protein transferase activity	1
enzyme regulator activity	1
DNA-binding transcription factor binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1711 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRIB2	RIBC2	Q9H4K1	901
TRIB2	TRIM21	P19474	742
TRIB2	AKT1	P31749	585
TRIB2	BTRC	Q9Y297	574
TRIB2	MAP2K1	Q02750	558
TRIB2	CEBPA	P49715	546
TRIB2	HCRT	O43612	541
TRIB2	MAP3K1	Q13233	506
TRIB2	COP1	Q8NHY2	474
TRIB2	KIF20A	O95235	471
TRIB2	ITGAV	P06756	464
TRIB2	OVCH2	Q7RTZ1	464
TRIB2	HCRTR2	O43614	438
TRIB2	CD44	P16070	420
TRIB2	FOXM1	Q08050	386

IntAct

30 interactions, top by confidence:

A	B	Type	Score
TFAP4	ANGPTL7	psi-mi:“MI:0914”(association)	0.640
TRIB2	COP1	psi-mi:“MI:0403”(colocalization)	0.620
TRIB2	PARVG	psi-mi:“MI:0915”(physical association)	0.560
TRIB2	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
TRIB2	POTEF	psi-mi:“MI:0914”(association)	0.530
TRIB2	UBE2E1	psi-mi:“MI:0914”(association)	0.530
LRRK2	TRIB2	psi-mi:“MI:0407”(direct interaction)	0.440
TRIB2	BTRC	psi-mi:“MI:0403”(colocalization)	0.430
TRIB2	EEF1G	psi-mi:“MI:0915”(physical association)	0.400
TRIB2	SLAMF7	psi-mi:“MI:0915”(physical association)	0.370
TRIB2	PRMT6	psi-mi:“MI:0915”(physical association)	0.370
TRIB2	MACROH2A1	psi-mi:“MI:0914”(association)	0.350
CCDC33	PRMT5	psi-mi:“MI:0914”(association)	0.350
TRIB2	CARD16	psi-mi:“MI:0914”(association)	0.350
TCF4	TRIB2	psi-mi:“MI:0403”(colocalization)	0.270
TRIB2	TCF4	psi-mi:“MI:0403”(colocalization)	0.270
TRIB2	CTNNB1	psi-mi:“MI:0403”(colocalization)	0.270
CTNNB1	TRIB2	psi-mi:“MI:0403”(colocalization)	0.270
TRIB2	SMURF1	psi-mi:“MI:0403”(colocalization)	0.270
PARVG	TRIB2	psi-mi:“MI:0915”(physical association)	0.000
UBQLN4	TRIB2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (79): RFWD2 (Affinity Capture-Western), BTRC (Affinity Capture-Western), SMURF1 (Affinity Capture-Western), TRIB2 (Affinity Capture-Western), TRIB2 (Affinity Capture-Western), TRIB2 (Biochemical Activity), DET1 (Affinity Capture-MS), STK40 (Affinity Capture-MS), RFWD2 (Affinity Capture-MS), GSTA4 (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), TRIB2 (Affinity Capture-MS), ISCA1 (Affinity Capture-MS), KIAA1217 (Affinity Capture-MS), TRIB1 (Affinity Capture-MS)

ESM2 similar proteins: A0AUV4, A1A5Q6, A1A5R7, A2KF29, B1WAS2, C0HKC8, C0HKC9, O60285, O74536, O88831, O88866, P35125, P51956, P57058, Q20443, Q28283, Q2T9U5, Q4R9F7, Q5GLH2, Q5R669, Q5R7G9, Q5XHI9, Q66HE5, Q68UT7, Q6P431, Q6VZ17, Q7TNJ7, Q7TNL4, Q8BHI9, Q8BZN4, Q8C078, Q8C0N0, Q8C0V7, Q8C0X8, Q8K4K4, Q8NE63, Q8WP28, Q91VB2, Q92519, Q96L34

Diamond homologs: A7E3X2, A8BPK8, A8X0C4, B0WAU8, D2I3C6, D4AE59, O75914, O80902, O88643, P18431, P35465, P35509, P36003, P36005, P39745, P40417, P62345, Q08E52, Q10452, Q13153, Q15772, Q15831, Q17850, Q21017, Q28283, Q39027, Q39193, Q40517, Q40884, Q4R9A9, Q54C77, Q54DF2, Q54LR6, Q54MV2, Q54PX0, Q54QB1, Q54VV7, Q54XQ2, Q55GS4, Q5GLH2

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
miR-155	“up-regulates quantity by expression”	TRIB2	“post transcriptional regulation”
TRIB2	“up-regulates activity”	PKM	phosphorylation
SMURF1	“down-regulates quantity by destabilization”	TRIB2	ubiquitination
RPS6KB1	“down-regulates quantity by destabilization”	TRIB2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 20 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.

GO biological processes:

GO term	Partners	Fold	FDR
ubiquitin-dependent protein catabolic process	5	19.5×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

736 predictions. Top by Δscore:

Variant	Effect	Δscore
2:12723257:TAGG:T	acceptor_loss	1.0000
2:12723548:GAGAG:G	donor_gain	1.0000
2:12723550:GAG:G	donor_gain	1.0000
2:12723553:GTA:G	donor_loss	1.0000
2:12723554:T:G	donor_loss	1.0000
2:12740321:TGCA:T	acceptor_loss	1.0000
2:12740323:CAG:C	acceptor_loss	1.0000
2:12740324:A:AC	acceptor_loss	1.0000
2:12740324:A:AG	acceptor_gain	1.0000
2:12740324:AG:A	acceptor_gain	1.0000
2:12740325:G:GC	acceptor_gain	1.0000
2:12740325:GG:G	acceptor_gain	1.0000
2:12740325:GGA:G	acceptor_gain	1.0000
2:12740325:GGAC:G	acceptor_gain	1.0000
2:12740325:GGACT:G	acceptor_gain	1.0000
2:12717011:G:GG	donor_gain	0.9900
2:12718578:GTAA:G	donor_loss	0.9900
2:12718579:T:A	donor_loss	0.9900
2:12723252:T:A	acceptor_gain	0.9900
2:12723258:A:AG	acceptor_gain	0.9900
2:12723259:G:GG	acceptor_gain	0.9900
2:12723259:GGT:G	acceptor_gain	0.9900
2:12723542:G:GT	donor_gain	0.9900
2:12723553:G:GG	donor_gain	0.9900
2:12740321:T:A	acceptor_gain	0.9900
2:12740323:CAGGA:C	acceptor_gain	0.9900
2:12717006:GCCAC:G	donor_gain	0.9800
2:12717011:GT:G	donor_loss	0.9800
2:12717012:TAAG:T	donor_loss	0.9800
2:12717013:AAG:A	donor_loss	0.9800

AlphaMissense

2257 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:12718574:C:G	C89W	1.000
2:12723401:C:G	H138D	1.000
2:12723411:T:A	V141D	1.000
2:12723487:C:G	C166W	1.000
2:12723510:G:C	R174P	1.000
2:12723513:A:C	D175A	1.000
2:12723513:A:G	D175G	1.000
2:12723513:A:T	D175V	1.000
2:12723516:T:A	L176H	1.000
2:12723516:T:C	L176P	1.000
2:12723518:A:G	K177E	1.000
2:12723520:G:C	K177N	1.000
2:12723520:G:T	K177N	1.000
2:12723530:T:C	F181L	1.000
2:12723531:T:C	F181S	1.000
2:12723532:C:A	F181L	1.000
2:12723532:C:G	F181L	1.000
2:12723537:T:C	F183S	1.000
2:12740403:G:A	G214D	1.000
2:12740405:T:C	C215R	1.000
2:12740409:C:A	P216Q	1.000
2:12740412:C:A	A217D	1.000
2:12740414:T:C	Y218H	1.000
2:12740420:A:C	S220R	1.000
2:12740422:C:A	S220R	1.000
2:12740422:C:G	S220R	1.000
2:12740424:C:A	P221Q	1.000
2:12740433:T:C	L224S	1.000
2:12740457:G:A	G232D	1.000
2:12740466:C:A	A235D	1.000

dbSNP variants (sampled 300 via entrez): RS1000000040 (2:12732231 A>C), RS1000050370 (2:12733681 G>A), RS1000109832 (2:12725980 A>G,T), RS1000214854 (2:12716724 C>A,G,T), RS1000265700 (2:12717032 C>T), RS1000380745 (2:12719646 C>T), RS1000513258 (2:12723632 C>A,T), RS1000598877 (2:12717912 A>G,T), RS1000615358 (2:12730797 G>A), RS1000980410 (2:12741441 G>T), RS1001093733 (2:12735400 C>T), RS1001446167 (2:12729314 A>G), RS1001506590 (2:12722862 G>C,T), RS1001546613 (2:12735081 C>G,T), RS1001813586 (2:12716706 G>A,T)

Disease associations

OMIM: gene MIM:609462 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST001522_1	Pericardial fat	5.000000e-14
GCST001713_15	Dental caries	1.000000e-07
GCST002762_24	Optic cup area	4.000000e-08
GCST002762_9	Optic cup area	1.000000e-09
GCST002875_35	Diisocyanate-induced asthma	1.000000e-06
GCST002875_56	Diisocyanate-induced asthma	7.000000e-06
GCST003968_1	Pericardial adipose tissue adjusted for height and weight	7.000000e-19
GCST003971_2	Pericardial fat	4.000000e-15
GCST004136_13	Methadone dose in opioid dependence	3.000000e-07
GCST004137_15	Optic cup area	4.000000e-08
GCST004137_31	Optic cup area	2.000000e-11
GCST005524_2	Autoimmune thyroid diseases (Graves disease or Hashimoto’s thyroiditis)	2.000000e-07
GCST005526_2	Graves’ disease	5.000000e-06
GCST005531_87	Multiple sclerosis	3.000000e-07
GCST006543_1	Pericardial adipose tissue adjusted for height and weight	2.000000e-11
GCST006544_2	Pericardial adipose tissue adjusted for height and weight	2.000000e-09
GCST006979_909	Heel bone mineral density	8.000000e-12
GCST007576_18	Chronotype	3.000000e-13
GCST007637_41	Diffusing capacity of carbon monoxide	9.000000e-06
GCST009144_21	Disease progression in age-related macular degeneration (adjusted for baseline)	1.000000e-06
GCST010796_5224	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-09
GCST010796_5225	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_5226	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_5227	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_5228	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_5229	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_5230	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-09
GCST011516_8	joint destruction in rheumatoid arthritis (rapid vs slow)	8.000000e-06
GCST011516_9	joint destruction in rheumatoid arthritis (rapid vs slow)	8.000000e-06
GCST90000050_10	Age at first birth	5.000000e-09

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0004338	body weight
EFO:0007907	methadone dose measurement
EFO:0009270	heel bone mineral density
EFO:0008328	chronotype measurement
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0008336	disease progression measurement
EFO:0004327	electrocardiography
EFO:0005413	joint damage measurement
EFO:0009101	age at first birth measurement
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL4523417 (SINGLE PROTEIN), CHEMBL6195508 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195552 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 4 (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
CHEMBL5426285	5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1	4

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10193126	Efficacy	3	allopurinol

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Trbl family

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
9.13	IC50	0.74	nM	CHEMBL6149926
9.13	IC50	0.74	nM	CHEMBL6120923
7.94	IC50	11.5	nM	5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-
7.19	IC50	65.21	nM	CHEMBL6149926
5.46	IC50	3500	nM	CHEMBL4800073

PubChem BioAssay actives

1 with measured affinity, of 17 total; 1 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
(5Z)-5-(1,3-benzothiazol-6-ylmethylidene)-2-[(2R)-1-methoxy-4-methylpentan-2-yl]iminoimidazolidin-4-one	2024515: Inhibition of human TRB2 assessed as remaining activity by eurofins-cerep kinase profiler analysis	ic50	0.0115	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression, affects expression, decreases methylation	7
sodium arsenite	decreases expression, increases expression, affects methylation	6
(+)-JQ1 compound	decreases expression, affects cotreatment	3
Estradiol	affects expression, affects cotreatment, decreases expression	3
entinostat	decreases expression, affects cotreatment	2
Progesterone	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Tretinoin	increases expression	2
sotorasib	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	decreases expression, increases expression	1
pyrrolidine dithiocarbamic acid	affects cotreatment, decreases expression, decreases reaction	1
potassium chromate(VI)	decreases expression	1
ferrous chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
diallyl trisulfide	decreases expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	decreases expression	1
GW 501516	affects binding, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
tricetin	increases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
mirdametinib	affects cotreatment, decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
trametinib	decreases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, decreases expression	1
Irinotecan	affects expression	1

ChEMBL screening assays

40 unique, capped per target: 40 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4314518	Binding	Inhibition of recombinant full-length human TRB2 assessed as residual activity at 10 uM using RRRFRPASPLRGPPK as substrate measured after 120 mins in presence of [gamma33P]ATP by scintillation counting method	Discovery of 3-(((9H-purin-6-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one derivatives as novel tubulin polymerization inhibitors for treatment of cancer. — Eur J Med Chem

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7P7	SEES3-1V human TRIB2, clone1	Embryonic stem cell	Male
CVCL_A7P8	SEES3-1V human TRIB2, clone2	Embryonic stem cell	Male
CVCL_A7P9	SEES3-1V human TRIB2, clone3	Embryonic stem cell	Male
CVCL_TT77	HAP1 TRIB2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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