TOX2

Summary

TOX2 (TOX high mobility group box family member 2, HGNC:16095) is a protein-coding gene on chromosome 20q13.12, encoding TOX high mobility group box family member 2 (Q96NM4). Putative transcriptional activator involved in the hypothalamo-pituitary-gonadal system.

Enables transcription coactivator activity. Involved in positive regulation of transcription by RNA polymerase II. Located in nucleoplasm.

Source: NCBI Gene 84969 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 76 total
• MANE Select transcript: NM_001098797

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16095
Approved symbol	TOX2
Name	TOX high mobility group box family member 2
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	dJ1108D11.2, GCX-1
Ensembl gene	ENSG00000124191
Ensembl biotype	protein_coding
OMIM	611163
Entrez	84969

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000341197, ENST00000358131, ENST00000372999, ENST00000413823, ENST00000423191, ENST00000435864, ENST00000864665, ENST00000864666, ENST00000956506, ENST00000956507

RefSeq mRNA: 4 — MANE Select: NM_001098797 NM_001098796, NM_001098797, NM_001098798, NM_032883

CCDS: CCDS13324, CCDS42875, CCDS46603

Canonical transcript exons

ENST00000341197 — 9 exons

Exon	Start	End
ENSE00001672982	44006547	44006792
ENSE00001771384	43914852	43914990
ENSE00003475677	44068650	44069616
ENSE00003607613	43973367	43973432
ENSE00003703421	44065712	44066107
ENSE00003704395	44064777	44064857
ENSE00003707155	44066730	44066857
ENSE00003708833	44054299	44054526
ENSE00003710272	44051306	44051545

Expression profiles

Bgee: expression breadth ubiquitous, 196 present calls, max score 96.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.7935 / max 302.7338, expressed in 1283 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184685	8.5399	1265
184691	0.4896	92
184688	0.2952	74
184692	0.2702	142
184687	0.1634	76
184690	0.0150	4
184689	0.0112	4
184693	0.0090	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	96.44	gold quality
thymus	UBERON:0002370	94.91	gold quality
mucosa of stomach	UBERON:0001199	94.10	gold quality
right lung	UBERON:0002167	93.54	gold quality
oocyte	CL:0000023	92.61	gold quality
lower lobe of lung	UBERON:0008949	91.56	gold quality
upper lobe of lung	UBERON:0008948	88.51	gold quality
upper lobe of left lung	UBERON:0008952	88.28	gold quality
lower esophagus muscularis layer	UBERON:0035833	87.99	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.93	gold quality
lower esophagus	UBERON:0013473	87.91	gold quality
hypothalamus	UBERON:0001898	87.40	gold quality
lower esophagus mucosa	UBERON:0035834	86.01	gold quality
descending thoracic aorta	UBERON:0002345	85.86	gold quality
pituitary gland	UBERON:0000007	85.26	gold quality
adenohypophysis	UBERON:0002196	84.51	gold quality
lung	UBERON:0002048	84.03	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.92	gold quality
right frontal lobe	UBERON:0002810	83.51	gold quality
prefrontal cortex	UBERON:0000451	83.33	gold quality
thoracic aorta	UBERON:0001515	82.79	gold quality
anterior cingulate cortex	UBERON:0009835	82.67	gold quality
Brodmann (1909) area 9	UBERON:0013540	82.44	gold quality
ascending aorta	UBERON:0001496	82.42	gold quality
substantia nigra	UBERON:0002038	82.18	gold quality
esophagus	UBERON:0001043	82.01	gold quality
left testis	UBERON:0004533	81.97	gold quality
frontal cortex	UBERON:0001870	81.57	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.41	gold quality
postcentral gyrus	UBERON:0002581	81.22	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	13.28
E-CURD-122	yes	10.63
E-ANND-3	yes	6.74
E-MTAB-6678	yes	4.88
E-MTAB-6075	no	557.67
E-MTAB-8060	no	47.16
E-CURD-112	no	3.25

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
ETS1	Activation
IL15	Activation
TBX21	Activation

miRNA regulators (miRDB)

61 targeting TOX2, 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-340-5P	100.00	72.50	4437
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-609	99.82	64.26	505
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-657	99.48	66.02	848
HSA-MIR-142-5P	99.48	70.92	2416
HSA-MIR-5590-3P	99.48	70.91	2429
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-593-5P	99.34	69.50	965
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-6829-5P	98.86	65.12	1480

Literature-anchored findings (GeneRIF, showing 7)

• Identification and functional analysis of the rat Gcx1 ortholog. (PMID:14764631)
• A novel aberrantly hypermethylated CpG island in cancer was discovered within the TOX2 promoter. TOX2 was unmethylated in normal cells. Expression of two novel TOX2 transcripts was significantly reduced in primary lung tumors. (PMID:22496870)
• TOX2 plays a crucial role in controlling normal NK cell development by acting upstream of TBX21 transcriptional regulation (PMID:25352127)
• A haplotype block across a 24-kb region within the TOX2 gene reached genome-wide significance in haplotype-block-based regional heritability mapping. Single-SNP- and haplotype-based association tests demonstrated that five of nine genotyped SNPs and two haplotypes within this block were significantly associated with major depressive disorder. (PMID:28153336)
• CD4+ T cells in classical Hodgkin lymphoma express exhaustion associated transcription factors TOX and TOX2: Characterizing CD4+ T cells in Hodgkin lymphoma. (PMID:35111387)
• TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells. (PMID:37467321)
• TOX2 nuclear-cytosol translocation is linked to leukemogenesis of acute T-cell leukemia by repressing TIM3 transcription. (PMID:39080376)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tox2	ENSDARG00000100055
mus_musculus	Tox2	ENSMUSG00000074607
rattus_norvegicus	Tox2	ENSRNOG00000008146
caenorhabditis_elegans	hmg-3	WBGENE00001973
caenorhabditis_elegans		WBGENE00001974

Paralogs (20): HMGB3 (ENSG00000029993), HMG20B (ENSG00000064961), SP100 (ENSG00000067066), SMARCE1 (ENSG00000073584), SP140 (ENSG00000079263), TOX4 (ENSG00000092203), HMGXB4 (ENSG00000100281), TOX3 (ENSG00000103460), TFAM (ENSG00000108064), UBTF (ENSG00000108312), HMGB1P1 (ENSG00000124097), SP110 (ENSG00000135899), HMG20A (ENSG00000140382), SSRP1 (ENSG00000149136), HMGB2 (ENSG00000164104), HMGB4 (ENSG00000176256), SP140L (ENSG00000185404), HMGB1 (ENSG00000189403), TOX (ENSG00000198846), UBTFL1 (ENSG00000255009)

Protein

Protein identifiers

TOX high mobility group box family member 2 — Q96NM4 (reviewed: Q96NM4)

Alternative names: Granulosa cell HMG box protein 1

All UniProt accessions (2): Q96NM4, Q5JYD4

UniProt curated annotations — full annotation on UniProt →

Function. Putative transcriptional activator involved in the hypothalamo-pituitary-gonadal system.

Subcellular location. Nucleus.

Isoforms (4)

UniProt ID	Names	Canonical?
Q96NM4-1	1	yes
Q96NM4-2	2
Q96NM4-3	3
Q96NM4-4	4

RefSeq proteins (4): NP_001092266, NP_001092267, NP_001092268, NP_116272 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR051365	TOX_HMG-box_domain	Family

Pfam: PF00505

UniProt features (18 total): compositionally biased region 5, region of interest 4, splice variant 3, sequence conflict 2, chain 1, DNA-binding region 1, sequence variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96NM4-F1	51.70	0.06

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 159 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, AREB6_03, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, ZHAN_MULTIPLE_MYELOMA_CD1_UP, KOYAMA_SEMA3B_TARGETS_UP, AACTTT_UNKNOWN, MYB_Q3, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, TGGNNNNNNKCCAR_UNKNOWN, HAN_SATB1_TARGETS_DN, MODULE_48, GRADE_COLON_AND_RECTAL_CANCER_DN, MODULE_95, RIGGI_EWING_SARCOMA_PROGENITOR_UP

GO Biological Process (2): regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (4): transcription coactivator activity (GO:0003713), chromatin DNA binding (GO:0031490), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), nucleoplasm (GO:0005654)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	2
positive regulation of DNA-templated transcription	2
regulation of DNA-templated transcription	1
regulation of transcription by RNA polymerase II	1
transcription coregulator activity	1
DNA binding	1
chromatin binding	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1176 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOX2	ZNF461	Q8TAF7	923
TOX2	PHGDH	O43175	686
TOX2	LGALS4	P56470	542
TOX2	TCF7	P36402	491
TOX2	TBX21	Q9UL17	417
TOX2	BATF	Q16520	404
TOX2	DENND2B	P78523	403
TOX2	TIGIT	Q495A1	401
TOX2	PDCD1	Q15116	400
TOX2	EOMES	O95936	399
TOX2	HAVCR2	Q8TDQ0	397
TOX2	LAG3	P18627	368
TOX2	PRDM1	O75626	353
TOX2	SLC1A2	P43004	352
TOX2	SLC32A1	Q9H598	349
TOX2	GNG3	P29798	349

IntAct

7 interactions, top by confidence:

A	B	Type	Score
TOX2	MFHAS1	psi-mi:“MI:0407”(direct interaction)	0.440
PKM	TOX2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
S100A6	VWA8	psi-mi:“MI:0914”(association)	0.350
TOX2	TOX4	psi-mi:“MI:0914”(association)	0.350
TSEN2	TMED8	psi-mi:“MI:0914”(association)	0.350

BioGRID (38): TOX (Affinity Capture-MS), TOX4 (Affinity Capture-MS), AKT3 (Affinity Capture-MS), GINS4 (Affinity Capture-MS), TOX2 (Reconstituted Complex), TOX2 (Two-hybrid), TOX2 (Two-hybrid), TOX2 (Two-hybrid), TOX2 (Two-hybrid), TOX2 (Two-hybrid), TOX2 (Two-hybrid), TOX2 (Two-hybrid), TOX2 (Two-hybrid), UNC5CL (Two-hybrid), P4HA3 (Two-hybrid)

ESM2 similar proteins: A1A5P0, A1XSY8, A1YF15, A1YG91, A2AFE9, A2D4Z7, A2T762, A5PJK7, A8WFF7, C0LZJ1, O36399, O43474, O75956, P03413, P08651, P09414, P17923, P21999, P22893, P26633, P26651, P41162, P46153, P47973, P97489, Q01196, Q02780, Q03347, Q08427, Q08775, Q12857, Q13761, Q13950, Q2HRB6, Q58CN7, Q60793, Q61169, Q63046, Q64131, Q76IQ7

Diamond homologs: A4QNP0, B2RPK0, B7SBD2, O15347, O15405, O54879, O94842, O94900, P0CO24, P0CO25, P11632, P11633, P11873, P12682, P40618, Q0P5K4, Q32L31, Q4IQX3, Q4PBZ9, Q4WY33, Q5B995, Q5R6A9, Q66JW3, Q6BRB4, Q6CC79, Q6CVH3, Q6DJL0, Q6IRR0, Q75B82, Q76IQ7, Q7S045, Q80W03, Q8BU11, Q96NM4, Q99PM1, Q9UVL1, Q9YH06, P07746, A9RA84, B0CM99

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TOX2	“up-regulates quantity by expression”	TBX21	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	70
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2004 predictions. Top by Δscore:

Variant	Effect	Δscore
20:43973365:A:AG	acceptor_gain	1.0000
20:43973365:AGTTT:A	acceptor_gain	1.0000
20:43973366:G:GG	acceptor_gain	1.0000
20:43973366:GTTTG:G	acceptor_gain	1.0000
20:44006536:T:A	acceptor_gain	1.0000
20:44006539:T:A	acceptor_gain	1.0000
20:44006543:TTAG:T	acceptor_loss	1.0000
20:44006544:TA:T	acceptor_loss	1.0000
20:44006545:A:AG	acceptor_gain	1.0000
20:44006545:AG:A	acceptor_loss	1.0000
20:44006546:G:GT	acceptor_gain	1.0000
20:44006546:GA:G	acceptor_gain	1.0000
20:44006546:GAC:G	acceptor_gain	1.0000
20:44006546:GACC:G	acceptor_gain	1.0000
20:44006546:GACCT:G	acceptor_gain	1.0000
20:44051304:A:AG	acceptor_gain	1.0000
20:44051305:G:GG	acceptor_gain	1.0000
20:44051305:GA:G	acceptor_gain	1.0000
20:44051519:G:GT	donor_gain	1.0000
20:44051531:G:GT	donor_gain	1.0000
20:44051545:GGT:G	donor_loss	1.0000
20:44051546:G:GC	donor_loss	1.0000
20:44051547:T:G	donor_loss	1.0000
20:44054523:GCAG:G	donor_gain	1.0000
20:44054524:CAGGT:C	donor_loss	1.0000
20:44054525:AGGTG:A	donor_loss	1.0000
20:44054527:GT:G	donor_loss	1.0000
20:44054528:T:A	donor_loss	1.0000
20:43957142:A:G	donor_gain	0.9900
20:43973366:GTTT:G	acceptor_gain	0.9900

AlphaMissense

3289 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:44054404:T:C	Y262H	1.000
20:44054404:T:G	Y262D	1.000
20:44054405:A:G	Y262C	1.000
20:44054411:T:C	L264P	1.000
20:44054413:T:C	F265L	1.000
20:44054414:T:C	F265S	1.000
20:44054414:T:G	F265C	1.000
20:44054415:C:A	F265L	1.000
20:44054415:C:G	F265L	1.000
20:44054416:T:A	F266I	1.000
20:44054416:T:C	F266L	1.000
20:44054416:T:G	F266V	1.000
20:44054417:T:C	F266S	1.000
20:44054417:T:G	F266C	1.000
20:44054418:C:A	F266L	1.000
20:44054418:C:G	F266L	1.000
20:44054420:G:C	R267T	1.000
20:44054420:G:T	R267I	1.000
20:44054421:A:C	R267S	1.000
20:44054421:A:T	R267S	1.000
20:44054430:G:C	Q270H	1.000
20:44054430:G:T	Q270H	1.000
20:44054438:T:A	I273N	1.000
20:44054438:T:C	I273T	1.000
20:44054438:T:G	I273S	1.000
20:44054440:A:G	K274E	1.000
20:44054442:G:C	K274N	1.000
20:44054442:G:T	K274N	1.000
20:44054464:T:C	F282L	1.000
20:44054465:T:C	F282S	1.000

dbSNP variants (sampled 300 via entrez): RS1000015465 (20:44061294 C>G,T), RS1000025640 (20:44067568 G>A), RS1000085334 (20:44060996 C>A), RS1000091428 (20:43914711 C>A,T), RS1000119553 (20:43970374 G>T), RS1000129791 (20:43983177 G>A), RS1000133547 (20:43945275 T>C), RS1000136583 (20:44022488 G>A), RS1000137066 (20:43993145 T>C), RS1000159573 (20:43926639 G>A), RS1000164111 (20:44043320 G>A), RS1000164552 (20:43949625 C>G,T), RS1000170804 (20:43927510 C>T), RS1000195242 (20:43988753 C>A,T), RS1000195583 (20:44011431 T>C,G)

Disease associations

OMIM: gene MIM:611163 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000713_10	Conduct disorder (symptom count)	6.000000e-06
GCST003265_339	Post bronchodilator FEV1/FVC ratio in COPD	6.000000e-07
GCST004601_197	Red blood cell count	4.000000e-09
GCST004602_232	Mean corpuscular volume	5.000000e-10
GCST007552_16	Colorectal cancer	4.000000e-07
GCST009597_105	Multiple sclerosis	6.000000e-09
GCST010002_68	Refractive error	1.000000e-08
GCST010219_20	Attention deficit hyperactivity disorder (inattention symptoms)	3.000000e-07
GCST90002381_361	Eosinophil count	4.000000e-22
GCST90002382_530	Eosinophil percentage of white cells	4.000000e-15
GCST90002390_670	Mean corpuscular hemoglobin	5.000000e-18
GCST90002392_107	Mean corpuscular volume	5.000000e-17
GCST90002397_279	Mean spheric corpuscular volume	8.000000e-10
GCST90002398_56	Neutrophil count	8.000000e-09
GCST90002403_319	Red blood cell count	2.000000e-14
GCST90002407_648	White blood cell count	1.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0004305	erythrocyte count
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004527	mean corpuscular hemoglobin
EFO:0004833	neutrophil count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	8
bisphenol A	affects cotreatment, decreases methylation, increases expression	2
belinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Cisplatin	affects expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
trichostatin A	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
ormosil	affects binding, increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	increases expression	1
dorsomorphin	increases expression, affects cotreatment, decreases expression	1
jinfukang	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Decitabine	affects expression	1

Clinical trials (associated diseases)

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