TOX

Summary

TOX (thymocyte selection associated high mobility group box, HGNC:18988) is a protein-coding gene on chromosome 8q12.1, encoding Thymocyte selection-associated high mobility group box protein TOX (O94900). Transcriptional regulator with a major role in neural stem cell commitment and corticogenesis as well as in lymphoid cell development and lymphoid tissue organogenesis.

The protein encoded by this gene contains a HMG box DNA binding domain. HMG boxes are found in many eukaryotic proteins involved in chromatin assembly, transcription and replication. This protein may function to regulate T-cell development.

Source: NCBI Gene 9760 — RefSeq curated summary.

At a glance

• GWAS associations: 27
• Clinical variants (ClinVar): 80 total
• MANE Select transcript: NM_014729

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18988
Approved symbol	TOX
Name	thymocyte selection associated high mobility group box
Location	8q12.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0808, TOX1
Ensembl gene	ENSG00000198846
Ensembl biotype	protein_coding
OMIM	606863
Entrez	9760

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000361421, ENST00000890858, ENST00000966263, ENST00000966264

RefSeq mRNA: 1 — MANE Select: NM_014729 NM_014729

CCDS: CCDS34897

Canonical transcript exons

ENST00000361421 — 9 exons

Exon	Start	End
ENSE00000980445	58939302	58939544
ENSE00001020338	58851524	58851805
ENSE00001020339	58815338	58815724
ENSE00001020341	58826822	58826902
ENSE00001020343	58808118	58808269
ENSE00001020345	58838081	58838311
ENSE00001136846	58959943	58960008
ENSE00001197897	58805412	58807783
ENSE00002717862	59118886	59119147

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 94.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.5234 / max 435.3418, expressed in 1062 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
93244	4.6842	754
93245	2.0955	682
93246	1.4277	589
93247	0.8666	423
93248	0.4378	249
93249	0.4027	171
93243	0.3585	113
93242	0.2505	93

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	94.51	gold quality
endothelial cell	CL:0000115	92.03	gold quality
ventricular zone	UBERON:0003053	91.32	gold quality
secondary oocyte	CL:0000655	89.20	gold quality
thymus	UBERON:0002370	87.51	gold quality
ganglionic eminence	UBERON:0004023	84.70	gold quality
mucosa of sigmoid colon	UBERON:0004993	84.66	gold quality
oocyte	CL:0000023	84.15	gold quality
orbitofrontal cortex	UBERON:0004167	83.31	gold quality
sigmoid colon	UBERON:0001159	82.70	gold quality
muscle layer of sigmoid colon	UBERON:0035805	82.37	gold quality
islet of Langerhans	UBERON:0000006	81.96	gold quality
colonic mucosa	UBERON:0000317	81.81	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.51	gold quality
prefrontal cortex	UBERON:0000451	81.49	gold quality
Brodmann (1909) area 9	UBERON:0013540	81.20	gold quality
jejunal mucosa	UBERON:0000399	80.58	gold quality
lymph node	UBERON:0000029	80.38	gold quality
rectum	UBERON:0001052	80.25	gold quality
large intestine	UBERON:0000059	79.82	gold quality
mucosa of stomach	UBERON:0001199	79.77	gold quality
neocortex	UBERON:0001950	79.69	gold quality
colon	UBERON:0001155	79.67	gold quality
frontal cortex	UBERON:0001870	79.40	gold quality
Brodmann (1909) area 23	UBERON:0013554	79.22	gold quality
cingulate cortex	UBERON:0003027	79.17	gold quality
intestine	UBERON:0000160	79.16	gold quality
Brodmann (1909) area 46	UBERON:0006483	79.05	gold quality
anterior cingulate cortex	UBERON:0009835	78.95	gold quality
superior frontal gyrus	UBERON:0002661	78.93	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	3123.86
E-GEOD-131882	yes	3093.12
E-HCAD-35	yes	62.73
E-GEOD-109979	yes	44.22
E-ANND-3	yes	10.23
E-CURD-112	yes	3.56
E-GEOD-70580	no	889.97

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
CRP
CYP27A1
NR0B1
OMP
TBXT
TOX

Upstream regulators (CollecTRI, top): GATA3, TOX, ZBTB7B

miRNA regulators (miRDB)

220 targeting TOX, 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-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834

Literature-anchored findings (GeneRIF, showing 35)

• expression of the HMG box protein TOX is sufficient to induce changes in coreceptor gene expression associated with beta-selection, including CD8 gene demethylation (PMID:15078895)
• results suggest that TOX is required for IL-15-mediated natural killer (NK) cell differentiation and affected expression of T-bet that plays critical roles in NK differentiation and maturation (PMID:21126536)
• Compared with TOX4, expression of TOX1, TOX2 and TOX3 in normal lung was 25, 44, and 88%lower, respectively, supporting the premise that reduced promoter activity confers increased susceptibility to methylation during lung carcinogenesis. (PMID:22496870)
• SNP rs2726600 is located in a transcription-factor binding site in the 3’ region of TOX. (PMID:23415668)
• TOX may be a specific marker for tumour cells in some types of cutaneous lymphoma. (PMID:25216799)
• High TOX transcript levels correlate with increased cutaneous T-cell lymphoma. (PMID:25548321)
• The SLC2A9 (rs7660895) and TOX (rs11777927) gene polymorphisms may be associated with formation of intracranial aneurysms, and rs7660895 may be associated with intracranial aneurysms rupture. (PMID:26125895)
• Significant associations between single nucleotide polymorphisms in TOX, CDKN2A/B and type 2 diabetes meillitus. (PMID:26139146)
• TOX expression is insufficient for diagnosis of cutaneous T-cell lymphoma (PMID:26931394)
• data suggest that GATA3 regulates TOX, revealing insight into TOX regulation (PMID:27345620)
• The expression of Sezary signature genes: FCRL3, Tox, and miR-214, was significantly higher in samples from Sezary syndrome patients with CD164 expressing CD4(+) T cells. (PMID:27766406)
• TOX gene SNP rs11777927 was associated with antipsychotic-induced weight gain. (PMID:28327672)
• TOX is an HMG box-containing protein that has important roles in T-ALL initiation and maintenance. TOX inhibits the recruitment of KU70/KU80 to DNA breaks, thereby inhibiting NHEJ repair. Thus, TOX is likely a dominant oncogenic driver in a large fraction of human T-ALL and enhances genomic instability (PMID:28974511)
• Suggest that F nucleatum may suppress antitumor immune responses by decreasing CD4(+) T-cell density and TOX expression in the progression of colorectal cancer. (PMID:29792893)
• hypothesis that TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer (PMID:31207604)
• TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology (PMID:31207605)
• Molecular profiling of TOX-deficient neoplastic cells in cutaneous T cell lymphoma. (PMID:31676945)
• The VEGF-A induces the expression of transcription factor TOX in T cells to drive exhaustion-specific transcription program in T cells. (PMID:31704735)
• High TOX expression is associated with pathogenesis of atherosclerosis. (PMID:31949884)
• Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer. (PMID:32111241)
• TOX is expressed by exhausted and polyfunctional human effector memory CD8(+) T cells. (PMID:32620560)
• Origin and fine-tuning of effector CD8 T cell subpopulations in chronic infection. (PMID:33137688)
• Increased TOX expression concurrent with PD-1, Tim-3, and CD244 in T cells from patients with non-Hodgkin lymphoma. (PMID:33608984)
• TOX Acts as a Tumor Suppressor by Inhibiting mTOR Signaling in Colorectal Cancer. (PMID:33897695)
• Normal and cancer fibroblasts differentially regulate TWIST1, TOX and cytokine gene expression in cutaneous T-cell lymphoma. (PMID:33941102)
• CD4+ T cells in classical Hodgkin lymphoma express exhaustion associated transcription factors TOX and TOX2: Characterizing CD4+ T cells in Hodgkin lymphoma. (PMID:35111387)
• The transcription factor TOX is involved in the regulation of T-cell exhaustion in neuroblastoma. (PMID:35691410)
• TOX promotes follicular helper T cell differentiation in patients with primary Sjogren’s syndrome. (PMID:35713502)
• Transcriptional Pattern Analysis of Virus-Specific CD8+ T Cells in Hepatitis C Infection: Increased Expression of TOX and Eomesodermin During and After Persistent Antigen Recognition. (PMID:35734162)
• Immune checkpoint receptor VISTA on immune cells is associated with expression of T-cell exhaustion marker TOX and worse prognosis in renal cell carcinoma with venous tumor thrombus. (PMID:36042047)
• High TOX expression on CD8[+] T cells in pure red cell aplasia. (PMID:36933041)
• TOX regulates T lymphocytes differentiation and its function in tumor. (PMID:36969216)
• TOX, TWIST1, STAT4, and SATB1 protein expressions in early-stage mycosis fungoides. (PMID:37932931)
• Evaluation of mRNA Expressions of TOX and NR4As in CD8+ T cells in Acute Leukemia. (PMID:37961948)
• TOX as a new diagnostic marker for T cell large granular lymphocytic leukaemia. (PMID:38087646)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tox	ENSDARG00000032317
mus_musculus	Tox	ENSMUSG00000041272
rattus_norvegicus	Tox	ENSRNOG00000010777
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), TOX2 (ENSG00000124191), SP110 (ENSG00000135899), HMG20A (ENSG00000140382), SSRP1 (ENSG00000149136), HMGB2 (ENSG00000164104), HMGB4 (ENSG00000176256), SP140L (ENSG00000185404), HMGB1 (ENSG00000189403), UBTFL1 (ENSG00000255009)

Protein

Protein identifiers

Thymocyte selection-associated high mobility group box protein TOX — O94900 (reviewed: O94900)

Alternative names: Thymus high mobility group box protein TOX

All UniProt accessions (1): O94900

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator with a major role in neural stem cell commitment and corticogenesis as well as in lymphoid cell development and lymphoid tissue organogenesis. Binds to GC-rich DNA sequences in the proximity of transcription start sites and may alter chromatin structure, modifying access of transcription factors to DNA. During cortical development, controls the neural stem cell pool by inhibiting the switch from proliferative to differentiating progenitors. Beyond progenitor cells, promotes neurite outgrowth in newborn neurons migrating to reach the cortical plate. May activate or repress critical genes for neural stem cell fate such as SOX2, EOMES and ROBO2. Plays an essential role in the development of lymphoid tissue-inducer (LTi) cells, a subset necessary for the formation of secondary lymphoid organs: peripheral lymph nodes and Peyer’s patches. Acts as a developmental checkpoint and regulates thymocyte positive selection toward T cell lineage commitment. Required for the development of various T cell subsets, including CD4-positive helper T cells, CD8-positive cytotoxic T cells, regulatory T cells and CD1D-dependent natural killer T (NKT) cells. Required for the differentiation of common lymphoid progenitors (CMP) to innate lymphoid cells (ILC). May regulate the NOTCH-mediated gene program, promoting differentiation of the ILC lineage. Required at the progenitor phase of NK cell development in the bone marrow to specify NK cell lineage commitment. Upon chronic antigen stimulation, diverts T cell development by promoting the generation of exhaustive T cells, while suppressing effector and memory T cell programming. May regulate the expression of genes encoding inhibitory receptors such as PDCD1 and induce the exhaustion program, to prevent the overstimulation of T cells and activation-induced cell death.

Subunit / interactions. Interacts with HBO1 complex composed at least of KAT7/HBO1, ING4, MEAF6, and JADE2; this complex is involved in histone acetylation. Interacts with DNMT1, LEO1, PAF1, SAP130 and SIN3A; these interactors regulate chromatin remodeling. Interacts with an array of proteins involved in RNA processing and translation and DNA replication.

Subcellular location. Nucleus.

Tissue specificity. Expressed in NK cells. Highly expressed in tumor-infiltrating CD8-positive T cells (at protein level).

Induction. Up-regulated during differentiation of NK cells from CD34-positive hematopoietic cells in the presence of IL15. Down-regulated in mature NK cells.

Similarity. Belongs to the high motility group (HMG) box superfamily.

RefSeq proteins (1): NP_055544* (*=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 (11 total): compositionally biased region 4, region of interest 2, chain 1, DNA-binding region 1, sequence conflict 1, short sequence motif 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94900-F1	54.57	0.13

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 360 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_NATURAL_KILLER_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, MODULE_169, PEREZ_TP63_TARGETS, GOBP_THYMIC_T_CELL_SELECTION, TTTGTAG_MIR520D, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_LYMPH_NODE_DEVELOPMENT, GOBP_NEUROGENESIS, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_FOREBRAIN_GENERATION_OF_NEURONS, GOBP_NEURAL_PRECURSOR_CELL_PROLIFERATION

GO Biological Process (18): natural killer cell differentiation (GO:0001779), CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment (GO:0002362), NK T cell lineage commitment (GO:0002364), leukocyte differentiation (GO:0002521), chromatin organization (GO:0006325), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of neuron projection development (GO:0010976), cerebral cortex neuron differentiation (GO:0021895), positive regulation of natural killer cell differentiation (GO:0032825), CD4-positive, alpha-beta T cell lineage commitment (GO:0043373), CD8-positive, alpha-beta T cell lineage commitment (GO:0043375), positive regulation of transcription by RNA polymerase II (GO:0045944), lymph node development (GO:0048535), Peyer’s patch development (GO:0048541), regulation of positive thymic T cell selection (GO:1902232), positive regulation of neural precursor cell proliferation (GO:2000179), nervous system development (GO:0007399), lymphocyte differentiation (GO:0030098)

GO Molecular Function (3): chromatin DNA binding (GO:0031490), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
alpha-beta T cell lineage commitment	3
transcription by RNA polymerase II	2
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	2
lymphocyte differentiation	1
natural killer cell activation	1
CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1
CD4-positive, alpha-beta T cell lineage commitment	1
NK T cell differentiation	1
hemopoiesis	1
cell differentiation	1
cellular component organization	1
regulation of DNA-templated transcription	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
forebrain neuron differentiation	1
natural killer cell differentiation	1
positive regulation of natural killer cell activation	1
regulation of natural killer cell differentiation	1
positive regulation of lymphocyte differentiation	1
CD4-positive, alpha-beta T cell differentiation	1
CD8-positive, alpha-beta T cell differentiation	1
regulation of transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
hematopoietic or lymphoid organ development	1
mucosa-associated lymphoid tissue development	1
regulation of T cell differentiation in thymus	1
positive thymic T cell selection	1
positive regulation of cell population proliferation	1
neural precursor cell proliferation	1
regulation of neural precursor cell proliferation	1
system development	1
lymphocyte activation	1
mononuclear cell differentiation	1
DNA binding	1
chromatin binding	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1072 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOX	CD5	P06127	592
TOX	CD8A	P01732	571
TOX	CD4	P01730	534
TOX	NFIL3	Q16649	459
TOX	TSPAN7	P41732	435
TOX	EOMES	O95936	432
TOX	LGALS9	O00182	424
TOX	TCF7	P36402	419
TOX	TBX21	Q9UL17	410
TOX	ZBTB7B	O15156	405
TOX	PDCD1	Q15116	391
TOX	HAVCR2	Q8TDQ0	380
TOX	LAG3	P18627	370
TOX	TIGIT	Q495A1	370
TOX	GATA3	P23771	354

IntAct

23 interactions, top by confidence:

A	B	Type	Score
TOX	KRTAP12-1	psi-mi:“MI:0915”(physical association)	0.560
TOX	DMRTB1	psi-mi:“MI:0915”(physical association)	0.560
TOX	BANP	psi-mi:“MI:0915”(physical association)	0.560
TOX	GRAP	psi-mi:“MI:0915”(physical association)	0.560
TOX	KRTAP26-1	psi-mi:“MI:0915”(physical association)	0.560
KLK6	TOX	psi-mi:“MI:0915”(physical association)	0.560
TOX	ZDHHC17	psi-mi:“MI:0915”(physical association)	0.370
TOX2	TOX4	psi-mi:“MI:0914”(association)	0.350
KRTAP12-1	TOX	psi-mi:“MI:0915”(physical association)	0.000
GRAP	TOX	psi-mi:“MI:0915”(physical association)	0.000
KRTAP26-1	TOX	psi-mi:“MI:0915”(physical association)	0.000
DMRTB1	TOX	psi-mi:“MI:0915”(physical association)	0.000
BANP	TOX	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (17): TOX (Two-hybrid), TOX (Affinity Capture-MS), TOX (Affinity Capture-MS), TOX (Two-hybrid), TOX (Two-hybrid), TOX (Two-hybrid), TOX (Two-hybrid), TOX (Two-hybrid), TOX (Affinity Capture-MS), TOX (Affinity Capture-MS), TOX (Affinity Capture-MS), TOX (Affinity Capture-MS), TOX (Affinity Capture-MS), TOX (Proximity Label-MS), KLHL6 (Affinity Capture-Western)

ESM2 similar proteins: A1L2P5, A8DT10, O08656, O42368, O42370, O93353, O94900, P09022, P09027, P09089, P23682, P31249, P46692, P49639, P50574, P53773, P53774, P53775, P56178, Q01702, Q08820, Q08821, Q1KKS7, Q1KKU6, Q1KKX7, Q1KL10, Q1KL12, Q1KL13, Q28IU6, Q3V5Z9, Q66JW3, Q6B3N0, Q6DCQ1, Q6NVT7, Q8AWZ2, Q8BUR3, Q90423, Q91690, Q91904, Q98875

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, A9RA84, B0CM99, B1MTB0

SIGNOR signaling

0 interactions.

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	62
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3505 predictions. Top by Δscore:

Variant	Effect	Δscore
8:58826898:TAGAC:T	acceptor_gain	1.0000
8:58826899:AGAC:A	acceptor_gain	1.0000
8:58826900:GAC:G	acceptor_gain	1.0000
8:58826901:AC:A	acceptor_gain	1.0000
8:58826901:ACCTG:A	acceptor_loss	1.0000
8:58826902:CC:C	acceptor_gain	1.0000
8:58826902:CCT:C	acceptor_loss	1.0000
8:58826903:C:CC	acceptor_gain	1.0000
8:58826910:A:T	acceptor_gain	1.0000
8:58826913:A:T	acceptor_gain	1.0000
8:58838075:CCTTA:C	donor_loss	1.0000
8:58838076:CTTA:C	donor_loss	1.0000
8:58838077:TTA:T	donor_loss	1.0000
8:58838078:TACC:T	donor_loss	1.0000
8:58838079:A:T	donor_loss	1.0000
8:58838307:TTGAT:T	acceptor_gain	1.0000
8:58838308:TGAT:T	acceptor_gain	1.0000
8:58838309:GAT:G	acceptor_gain	1.0000
8:58838310:AT:A	acceptor_gain	1.0000
8:58838310:ATCTG:A	acceptor_loss	1.0000
8:58838312:C:CC	acceptor_gain	1.0000
8:58838312:CT:C	acceptor_loss	1.0000
8:58838313:T:G	acceptor_loss	1.0000
8:58939301:CCA:C	donor_gain	1.0000
8:58939333:T:TA	donor_gain	1.0000
8:58939540:TAGGA:T	acceptor_gain	1.0000
8:58939541:AGGA:A	acceptor_gain	1.0000
8:58939542:GGA:G	acceptor_gain	1.0000
8:58939543:GA:G	acceptor_gain	1.0000
8:58939545:C:CC	acceptor_gain	1.0000

AlphaMissense

3491 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:58826832:A:G	L332P	1.000
8:58826838:G:T	A330D	1.000
8:58826839:C:G	A330P	1.000
8:58826840:T:A	R329S	1.000
8:58826840:T:G	R329S	1.000
8:58826841:C:A	R329I	1.000
8:58826841:C:G	R329T	1.000
8:58826842:T:C	R329G	1.000
8:58826844:T:C	Y328C	1.000
8:58826844:T:G	Y328S	1.000
8:58826845:A:C	Y328D	1.000
8:58826845:A:G	Y328H	1.000
8:58826845:A:T	Y328N	1.000
8:58826848:C:G	A327P	1.000
8:58826850:G:T	A326E	1.000
8:58826851:C:G	A326P	1.000
8:58826853:A:G	L325P	1.000
8:58826853:A:T	L325H	1.000
8:58826854:G:A	L325F	1.000
8:58826856:T:G	Q324P	1.000
8:58826858:C:A	K323N	1.000
8:58826858:C:G	K323N	1.000
8:58826862:A:G	L322P	1.000
8:58826862:A:T	L322Q	1.000
8:58826865:T:C	Y321C	1.000
8:58826865:T:G	Y321S	1.000
8:58826866:A:C	Y321D	1.000
8:58826866:A:G	Y321H	1.000
8:58826866:A:T	Y321N	1.000
8:58826873:C:A	K318N	1.000

dbSNP variants (sampled 300 via entrez): RS1000002032 (8:58844565 C>T), RS1000004908 (8:59051390 C>A,T), RS1000005626 (8:59093634 C>T), RS1000010529 (8:59023636 T>C), RS1000025696 (8:59104753 A>C), RS1000057137 (8:58998470 T>C,G), RS1000057381 (8:58868245 G>A), RS1000062766 (8:59045079 T>C), RS1000081147 (8:58890232 T>C), RS1000087657 (8:59029463 A>C,G), RS1000088110 (8:58965819 T>C), RS1000093354 (8:59045456 A>G,T), RS1000106938 (8:58911320 C>T), RS1000119109 (8:58857856 G>A,C,T), RS1000126264 (8:59119580 A>C,G)

Disease associations

OMIM: gene MIM:606863 | disease phenotypes: MIM:206200

GenCC curated gene-disease

Mondo (1): IRIDA syndrome (MONDO:0008788)

Orphanet (1): IRIDA syndrome (Orphanet:209981)

HPO phenotypes

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

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST000477_13	Cognitive performance	6.000000e-06
GCST001524_5	Visceral adipose tissue/subcutaneous adipose tissue ratio	2.000000e-06
GCST001858_6	Refractive error	4.000000e-12
GCST002615_2	Myopia	1.000000e-08
GCST002617_2	Hyperopia	2.000000e-11
GCST002685_4	Refractive astigmatism	3.000000e-07
GCST002927_6	Mercury levels	6.000000e-06
GCST003455_2	Spherical equivalent (joint analysis main effects and education interaction)	1.000000e-14
GCST003455_26	Spherical equivalent (joint analysis main effects and education interaction)	8.000000e-18
GCST003659_3	Modified Stumvoll Insulin Sensitivity Index (BMI interaction)	4.000000e-06
GCST003997_21	Myopia	6.000000e-41
GCST006624_105	Systolic blood pressure	3.000000e-08
GCST006701_16	Parental longevity (father’s attained age)	3.000000e-08
GCST007323_58	Risk-taking tendency (4-domain principal component model)	2.000000e-14
GCST007327_159	Smoking status (ever vs never smokers)	4.000000e-11
GCST007576_150	Chronotype	9.000000e-09
GCST007603_3	Smoking initiation	1.000000e-09
GCST007947_4	Psychological resilience (outcome-based)	6.000000e-07
GCST008810_43	Smoking initiation (ever regular vs never regular)	1.000000e-09
GCST008839_123	Height	2.000000e-09
GCST009256_6	Superior temporal sulcus banks volume	9.000000e-06
GCST009962_11	High myopia	2.000000e-08
GCST010002_301	Refractive error	1.000000e-153
GCST010135_52	Oily fish consumption	5.000000e-08
GCST010140_42	Pork consumption	5.000000e-08
GCST011703_86	Smoking initiation	6.000000e-13
GCST90014023_25	Type 1 diabetes	2.000000e-09

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0004767	visceral:subcutaneous adipose tissue ratio
EFO:0004784	self reported educational attainment
EFO:0004340	body mass index
EFO:0004471	insulin sensitivity measurement
EFO:0006335	systolic blood pressure
EFO:0007796	parental longevity
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0008328	chronotype measurement
EFO:0005670	smoking initiation
EFO:0009945	psychological resilience measurement
EFO:0008111	diet measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562385	Iron-Refractory Iron Deficiency Anemia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	6
bisphenol A	increases expression, affects cotreatment, increases methylation, decreases expression	3
trichostatin A	affects cotreatment, increases expression	3
potassium chromate(VI)	affects cotreatment, decreases expression, increases expression	2
nickel sulfate	decreases expression, increases expression	2
mercuric bromide	affects cotreatment, increases expression	2
chromium hexavalent ion	affects expression, decreases expression, increases abundance	2
entinostat	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Estradiol	affects expression, affects cotreatment, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
arsenite	increases methylation	1
sulforaphane	decreases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
cobaltous chloride	decreases expression	1
zinc chromate	increases abundance, decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects methylation	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TT34	HAP1 TOX (-) 1	Cancer cell line	Male
CVCL_TT35	HAP1 TOX (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02905981	PHASE2	TERMINATED	Triferic IRIDA (Iron-Refractory Iron-Deficiency Anemia) Protocol