TOX3

Summary

TOX3 (TOX high mobility group box family member 3, HGNC:11972) is a protein-coding gene on chromosome 16q12.1, encoding TOX high mobility group box family member 3 (O15405). Transcriptional coactivator of the p300/CBP-mediated transcription complex.

The protein encoded by this gene contains an HMG-box, indicating that it may be involved in bending and unwinding of DNA and alteration of chromatin structure. The C-terminus of the encoded protein is glutamine-rich due to CAG repeats in the coding sequence. A minor allele of this gene has been implicated in an elevated risk of breast cancer. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 27324 — RefSeq curated summary.

At a glance

• GWAS associations: 47
• Clinical variants (ClinVar): 93 total
• MANE Select transcript: NM_001080430

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11972
Approved symbol	TOX3
Name	TOX high mobility group box family member 3
Location	16q12.1
Locus type	gene with protein product
Status	Approved
Aliases	CAGF9
Ensembl gene	ENSG00000103460
Ensembl biotype	protein_coding
OMIM	611416
Entrez	27324

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000219746, ENST00000407228, ENST00000563091, ENST00000566696, ENST00000568436, ENST00000873102, ENST00000912162, ENST00000912163

RefSeq mRNA: 2 — MANE Select: NM_001080430 NM_001080430, NM_001146188

CCDS: CCDS54008, CCDS54009

Canonical transcript exons

ENST00000219746 — 7 exons

Exon	Start	End
ENSE00001223393	52445994	52446221
ENSE00001223408	52444276	52444356
ENSE00001504032	52450277	52450546
ENSE00001504033	52463934	52464188
ENSE00002576203	52436417	52439968
ENSE00002629852	52546637	52547143
ENSE00003570139	52468509	52468574

Expression profiles

Bgee: expression breadth ubiquitous, 220 present calls, max score 97.03.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9397 / max 89.3412, expressed in 383 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157383	1.0181	332
157382	0.6263	151
157381	0.2466	148
157380	0.0444	24
157384	0.0043	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of sigmoid colon	UBERON:0004993	97.03	gold quality
pancreatic ductal cell	CL:0002079	96.63	gold quality
colonic mucosa	UBERON:0000317	96.61	gold quality
ventricular zone	UBERON:0003053	95.65	gold quality
bronchial epithelial cell	CL:0002328	95.32	gold quality
jejunal mucosa	UBERON:0000399	95.20	gold quality
epithelium of bronchus	UBERON:0002031	93.38	gold quality
bronchus	UBERON:0002185	93.10	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.55	gold quality
nephron tubule	UBERON:0001231	91.82	gold quality
endothelial cell	CL:0000115	91.17	gold quality
embryo	UBERON:0000922	90.41	gold quality
ganglionic eminence	UBERON:0004023	90.14	gold quality
pylorus	UBERON:0001166	89.99	gold quality
epithelial cell of pancreas	CL:0000083	89.76	gold quality
cortical plate	UBERON:0005343	89.28	gold quality
renal medulla	UBERON:0000362	88.76	gold quality
rectum	UBERON:0001052	87.06	gold quality
cardia of stomach	UBERON:0001162	87.04	gold quality
cauda epididymis	UBERON:0004360	86.52	gold quality
trachea	UBERON:0003126	86.51	gold quality
duodenum	UBERON:0002114	86.10	gold quality
kidney epithelium	UBERON:0004819	85.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.65	gold quality
nasal cavity epithelium	UBERON:0005384	84.07	gold quality
kidney	UBERON:0002113	83.31	gold quality
corpus epididymis	UBERON:0004359	82.98	gold quality
ileal mucosa	UBERON:0000331	82.97	gold quality
nasal cavity mucosa	UBERON:0001826	81.93	gold quality
islet of Langerhans	UBERON:0000006	81.37	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	47.41
E-GEOD-93593	yes	6.84
E-ANND-3	yes	6.62

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
BCL2
BRCA1	Unknown
C3	Activation
CITED1
CREBBP
FOS	Activation

miRNA regulators (miRDB)

251 targeting TOX3, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9-3P	99.96	70.88	2068

Literature-anchored findings (GeneRIF, showing 40)

• Heterozygote carriers and minor allele homozygote carriers for SNP rs3803662 near the TNCR9 gene were more likely to be diagnosed before the age of 60 years (P = 0.025) relative to major allele homozygote carriers (PMID:17997823)
• The polymorphism rs12443621 in TOX3 was associated with percent dense area in breast cancer. (PMID:19232126)
• Low-risk variants of TNRC9 is associated with familial breast cancer. (PMID:19856316)
• Suggest that genetic variants of TNRC9 may contribute to the development of estrogen receptor positive breast cancer in a Chinese population. (PMID:20213080)
• Single nucleotide polymorphism in TOX3 is associated with breast cancer. (PMID:20406955)
• findings strengthen the existing evidence that FGFR2-rs2981582 and TNRC9-rs3803662 are predominantly associated with ER-positive breast cancer (PMID:20664043)
• Polymorphisms of trinucleotide repeat containing 9 gene is associated with breast cancer. (PMID:20703937)
• TOX3 induces transcription in neuron depending on the presence of CITED1 or phosphorylated CREB in the transcriptionally active complex. (PMID:21172805)
• 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)
• risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, thereby resulting in allele-specific gene expression, which is exemplified by the effect of the rs4784227 SNP on the TOX3 gene within the 16q12.1 risk locus. (PMID:23001124)
• Evidence of association with mammographic density was found for variant rs3803662 (TOX3). (PMID:23021931)
• the minor allele of SNP rs3803662 was associated with shorter survival in breast cancer patients with luminal A tumours, with lower mRNA expression of TOX3 (PMID:23270421)
• TNRC9 gene is amplified and associated with poor prognosis in advanced breast cancer. TNRC9 promotes cancer cell proliferation, migration, and survival both in vitro and in vivo. TNRC9 and BRCA1 expression are inversely correlated. (PMID:23447579)
• TOX3 loci plays a role in the male breast cancer susceptibility. (PMID:23468243)
• TOX3 rs3803662 might play an important role in the prognostic outcome and treatment of gastric cancer, especially perhaps further help in explaining the reduced risk of death associated with diffuse-type gastric cancer. (PMID:24069142)
• mutations of TOX3 are present at low frequency in tumours. Our results support that TOX3 should be further investigated to elucidate its role in breast cancer biology. (PMID:24069272)
• T allele and the TT genotype of the SNP rs38033662 is significantly associated with risk for breast cancer in Chinese Han women. (PMID:24446301)
• The T-rs8051542 allele was significantly associated with ER-positive and HER2-negative carriers. No significant association existed between rs12443621, rs3803662, and rs3112612 polymorphisms and risk of breast cancer. (PMID:24481062)
• These results indicate an additive effect of the TOX3 rs3803662 and 2q35 rs13387042 alleles for breast cancer risk. (PMID:24532140)
• Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD (PMID:25142570)
• Mutations in TOX3 are not common in Chinese Han women with polycystic ovary syndrome. (PMID:25311971)
• Single nucleotide polymorphism in TOX3 gene is associated with breast cancer risk. (PMID:25531440)
• TOX3 is expressed in mammary ER(+) epithelial cells and regulates ER target genes in luminal breast cancer (PMID:25632947)
• TOX3 and FGFR2 are breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population. (PMID:25956309)
• data suggest that central inhibition of IL-1alpha or Tox3 overexpression during the acute phase of a CNS insult may be an effective means for preventing the loss of neurological function (PMID:26224856)
• The TOX3 SNPs rs3803662 C > T, rs12443621 A > G and rs8051542 C > T were all correlated with increased risk of breast cancer in the European and Asian populations, but not in the African one. (PMID:26239137)
• The genotype of rs3803662 from TOX3 is associated with breast cancer. (PMID:26803517)
• TNRC9 GG genotype of rs3803662 is associated with increased breast cancer risk. (PMID:26911390)
• Data show that three SNPs (rs9933638, rs12443621, and rs3104746) at the TOX3/LOC643714 locus contributed to lung cancer risk, suggesting that lung cancer and breast cancer are linked at the molecular and genetic level to a certain extent. (PMID:27486757)
• The TNRC9 rs3803662 C>T polymorphism is greatly related to increased risk of breast cancer, in both Asian and Caucasian populations. (PMID:27525937)
• Significant associations were observed between Breast Cancer risk and two Single nucleotide polymorphisms of FGFR2 [rs2981582 (P=0.005), rs1219648 (P=9.08e006)] and one Single nucleotide polymorphisms of TNRC9 [rs3803662) (P=0.012)] in Pakistani women. (PMID:27572905)
• Data support a plausible molecular mechanism integrating epigenetic modifications of the TOX3 promoter and allele specific expression of SNPs in aggressive behavior of luminal breast tumors with high TOX3 expression. (PMID:27806084)
• abnormal TOX3 methylation possibly resulting in changes in TOX3 protein expression is closely related to the occurrence of polycystic ovarian syndrome and may play a role the development of the pathology (PMID:28537684)
• The carriers of homozygous minor alleles of the TOX3 gene are not a risk factor for the development of breast cancer under conditions of exposure to ionizing radiation in the study group of the Ukrainian population. (PMID:29286526)
• The results confirm the association between the TOX3 SNP rs3104767 and restless legs syndrome and suggest that TOX3 variants are involved in both RLS and Parkinson’s disease, but with different or even opposite effects. (PMID:29404899)
• This meta-analysis suggested that TOX3 rs3803662 polymorphism was associated with increased breast cancer risk. (PMID:29578175)
• there was a relationship between rs2046210 and rs3803662, and the risk of developing this disease in Vietnamese women. The A allele is the risk allele for both rs2046210 (OR [95% CI] = 1.43 [1.14 - 1.78], P = 0.0015) and rs3803662 (OR [95% CI] = 1.45 [1.16 - 1.83], P = 0.001). We conclude that two polymorphisms, rs2046210 in ESR1 and rs3803662 in TNRC9, are associated with breast cancer risk in the Vietnamese population. (PMID:30078824)
• TOX3-rs3803662, may confer some degrees of risk of breast cancer in Iranian population. (PMID:30515698)
• Study identified TOX3 as a novel cancer suppressor gene in clear cell renal cell carcinoma (ccRCC). Hypermethylation in the promoter region was associated with its functional loss and poor outcome in ccRCC patients. Downregulation of TOX3 could accelerate the EMT by decreasing transcriptional repression of SNAI1 and SNAI2. Its overexpression inhibited RCC cell growth, migration and invasion. (PMID:30772441)
• Low copy number of Tox3 is associated with nonsyndromic cleft lip and/or palate. (PMID:30924295)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tox3	ENSDARG00000073957
mus_musculus	Tox3	ENSMUSG00000043668
rattus_norvegicus	Tox3	ENSRNOG00000028649
caenorhabditis_elegans	hmg-3	WBGENE00001973
caenorhabditis_elegans		WBGENE00001974

Paralogs (20): HMGB3 (ENSG00000029993), HMG20B (ENSG00000064961), SP100 (ENSG00000067066), SMARCE1 (ENSG00000073584), SP140 (ENSG00000079263), TOX4 (ENSG00000092203), HMGXB4 (ENSG00000100281), TFAM (ENSG00000108064), UBTF (ENSG00000108312), HMGB1P1 (ENSG00000124097), TOX2 (ENSG00000124191), 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 3 — O15405 (reviewed: O15405)

Alternative names: CAG trinucleotide repeat-containing gene F9 protein, Trinucleotide repeat-containing gene 9 protein

All UniProt accessions (3): O15405, H3BTZ9, J3QQQ6

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional coactivator of the p300/CBP-mediated transcription complex. Activates transactivation through cAMP response element (CRE) sites. Protects against cell death by inducing antiapoptotic and repressing pro-apoptotic transcripts. Stimulates transcription from the estrogen-responsive or BCL-2 promoters. Required for depolarization-induced transcription activation of the C-FOS promoter in neurons. Associates with chromatin to the estrogen-responsive C3 promoter region.

Subunit / interactions. Homodimer. Interacts with CREB1; the interaction is not depolarization dependent. Interacts with CREBBP (via C-terminus). Interacts (via HGM box) with CITED1 (via C-terminus); the interaction increases estrogen-response element (ERE)-dependent transcription and protection against cell death. Interacts with CREB1 (phosphorylated form).

Subcellular location. Nucleus.

Tissue specificity. Expressed mainly in epithelial cells. Expressed in the central nervous system (CNS), in the ileum and within the brain in the frontal and occipital lobe.

Domain organisation. The C-terminus is required for calcium responsiveness but not for transactivation activity. The N-terminus is absolutely necessary for transactivation activity.

Induction. Up-regulated by GPR39 in neuronal cells.

Isoforms (2)

UniProt ID	Names	Canonical?
O15405-1	1	yes
O15405-2	2

RefSeq proteins (2): NP_001073899, NP_001139660 (=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 (15 total): compositionally biased region 6, region of interest 3, splice variant 2, sequence variant 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15405-F1	60.22	0.23

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 210 (showing top): GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, SMID_BREAST_CANCER_RELAPSE_IN_LUNG_DN, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, SHEPARD_BMYB_MORPHOLINO_DN, RODRIGUES_NTN1_TARGETS_UP, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, SMID_BREAST_CANCER_LUMINAL_B_UP, LIAO_METASTASIS, GOBP_NEURON_APOPTOTIC_PROCESS, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, FLECHNER_BIOPSY_KIDNEY_TRANSPLANT_REJECTED_VS_OK_DN, HUANG_FOXA2_TARGETS_UP, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, SHEPARD_BMYB_TARGETS, PARENT_MTOR_SIGNALING_DN

GO Biological Process (5): regulation of transcription by RNA polymerase II (GO:0006357), apoptotic process (GO:0006915), regulation of apoptotic process (GO:0042981), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (7): chromatin binding (GO:0003682), transcription coactivator activity (GO:0003713), chromatin DNA binding (GO:0031490), protein homodimerization activity (GO:0042803), phosphoprotein binding (GO:0051219), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829)

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
binding	2
cellular anatomical structure	2
regulation of DNA-templated transcription	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
apoptotic process	1
regulation of programmed cell death	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
regulation of transcription by RNA polymerase II	1
transcription coregulator activity	1
DNA binding	1
chromatin binding	1
identical protein binding	1
protein dimerization activity	1
protein binding	1
nucleic acid binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1

Protein interactions and networks

STRING

1420 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOX3	LSP1	P33241	892
TOX3	MAP3K1	Q13233	833
TOX3	FGFR2	P18443	818
TOX3	BRCA2	P51587	797
TOX3	SLC4A7	Q9Y6M7	776
TOX3	NEK10	Q6ZWH5	763
TOX3	BRCA1	P38398	759
TOX3	COX11	Q9Y6N1	750
TOX3	RAD51B	O15315	746
TOX3	DENND1A	Q8TEH3	714
TOX3	BTBD9	Q96Q07	710
TOX3	AOPEP	Q8N6M6	642
TOX3	MRPS30	Q9NP92	609
TOX3	SUOX	P51687	596
TOX3	RAB5B	P35239	587
TOX3	KRR1	Q13601	587

IntAct

5 interactions, top by confidence:

A	B	Type	Score
Dlg4	TOX3	psi-mi:“MI:0407”(direct interaction)	0.440
TOX3	TFAP2A	psi-mi:“MI:0915”(physical association)	0.370
ODF2	CCDC66	psi-mi:“MI:2364”(proximity)	0.270
TMEM67	PGRMC2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (29): TOX3 (Proximity Label-MS), TOX3 (Proximity Label-MS), TOX3 (Affinity Capture-RNA), AES (Two-hybrid), FHL2 (Two-hybrid), GCM2 (Two-hybrid), PIN1 (Two-hybrid), TSTD2 (Two-hybrid), SEZ6L2 (Two-hybrid), IST1 (Two-hybrid), KRTAP9-8 (Two-hybrid), DUSP21 (Two-hybrid), POM121 (Two-hybrid), NUP62CL (Two-hybrid), KRTAP9-3 (Two-hybrid)

ESM2 similar proteins: A0A0K3AUE4, A8JR92, B3MLB7, B3NAM7, B4JND4, B4JQ42, B4KFE1, B4LV24, B4MUE1, B4NEU8, B4NXA8, B7SBD2, O15405, O46248, P09087, P09956, P10105, P11536, P13055, P25724, P39769, P41046, P51521, P52172, Q0VH32, Q17PR1, Q24523, Q24762, Q29KG4, Q3LHL9, Q6AWG9, Q7KHG2, Q7Z589, Q7ZUV7, Q80W03, Q86NP2, Q86P48, Q8BMB0, Q8I7C3, Q8IRW8

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

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	83
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1654 predictions. Top by Δscore:

Variant	Effect	Δscore
16:52439966:AGCC:A	acceptor_loss	1.0000
16:52439969:C:CC	acceptor_gain	1.0000
16:52439969:C:CG	acceptor_loss	1.0000
16:52439970:T:A	acceptor_loss	1.0000
16:52450275:A:AC	donor_gain	1.0000
16:52450276:C:CC	donor_gain	1.0000
16:52450276:CT:C	donor_gain	1.0000
16:52464046:C:A	donor_gain	1.0000
16:52468504:CCTA:C	donor_loss	1.0000
16:52468505:CTA:C	donor_loss	1.0000
16:52468506:TA:T	donor_loss	1.0000
16:52468507:ACC:A	donor_loss	1.0000
16:52468508:C:G	donor_loss	1.0000
16:52468570:CCAAA:C	acceptor_gain	1.0000
16:52468571:CAAA:C	acceptor_gain	1.0000
16:52468571:CAAAC:C	acceptor_gain	1.0000
16:52468572:AAA:A	acceptor_gain	1.0000
16:52468572:AAAC:A	acceptor_loss	1.0000
16:52468573:AA:A	acceptor_gain	1.0000
16:52468574:AC:A	acceptor_loss	1.0000
16:52468575:C:CC	acceptor_gain	1.0000
16:52468576:T:A	acceptor_loss	1.0000
16:52498770:AT:A	donor_gain	1.0000
16:52439964:GCAGC:G	acceptor_gain	0.9900
16:52439965:CAGC:C	acceptor_gain	0.9900
16:52439965:CAGCC:C	acceptor_gain	0.9900
16:52439966:AGC:A	acceptor_gain	0.9900
16:52439967:GC:G	acceptor_gain	0.9900
16:52439968:CC:C	acceptor_gain	0.9900
16:52439974:T:TC	acceptor_gain	0.9900

AlphaMissense

3810 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:52444283:A:T	V327D	1.000
16:52444286:A:G	L326P	1.000
16:52444293:C:G	A324P	1.000
16:52444294:C:A	R323S	1.000
16:52444294:C:G	R323S	1.000
16:52444295:C:A	R323M	1.000
16:52444295:C:G	R323T	1.000
16:52444296:T:A	R323W	1.000
16:52444296:T:C	R323G	1.000
16:52444298:T:C	Y322C	1.000
16:52444298:T:G	Y322S	1.000
16:52444299:A:C	Y322D	1.000
16:52444299:A:G	Y322H	1.000
16:52444299:A:T	Y322N	1.000
16:52444302:C:G	A321P	1.000
16:52444304:G:T	A320E	1.000
16:52444305:C:G	A320P	1.000
16:52444307:A:G	L319P	1.000
16:52444307:A:T	L319Q	1.000
16:52444311:C:G	A318P	1.000
16:52444316:A:G	L316P	1.000
16:52444316:A:T	L316Q	1.000
16:52444319:T:C	Y315C	1.000
16:52444319:T:G	Y315S	1.000
16:52444320:A:C	Y315D	1.000
16:52444320:A:G	Y315H	1.000
16:52444327:T:A	K312N	1.000
16:52444327:T:G	K312N	1.000
16:52444328:T:A	K312I	1.000
16:52444329:T:C	K312E	1.000

dbSNP variants (sampled 300 via entrez): RS1000014667 (16:52531839 T>A,G), RS1000035309 (16:52490826 T>A), RS1000060269 (16:52520406 A>G), RS1000060787 (16:52449612 A>G), RS1000069402 (16:52469547 C>T), RS1000080046 (16:52440963 C>A,G), RS1000122922 (16:52492446 AC>A), RS1000165705 (16:52515600 G>A), RS1000169440 (16:52532242 C>T), RS1000228125 (16:52491951 G>A,C), RS1000275672 (16:52509269 T>A), RS1000296508 (16:52538124 A>G), RS1000298021 (16:52468699 C>T), RS1000326736 (16:52497761 T>A,C,G), RS1000347614 (16:52498586 GT>G,GTT)

Disease associations

OMIM: gene MIM:611416 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

47 associations (top):

Study	Trait	p-value
GCST000035_1	Breast cancer	1.000000e-36
GCST000037_2	Breast cancer	6.000000e-19
GCST000365_5	Breast cancer	1.000000e-09
GCST000678_10	Breast cancer	3.000000e-15
GCST000709_1	Breast cancer	1.000000e-28
GCST000811_1	Breast cancer	4.000000e-07
GCST000952_4	Breast cancer	4.000000e-10
GCST001159_6	Restless legs syndrome	9.000000e-19
GCST001634_9	Polycystic ovary syndrome	4.000000e-11
GCST001690_3	Breast cancer (male)	4.000000e-15
GCST001930_6	Breast cancer	6.000000e-13
GCST001937_42	Breast cancer	2.000000e-114
GCST002234_2	Breast cancer	4.000000e-10
GCST002234_3	Breast cancer	3.000000e-11
GCST002346_18	Breast cancer (early onset)	6.000000e-21
GCST002662_1	Breast cancer	3.000000e-09
GCST002895_2	Breast cancer	2.000000e-07
GCST003429_4	Morning vs. evening chronotype	2.000000e-12
GCST003842_15	Breast cancer (estrogen-receptor negative)	1.000000e-14
GCST003845_16	Breast cancer	6.000000e-15
GCST003875_19	Gut microbiota (bacterial taxa)	2.000000e-08
GCST004797_6	Brain volume in infants (grey matter)	4.000000e-07
GCST004902_38	Parkinson’s disease	1.000000e-10
GCST004988_265	Breast cancer	7.000000e-201
GCST005042_17	Restless legs syndrome	7.000000e-133
GCST005749_21	Digit length ratio (left hand)	1.000000e-07
GCST005749_22	Digit length ratio (left hand)	2.000000e-08
GCST005750_10	Digit length ratio	3.000000e-07
GCST006041_25	Major depressive disorder	3.000000e-07
GCST006719_13	BRCA1/2-negative high-risk breast cancer	9.000000e-09

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0007883	taxonomic microbiome measurement
EFO:0008368	infant grey matter volume measurement
EFO:0004841	digit length ratio
EFO:0009443	BRCAX breast cancer
EFO:0008328	chronotype measurement
EFO:0004346	neuroimaging measurement
EFO:0007796	parental longevity
EFO:0009762	healthspan
EFO:0011021	BRCA1 mutation carier status
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, decreases methylation, increases expression	8
trichostatin A	affects cotreatment, decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Cisplatin	affects expression, affects cotreatment, decreases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Cyclosporine	increases expression	2
methylmercuric chloride	decreases expression	1
methyleugenol	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	affects methylation	1
ferrous chloride	decreases expression	1
aflatoxin B2	affects methylation	1
perfluoro-n-nonanoic acid	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
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Vorinostat	affects cotreatment, decreases expression	1
Leflunomide	increases expression	1
Amphotericin B	decreases expression	1
Calcitriol	increases expression, affects cotreatment	1
Diethylhexyl Phthalate	decreases expression	1
Dimethyl Sulfoxide	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_TT36	HAP1 TOX3 (-) 1	Cancer cell line	Male
CVCL_TT37	HAP1 TOX3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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