TMBIM6

Summary

TMBIM6 (transmembrane BAX inhibitor motif containing 6, HGNC:11723) is a protein-coding gene on chromosome 12q13.12, encoding Bax inhibitor 1 (P55061). Endoplasmic reticulum (ER)-resident protein that confers cellular protection as an anti-apoptotic protein by limiting multiple stress-inducing pathways surrounding the endoplasmic reticulum and mitochondria.

Enables endoribonuclease inhibitor activity and ubiquitin protein ligase binding activity. Involved in several processes, including negative regulation of RNA splicing; negative regulation of intracellular signal transduction; and response to L-glutamate. Acts upstream of or within negative regulation of calcium ion transport into cytosol. Located in endoplasmic reticulum membrane. Biomarker of cervical squamous cell carcinoma and prostate carcinoma.

Source: NCBI Gene 7009 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 67 total
• Druggable target: yes
• MANE Select transcript: NM_003217

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11723
Approved symbol	TMBIM6
Name	transmembrane BAX inhibitor motif containing 6
Location	12q13.12
Locus type	gene with protein product
Status	Approved
Aliases	BI-1, BAXI1
Ensembl gene	ENSG00000139644
Ensembl biotype	protein_coding
OMIM	600748
Entrez	7009

Gene structure

Transcript identifiers

Ensembl transcripts: 76 — 69 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000267115, ENST00000395006, ENST00000423828, ENST00000546796, ENST00000546885, ENST00000546914, ENST00000547013, ENST00000547187, ENST00000547798, ENST00000547832, ENST00000548201, ENST00000548589, ENST00000548713, ENST00000548809, ENST00000548894, ENST00000549130, ENST00000549385, ENST00000549445, ENST00000549471, ENST00000549966, ENST00000550040, ENST00000550445, ENST00000550951, ENST00000551154, ENST00000552370, ENST00000552635, ENST00000552699, ENST00000553022, ENST00000860405, ENST00000860406, ENST00000860407, ENST00000860408, ENST00000860409, ENST00000860410, ENST00000860411, ENST00000860412, ENST00000860413, ENST00000860414, ENST00000860415, ENST00000860416, ENST00000860417, ENST00000860418, ENST00000860419, ENST00000860420, ENST00000860421, ENST00000860422, ENST00000860423, ENST00000860424, ENST00000860425, ENST00000860426, ENST00000860427, ENST00000860428, ENST00000860429, ENST00000860430, ENST00000860431, ENST00000860432, ENST00000860433, ENST00000860434, ENST00000860435, ENST00000860436, ENST00000860437, ENST00000860438, ENST00000860439, ENST00000860440, ENST00000860441, ENST00000860442, ENST00000924213, ENST00000924214, ENST00000924215, ENST00000924216, ENST00000924217, ENST00000941134, ENST00000941135, ENST00000941136, ENST00000941137, ENST00000941138

RefSeq mRNA: 5 — MANE Select: NM_003217 NM_001098576, NM_001414462, NM_001414463, NM_001414464, NM_003217

CCDS: CCDS31797, CCDS44875

Canonical transcript exons

ENST00000267115 — 10 exons

Exon	Start	End
ENSE00001163091	49752973	49753081
ENSE00001229267	49762873	49764934
ENSE00002273851	49741557	49741611
ENSE00003461463	49758227	49758275
ENSE00003470288	49761704	49761779
ENSE00003474504	49758683	49758762
ENSE00003497462	49759221	49759321
ENSE00003562177	49758383	49758480
ENSE00003564981	49752464	49752549
ENSE00003665643	49755635	49755755

Expression profiles

Bgee: expression breadth ubiquitous, 308 present calls, max score 99.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 509.8071 / max 4050.2871, expressed in 1828 samples.

FANTOM5 promoters (22 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125352	454.1470	1828
125353	33.8407	1813
125362	3.7367	546
125369	3.1307	1413
125370	2.5019	1267
125366	2.2677	1142
125356	2.0424	1038
125367	1.7650	1015
125363	1.6730	930
125358	1.1030	520

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	99.69	gold quality
renal medulla	UBERON:0000362	99.60	gold quality
parotid gland	UBERON:0001831	99.60	gold quality
endometrium epithelium	UBERON:0004811	99.58	gold quality
right testis	UBERON:0004534	99.55	gold quality
left testis	UBERON:0004533	99.53	gold quality
ventricular zone	UBERON:0003053	99.51	gold quality
ileal mucosa	UBERON:0000331	99.48	gold quality
gall bladder	UBERON:0002110	99.48	gold quality
rectum	UBERON:0001052	99.47	gold quality
adrenal tissue	UBERON:0018303	99.46	gold quality
right adrenal gland cortex	UBERON:0035827	99.46	gold quality
right lobe of liver	UBERON:0001114	99.45	gold quality
bronchial epithelial cell	CL:0002328	99.44	gold quality
adult mammalian kidney	UBERON:0000082	99.42	gold quality
epithelium of bronchus	UBERON:0002031	99.42	gold quality
ileum	UBERON:0002116	99.42	silver quality
right adrenal gland	UBERON:0001233	99.41	gold quality
left adrenal gland	UBERON:0001234	99.40	gold quality
bronchus	UBERON:0002185	99.40	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.40	gold quality
adrenal gland	UBERON:0002369	99.38	gold quality
duodenum	UBERON:0002114	99.37	gold quality
stromal cell of endometrium	CL:0002255	99.36	gold quality
left lobe of thyroid gland	UBERON:0001120	99.36	gold quality
adrenal cortex	UBERON:0001235	99.36	gold quality
liver	UBERON:0002107	99.36	gold quality
left adrenal gland cortex	UBERON:0035825	99.36	gold quality
body of pancreas	UBERON:0001150	99.35	gold quality
body of stomach	UBERON:0001161	99.35	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-9467	yes	46.72
E-HCAD-10	yes	33.92
E-MTAB-10042	yes	4.27
E-MTAB-7606	no	2239.64
E-MTAB-6911	no	2184.76
E-MTAB-6819	no	1066.56
E-MTAB-10596	no	764.75
E-GEOD-93593	no	8.38
E-MTAB-9388	no	7.48
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
EDEM1	Repression

Upstream regulators (CollecTRI, top): CTCF, KLF10

miRNA regulators (miRDB)

89 targeting TMBIM6, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-605-3P	99.88	69.22	1833

Literature-anchored findings (GeneRIF, showing 40)

• Results indicate that the human Bax inhibitor-1 gene may serve as a prostate cancer expression marker based on its overexpression in prostate carcinoma and prostate cancer cell lines. (PMID:12875974)
• BI-1 gene expression is conserved evolutionarily and may act as a key regulator of the apoptotic pathway in bronchiolalveolar carcinoma (PMID:16353209)
• BI-1 can inhibit the endoplasmic reticulum stress proteins as well as the accumulation of Rreactive oxygen species, thereby protecting the cells. (PMID:17526500)
• BI-1 and Bcl-X(L) operate downstream of or parallel to Bax/Bak (PMID:18299329)
• BI-1 increases Ca(2+) leak rates from the ER through a mechanism that is dependent on pH and on the carboxyl-terminal cytosolic region of the BI-1 protein. (PMID:18378668)
• The tmbim6 may participate in cell death regulation by interacting with proteins of Bcl-2 family, promoting tumor metastasis, which is deduced from the evolutionary conservation of the membrane protein family containing multiple membrane spanning segments (PMID:18440869)
• Results report the simultaneous refolding and reconstitution of the recombinant Bax inhibitor-1 (BI-1) from inclusion bodies expressed in Escherichia coli. (PMID:19284981)
• These results suggest that reconstituted Bax inhibitor-1 has a Ca(2+)/H(+) antiporter-like activity. (PMID:19290886)
• Bax inhibitor 1 regulates ER-stress-induced ROS accumulation through the regulation of cytochrome P450 2E1. (PMID:19339548)
• Bax inhibitor-1 overexpression in 3T3-L1 preadipocytes inhibits calcium mobilizing agent-induced suppression of adipogenesis. (PMID:19433315)
• down-regulation of BI-1 lead to the activation of the associated cell death pathways (PMID:19579059)
• Data show that BI-1 increased actin polymerization and cell adhesion through Ca2+ regulation and actin interaction. (PMID:20123969)
• BI-1 expression is down-regulated as liver damage progresses. (PMID:20359348)
• post-translational regulation of the BI-1 protein by E3 ligase BAR contributes to the dynamic control of IRE1 signaling during endoplasmic reticulum stress (PMID:21068390)
• Brain tissue from BI-1 transgenic mice shows reduced levels of apoptotic cells and reduced induction of markers of endoplasmic reticulum stress after brain injury. (PMID:21075086)
• the pathway by which estrogen induces apoptosis is possibly through an up-regulation of Klf10 that decreases BI-1 and finally increases the concentration of cytoplasmic calcium (PMID:21262377)
• Studies indicate that manipulation of BI-1 has the potential for significant therapeutic benefit in a wide range of diseases. (PMID:21297665)
• These findings suggest that BI-1 can lead cancer invasion and metastasis by inducing extracellular environment acidic. (PMID:21537843)
• Lentivirus-mediated RNA interference targeting Bax inhibitor-1 suppresses ex vivo cell proliferation and in vivo tumor growth of nasopharyngeal carcinoma. (PMID:21545297)
• highly maintained lysosomal activity may be one of the mechanisms by which BI-1 exerts its regulatory effects on the ER stress response and cell death. (PMID:21586565)
• expression of BAX inhibitor-1 is associated with acidic pH-induced calcium release, cell death, and pro-inflammatory cytokine release in human osteoblasts (PMID:21601004)
• The C terminus of Bax inhibitor-1 forms a Ca2+-permeable channel pore. (PMID:22128171)
• Data indicate that GAAP and BI-1 have a six membrane-spanning topology with cytosolic N and C termini and a C-terminal reentrant loop. (PMID:22418439)
• The results reveal BI-1 as a novel autophagy regulator that bridges Ca(2) signaling between ER and mitochondria, reducing cellular oxygen consumption and contributing to cellular resilience in the face of metabolic stress. (PMID:22588718)
• The effect of Bax Inhibitor-1(TMBIM6) as a regulatorof endoplasmic reticulum Ca2+ homeostasis is regulated by intracellular pH by removing negative charges. (PMID:23867001)
• BI-1 enhances glucose metabolism, leading to high activation of the sodium/hydrogen exchange for intracellular pH homeostasis. (PMID:24314142)
• Constructed lentivirus expression vector for transfecting BI-1. (PMID:24344041)
• Results highlight the regulatory role of BI-1 in idiopathic pulmonary fibrosis. (PMID:24625972)
• Bax inhibitor-1 is likely a pH-sensitive calcium leak channel, not a H+/Ca2+ exchanger. (PMID:25227609)
• These results suggest that the TMBIM family has comparable functions in the maintenance of intracellular Ca(2) homeostasis in a wide variety of tissues (PMID:25764978)
• BI-1 is overexpressed and promotes the progression and metastasis of non-small cell lung cancer (PMID:25973025)
• Targeting IRE1alpha-dependent NLRP3 inflammasome signaling with pharmacological agents or by BI-1 may represent a tangible therapeutic strategy for nonalcoholic steatohepatitis (PMID:29457838)
• stable interacting partner of presenilin 1 (PS1), but not the intact gamma-secretase (PMID:30559186)
• BAX inhibitor-1: between stress and survival. (PMID:31841271)
• Bax inhibitor 1 preserves mitochondrial homeostasis in acute kidney injury through promoting mitochondrial retention of PHB2. (PMID:31903127)
• TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy through regulation of lysosomal calcium. (PMID:32167007)
• TMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation. (PMID:32782388)
• Long non-coding RNA plasmacytoma variant translocation 1 (PVT1) promotes glioblastoma multiforme progression via regulating miR-1301-3p/TMBIM6 axis. (PMID:33275233)
• RBM15 facilitates laryngeal squamous cell carcinoma progression by regulating TMBIM6 stability through IGF2BP3 dependent. (PMID:33637103)
• TMBIM6, a potential virus target protein identified by integrated multiomics data analysis in SARS-CoV-2-infected host cells. (PMID:33744846)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tegt	ENSDARG00000077934
mus_musculus	Tmbim6	ENSMUSG00000023010
rattus_norvegicus	Tmbim6	ENSRNOG00000055579
drosophila_melanogaster	BI-1	FBGN0035871

Paralogs (5): FAIM2 (ENSG00000135472), TMBIM1 (ENSG00000135926), TMBIM4 (ENSG00000155957), GHITM (ENSG00000165678), GRINA (ENSG00000178719)

Protein

Protein identifiers

Bax inhibitor 1 — P55061 (reviewed: P55061)

Alternative names: Testis-enhanced gene transcript protein, Transmembrane BAX inhibitor motif-containing protein 6

All UniProt accessions (14): A0A0G2JKZ4, P55061, F8VPI1, F8VQQ5, F8VQW0, F8VR05, F8VSI7, F8VVJ4, F8VX73, F8VY06, F8W086, F8W1G3, F8W1V3, F8W201

UniProt curated annotations — full annotation on UniProt →

Function. Endoplasmic reticulum (ER)-resident protein that confers cellular protection as an anti-apoptotic protein by limiting multiple stress-inducing pathways surrounding the endoplasmic reticulum and mitochondria. Inhibits the activities of the key sensor for the endoplasmic reticulum unfolded protein response IRE1alpha/ERN1 both directly and by blocking BAX/BAK binding. Modulates ER calcium homeostasis by acting as a calcium-leak channel. Negatively regulates autophagy and autophagosome formation, especially during periods of nutrient deprivation, and reduces cell survival during starvation.

Subunit / interactions. Interacts with BCL2 and BCL2L1. Interacts with ERN1.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Highly abundant in testis.

Post-translational modifications. Ubiquitinated by BFAR, leading to proteasomal degradation.

Domain organisation. The intra-membrane loop at the C-terminus acts as a calcium pore, mediating calcium leak from the ER into the cytosol.

Similarity. Belongs to the BI1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P55061-1	1	yes
P55061-2	2

RefSeq proteins (5): NP_001092046, NP_001401391, NP_001401392, NP_001401393, NP_003208* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006213	Bax_inhbtr1_CS	Conserved_site
IPR006214	Bax_inhibitor_1-related	Family

Pfam: PF01027

UniProt features (23 total): topological domain 8, transmembrane region 6, sequence conflict 3, mutagenesis site 2, chain 1, intramembrane region 1, cross-link 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55061-F1	91.56	0.79

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 7

Mutagenesis-validated functional residues (2):

Position	Phenotype
209	abolishes calcium flux properties.
213	abolishes calcium flux properties.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 323 (showing top): MORF_MTA1, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_IRE1_MEDIATED_UNFOLDED_PROTEIN_RESPONSE, MORF_RAB5A, GOBP_RESPONSE_TO_ACID_CHEMICAL, YANG_BREAST_CANCER_ESR1_BULK_UP, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_NEGATIVE_REGULATION_OF_PRODUCTION_OF_MOLECULAR_MEDIATOR_OF_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_RNA_SPLICING, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, MORF_RAD21, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, HSIAO_HOUSEKEEPING_GENES

GO Biological Process (20): negative regulation of transcription by RNA polymerase II (GO:0000122), negative regulation of immunoglobulin production (GO:0002638), autophagy (GO:0006914), negative regulation of calcium ion transport into cytosol (GO:0010523), endoplasmic reticulum calcium ion homeostasis (GO:0032469), negative regulation of RNA splicing (GO:0033119), cellular response to unfolded protein (GO:0034620), neuron intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0036483), negative regulation of apoptotic process (GO:0043066), response to L-glutamate (GO:1902065), negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway (GO:1902236), negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway (GO:1903298), negative regulation of IRE1-mediated unfolded protein response (GO:1903895), negative regulation of apoptotic signaling pathway (GO:2001234), apoptotic process (GO:0006915), response to unfolded protein (GO:0006986), response to endoplasmic reticulum stress (GO:0034976), IRE1-mediated unfolded protein response (GO:0036498), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (5): calcium channel activity (GO:0005262), enzyme binding (GO:0019899), ubiquitin protein ligase binding (GO:0031625), endoribonuclease inhibitor activity (GO:0060698), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	2
negative regulation of intrinsic apoptotic signaling pathway	2
apoptotic signaling pathway	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
immunoglobulin production	1
regulation of immunoglobulin production	1
negative regulation of production of molecular mediator of immune response	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
regulation of calcium ion transport into cytosol	1
negative regulation of cytosolic calcium ion concentration	1
calcium ion transport into cytosol	1
negative regulation of calcium ion transmembrane transport	1
endoplasmic reticulum	1
intracellular calcium ion homeostasis	1
RNA splicing	1
negative regulation of gene expression	1
regulation of RNA splicing	1
response to unfolded protein	1
cellular response to topologically incorrect protein	1
neuron apoptotic process	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
response to amino acid	1
response to nitrogen compound	1
response to oxygen-containing compound	1
regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1
negative regulation of response to endoplasmic reticulum stress	1
negative regulation of cellular response to hypoxia	1
regulation of hypoxia-induced intrinsic apoptotic signaling pathway	1
intrinsic apoptotic signaling pathway in response to hypoxia	1
IRE1-mediated unfolded protein response	1
negative regulation of endoplasmic reticulum unfolded protein response	1
regulation of IRE1-mediated unfolded protein response	1

Protein interactions and networks

STRING

1536 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMBIM6	BCL2L1	Q07817	954
TMBIM6	BCL2	P10415	879
TMBIM6	ERN1	O75460	851
TMBIM6	BECN1	Q14457	801
TMBIM6	GRINA	Q7Z429	688
TMBIM6	FAIM2	Q9BWQ8	669
TMBIM6	ITPR3	Q14573	657
TMBIM6	TMBIM1	Q969X1	656
TMBIM6	ITPR1	Q14643	655
TMBIM6	BAX	P55269	611
TMBIM6	XBP1	P17861	567
TMBIM6	MAP3K5	Q99683	562
TMBIM6	FAS	P25445	554
TMBIM6	PARP16	Q8N5Y8	553
TMBIM6	PTPN1	P18031	549

IntAct

294 interactions, top by confidence:

A	B	Type	Score
RNF185	TMBIM6	psi-mi:“MI:0914”(association)	0.740
TMBIM6	RNF185	psi-mi:“MI:0915”(physical association)	0.740
TMBIM6	ODF4	psi-mi:“MI:0915”(physical association)	0.740
TMBIM6	SCN3B	psi-mi:“MI:0915”(physical association)	0.670
PSEN1	TMBIM6	psi-mi:“MI:0915”(physical association)	0.660
PSEN1	TMBIM6	psi-mi:“MI:0403”(colocalization)	0.660
PSEN1	TMBIM6	psi-mi:“MI:0407”(direct interaction)	0.660
PSEN1	TMBIM6	psi-mi:“MI:0914”(association)	0.660
C5orf46	TMBIM6	psi-mi:“MI:0914”(association)	0.560
TMBIM6	CD79A	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	REEP2	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	SYT9	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	CD99L2	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	GJA8	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	ESAM	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	PIANP	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	TEX29	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	GYPA	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	PVR	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	ENPP4	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	GPR42	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (174): TMBIM6 (Affinity Capture-MS), TMBIM6 (Affinity Capture-MS), TMBIM6 (Affinity Capture-MS), TMBIM6 (Affinity Capture-MS), TMBIM6 (PCA), TMBIM6 (Affinity Capture-MS), TMBIM6 (Affinity Capture-MS), TMBIM6 (Affinity Capture-MS), TMBIM6 (Affinity Capture-MS), TMBIM6 (Affinity Capture-MS), TMBIM6 (Affinity Capture-MS), TMBIM6 (Affinity Capture-MS), TMBIM6 (Affinity Capture-MS), TMBIM6 (Affinity Capture-MS), TMBIM6 (Affinity Capture-MS)

ESM2 similar proteins: F4JIE8, O25578, O31539, O51489, O74888, O84826, O95562, P0AAC4, P0AAC5, P0AAC6, P0AAC7, P0DA10, P0DA11, P0DXN1, P0DXN2, P0DXN3, P44477, P48558, P55061, P55062, P63701, P63702, Q0V882, Q11080, Q4FZV2, Q54K40, Q5R7R1, Q5U3Y5, Q5XDQ1, Q66RM2, Q8BJZ3, Q8P2D4, Q94A20, Q969X1, Q9A1B9, Q9A2A3, Q9CEU8, Q9CNM5, Q9D2C7, Q9DA39

Diamond homologs: O74888, P55061, P55062, Q0V882, Q54K40, Q5R7R1, Q5XIA8, Q66RM2, Q9D2C7, Q9H3K2, Q9HC24, Q9IA79, Q9KSA1, Q9LD45, Q9MBD8, Q9VSH3, P0DXN1, P0DXN2, P0DXN3, Q9ZE15, Q91VC9, F4JIE8, O25578, O88407, P0AAC4, P0AAC5, Q03268, Q11080, Q1LZ71, Q32L53, Q5R4I4, Q6P6R0, Q7Z429, Q8K097, Q94A20, Q969X1, Q9A2A3, Q9BWQ8, Q9DA39, Q9ESF4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
BFAR	“down-regulates quantity by destabilization”	TMBIM6	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1463 predictions. Top by Δscore:

Variant	Effect	Δscore
12:49750199:G:T	donor_gain	1.0000
12:49752455:A:AG	acceptor_gain	1.0000
12:49752456:T:G	acceptor_gain	1.0000
12:49752459:TGCAG:T	acceptor_gain	1.0000
12:49752461:CAG:C	acceptor_gain	1.0000
12:49752461:CAGAG:C	acceptor_loss	1.0000
12:49752462:A:AG	acceptor_gain	1.0000
12:49752462:AGA:A	acceptor_gain	1.0000
12:49752462:AGAGT:A	acceptor_gain	1.0000
12:49752463:G:GA	acceptor_gain	1.0000
12:49752463:GA:G	acceptor_gain	1.0000
12:49752463:GAG:G	acceptor_gain	1.0000
12:49752463:GAGT:G	acceptor_gain	1.0000
12:49752463:GAGTG:G	acceptor_gain	1.0000
12:49752545:CATAT:C	donor_gain	1.0000
12:49752546:ATAT:A	donor_gain	1.0000
12:49752547:TAT:T	donor_gain	1.0000
12:49752548:AT:A	donor_gain	1.0000
12:49752548:ATG:A	donor_loss	1.0000
12:49752549:TGTAA:T	donor_loss	1.0000
12:49752550:G:C	donor_loss	1.0000
12:49752550:G:GG	donor_gain	1.0000
12:49752551:T:A	donor_loss	1.0000
12:49752969:TTAG:T	acceptor_loss	1.0000
12:49752971:A:AG	acceptor_gain	1.0000
12:49752971:A:G	acceptor_loss	1.0000
12:49752972:G:GG	acceptor_gain	1.0000
12:49752972:GA:G	acceptor_gain	1.0000
12:49752972:GAA:G	acceptor_gain	1.0000
12:49752972:GAAC:G	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000220250 (12:49740551 G>A,C,T), RS1000222466 (12:49755053 G>A), RS1000296185 (12:49755262 T>C), RS1000798021 (12:49760670 G>A), RS1001027312 (12:49742602 T>C), RS1001166520 (12:49760417 A>C), RS1001257956 (12:49756191 A>G), RS1001289079 (12:49756389 C>T), RS1001319229 (12:49749695 A>C,G), RS1001477169 (12:49750287 G>A), RS1001689451 (12:49758045 AAAC>A), RS1001758423 (12:49763811 T>G), RS1001762775 (12:49761569 A>G,T), RS1001800288 (12:49749975 G>C), RS1002013063 (12:49739863 T>A)

Disease associations

OMIM: gene MIM:600748 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006269_1216	General cognitive ability	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724791 (SINGLE PROTEIN)

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, increases expression	3
sodium arsenite	affects cotreatment, decreases expression, increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases expression, increases oxidation, affects expression	2
Ozone	increases oxidation, increases abundance, affects expression, affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases expression, increases oxidation, increases abundance, affects cotreatment	1
deoxynivalenol	decreases expression	1
lead acetate	affects cotreatment, decreases expression	1
methylparaben	increases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases oxidation, increases abundance	1
celastrol	increases expression	1
tamibarotene	affects expression	1
azoxystrobin	increases expression	1
corosolic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
pyrimidifen	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
picoxystrobin	increases expression	1
Sunitinib	increases expression	1
Acrolein	increases expression, increases oxidation, increases abundance, affects cotreatment	1
Benzo(a)pyrene	increases methylation	1
Carmustine	decreases expression, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	increases expression	1
Gallic Acid	increases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5576277	Binding	Thermal stabilization of TMBIM6 in human A549 cells at 46 to 60 degreeC at 100 uM incubated for 2 hrs by CETSA based Western blot analysis	13-oxyingenol dodecanoate derivatives induce mitophagy and ferroptosis through targeting TMBIM6 as potential anti-NSCLC agents. — Eur J Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TS64	HAP1 TMBIM6 (-) 1	Cancer cell line	Male
CVCL_TS65	HAP1 TMBIM6 (-) 2	Cancer cell line	Male
CVCL_TS66	HAP1 TMBIM6 (-) 3	Cancer cell line	Male
CVCL_TS67	HAP1 TMBIM6 (-) 4	Cancer cell line	Male
CVCL_TS68	HAP1 TMBIM6 (-) 5	Cancer cell line	Male

Clinical trials (associated diseases)

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