TOMM70

Summary

TOMM70 (translocase of outer mitochondrial membrane 70, HGNC:11985) is a protein-coding gene on chromosome 3q12.2, encoding Mitochondrial import receptor subunit TOM70 (O94826). Acts as a receptor of the preprotein translocase complex of the outer mitochondrial membrane (TOM complex). It is a selective cancer dependency (DepMap: 24.2% of cell lines).

This gene encodes an import receptor of the outer mitochondrial membrane that is part of the translocase of the outer membrane complex. This protein is involved in the import of mitochondrial precursor proteins. The protein interacts with the SARS-CoV and SARS-Cov-2 ORF9b proteins.

Source: NCBI Gene 9868 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukodystrophy (Moderate, GenCC) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 28 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 24.2% of screened cell lines
• MANE Select transcript: NM_014820

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11985
Approved symbol	TOMM70
Name	translocase of outer mitochondrial membrane 70
Location	3q12.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0719, Tom70
Ensembl gene	ENSG00000154174
Ensembl biotype	protein_coding
OMIM	606081
Entrez	9868

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 2 retained_intron

ENST00000284320, ENST00000483945, ENST00000492171, ENST00000906284, ENST00000906285, ENST00000935871, ENST00000935872, ENST00000957325

RefSeq mRNA: 1 — MANE Select: NM_014820 NM_014820

CCDS: CCDS33807

Canonical transcript exons

ENST00000284320 — 12 exons

Exon	Start	End
ENSE00001014399	100375018	100375152
ENSE00001014400	100384479	100384588
ENSE00001014401	100381615	100381763
ENSE00001014402	100369038	100369135
ENSE00001014404	100368044	100368166
ENSE00001014405	100377705	100377912
ENSE00001014406	100386218	100386344
ENSE00001014408	100372606	100372722
ENSE00001014409	100373538	100373645
ENSE00001151442	100363431	100365717
ENSE00001227096	100386805	100386978
ENSE00001227107	100400626	100401089

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 98.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 53.3986 / max 499.7468, expressed in 1821 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
43487	37.1243	1817
43489	12.8457	1732
43486	2.6521	1369
43488	0.7721	445
202860	0.0043	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.03	gold quality
gluteal muscle	UBERON:0002000	97.71	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.69	gold quality
deltoid	UBERON:0001476	97.68	gold quality
triceps brachii	UBERON:0001509	97.57	gold quality
parotid gland	UBERON:0001831	97.57	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.50	gold quality
biceps brachii	UBERON:0001507	97.40	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.29	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.26	gold quality
middle temporal gyrus	UBERON:0002771	97.16	gold quality
secondary oocyte	CL:0000655	97.12	gold quality
vastus lateralis	UBERON:0001379	97.12	gold quality
tibialis anterior	UBERON:0001385	97.07	gold quality
orbitofrontal cortex	UBERON:0004167	97.01	gold quality
tongue squamous epithelium	UBERON:0006919	96.99	gold quality
middle frontal gyrus	UBERON:0002702	96.98	gold quality
pons	UBERON:0000988	96.86	gold quality
left ventricle myocardium	UBERON:0006566	96.61	gold quality
diaphragm	UBERON:0001103	96.49	gold quality
cervix squamous epithelium	UBERON:0006922	96.49	gold quality
myocardium	UBERON:0002349	96.39	gold quality
body of tongue	UBERON:0011876	96.38	gold quality
skeletal muscle tissue	UBERON:0001134	96.36	gold quality
quadriceps femoris	UBERON:0001377	96.28	gold quality
cortical plate	UBERON:0005343	96.28	gold quality
lateral globus pallidus	UBERON:0002476	96.23	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.99	gold quality
ileal mucosa	UBERON:0000331	95.98	gold quality
muscle tissue	UBERON:0002385	95.88	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.30

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GABPA, SPI1, ZNF699

miRNA regulators (miRDB)

122 targeting TOMM70, 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-5193	100.00	67.26	1744
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-548AC	99.84	70.77	4351

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 24.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 24)

• TOMM70A is ubiquitously expressed in human tissues, maps on chromosome 3q13.1-q13.2 and consists of 12 coding exons spanning over 37 kb. (PMID:12200962)
• The internal EELD domain facilitates mitochondrial targeting of Mcl-1 via a Tom70-dependent pathway. (PMID:16822835)
• suggests a novel active role for Hsp90 in import steps subsequent to Tom70 targeting. (PMID:16968702)
• S100A2 and S100A6 interact with another TPR protein Tom70 and regulate the Tom70-ligand interaction in vitro (PMID:18669640)
• nuclear respiratory factor-2 binding site methylation suppresses the promoter activity of the human TOMM70 gene (PMID:18852034)
• results indicate that the Tom70 monomers are the functional form of the receptor, whereas the homodimers appear to be a minor population, and may represent an inactive state (PMID:20504278)
• Tom70 as a critical adaptor linking MAVS to TBK1/IRF3, revealing that mitochondrion is evolutionarily integrated with innate immunity. (PMID:20628368)
• This study revealed a novel finding, that is, human TOM70 is linked with the hepatitis C virus NS3 protein and the apoptotic response. (PMID:21412788)
• a novel model in which Tom20 binds Tom70 to facilitate preprotein release from the chaperones by competition (PMID:21771790)
• used biophysical tools to study the interaction between the C-terminal domain of Hsp90 (C-Hsp90), which contains the EEVD motif that binds to TPR domains, and the cytosolic fragment of Tom70 (PMID:21781956)
• The hepatitis C virus NS3/4A protein induced Tom70 expression. (PMID:22032846)
• PINK1 is imported into mitochondria by a unique pathway that is independent of the TOM core complex but crucially depends on the import receptor Tom70 (PMID:23472196)
• Blockade of mitochondrial protein import triggers the recruitment of PARK2, by PINK1, to the TOMM machinery. (PMID:24149440)
• Tom70 acts as a molecular switch that orchestrates hypertrophic stresses and mitochondrial responses to determine pathological cardiac hypertrophy. (PMID:25022898)
• Collectively, this study characterizes a novel protein complex, Tom70/Hsp90/IRF3/Bax, that is important for Sendai virus-induced apoptosis. (PMID:25609812)
• TOM70, but not TOM20, clusters in distinct OMM foci, frequently overlapping with sites in which the endoplasmic reticulum (ER) contacts mitochondria. Functionally, TOM70 depletion specifically impairs inositol trisphosphates (IP3)-linked ER to mitochondria Ca(2+) transfer. This phenomenon is dependent on the capacity of TOM70 to interact with IP3-receptors and favor their functional recruitment close to mitochondria. (PMID:29395920)
• Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay. (PMID:31907385)
• De novo mutations in TOMM70, a receptor of the mitochondrial import translocase, cause neurological impairment. (PMID:32356556)
• SARS-CoV-2 Orf9b suppresses type I interferon responses by targeting TOM70. (PMID:32728199)
• Crystal structure of SARS-CoV-2 Orf9b in complex with human TOM70 suggests unusual virus-host interactions. (PMID:33990585)
• Relation between ORF8a and the mitochondrial protein TOM70 in SARS-CoV-2 infection. (PMID:34228876)
• Phosphorylation of SARS-CoV-2 Orf9b Regulates Its Targeting to Two Binding Sites in TOM70 and Recruitment of Hsp90. (PMID:34502139)
• Mitochondria shed their outer membrane in response to infection-induced stress. (PMID:35025629)
• The Orf9b protein of SARS-CoV-2 modulates mitochondrial protein biogenesis. (PMID:37682539)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tomm70a	ENSDARG00000029639
mus_musculus	Tomm70a	ENSMUSG00000022752
rattus_norvegicus	Tomm70	ENSRNOG00000001640
drosophila_melanogaster	Tom70	FBGN0032397

Paralogs (18): RPAP3 (ENSG00000005175), TOMM34 (ENSG00000025772), ST13 (ENSG00000100380), STUB1 (ENSG00000103266), SPAG1 (ENSG00000104450), SGTA (ENSG00000104969), TTC1 (ENSG00000113312), TTC31 (ENSG00000115282), UNC45A (ENSG00000140553), UNC45B (ENSG00000141161), SPATA16 (ENSG00000144962), TTC12 (ENSG00000149292), SUGT1 (ENSG00000165416), STIP1 (ENSG00000168439), TTC32 (ENSG00000183891), SGTB (ENSG00000197860), TTC4 (ENSG00000243725), DNAAF4 (ENSG00000256061)

Protein

Protein identifiers

Mitochondrial import receptor subunit TOM70 — O94826 (reviewed: O94826)

Alternative names: Mitochondrial precursor proteins import receptor, Translocase of outer membrane 70 kDa subunit, Translocase of outer mitochondrial membrane protein 70

All UniProt accessions (1): O94826

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a receptor of the preprotein translocase complex of the outer mitochondrial membrane (TOM complex). Recognizes and mediates the translocation of mitochondrial preproteins from the cytosol into the mitochondria in a chaperone dependent manner. Mediates TBK1 and IRF3 activation induced by MAVS in response to Sendai virus infection and promotes host antiviral responses during virus infection. Upon Sendai virus infection, recruits HSP90AA1:IRF3:BAX in mitochondrion and the complex induces apoptosis.

Subunit / interactions. Forms part of the preprotein translocase complex of the outer mitochondrial membrane (TOM complex) which consists of at least 7 different proteins (TOMM5, TOMM6, TOMM7, TOMM20, TOMM22, TOMM40 and TOMM70). Interacts with CAPN8. Interacts with TRADD, TRAF6 and STING. Interacts with MAVS; the interaction is enhanced by Sendai virus infection. Interacts with HSPA8 and HSP90AA1; both interactions are required for preprotein mitochondrial import. The interaction with HSP90AA1 is direct and mediates the association of TOMM70 with IRF3 and TBK1. Upon mitochondrial depolarization, interacts with PINK1; the interaction is required for PINK1-TOM-TIM23 supercomplex formation which is critical for PINK1 stabilization at the outer mitochondrial membrane, kinase activation and downstream mitophagy. (Microbial infection) Interacts (via C-terminus) with SARS coronaviru/SARS-CoV and SARS coronavirus-2/SARS-CoV-2 virus protein ORF9b. (Microbial infection) Interacts with parasite T.gondii RH strain MAF1b1; the interaction impairs TOMM70 import activity, enables the parasite to associate with the host mitochondria and facilitates the association of MAF1b1 with MIB complex component SAMM50, promoting the formation of SPOTs (structures positive for outer mitochondrial membrane (OMM)); the interaction is probably indirect.

Subcellular location. Mitochondrion outer membrane.

Similarity. Belongs to the Tom70 family.

RefSeq proteins (1): NP_055635* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat

Pfam: PF00515, PF13181

UniProt features (56 total): helix 27, repeat 10, modified residue 7, topological domain 2, mutagenesis site 2, turn 2, initiator methionine 1, chain 1, region of interest 1, cross-link 1, transmembrane region 1, strand 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9PKQ	X-RAY DIFFRACTION	2
7DHG	X-RAY DIFFRACTION	2.2
7KDT	ELECTRON MICROSCOPY	3.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94826-F1	81.40	0.63

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 (8): 2, 71, 91, 96, 110, 185, 434, 275

Mutagenesis-validated functional residues (2):

Position	Phenotype
192	unable to induce irf3 activation upon sendai virus infection. loss of interaction with hspa8 and hsp90aa1. no effect on
195	no effect on interaction with hsp90aa1.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta
R-HSA-5205685	PINK1-PRKN Mediated Mitophagy
R-HSA-5689880	Ub-specific processing proteases
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses

MSigDB gene sets: 363 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_CELLULAR_RESPONSE_TO_VIRUS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GCM_ZNF198, MORF_RRM1

GO Biological Process (14): activation of innate immune response (GO:0002218), positive regulation of defense response to virus by host (GO:0002230), obsolete protein targeting to mitochondrion (GO:0006626), protein import into mitochondrial matrix (GO:0030150), positive regulation of interferon-beta production (GO:0032728), regulation of apoptotic process (GO:0042981), protein insertion into mitochondrial inner membrane (GO:0045039), protein insertion into mitochondrial outer membrane (GO:0045040), negative regulation of cell growth involved in cardiac muscle cell development (GO:0061052), response to thyroxine (GO:0097068), cellular response to virus (GO:0098586), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955), mRNA transcription (GO:0009299), antiviral innate immune response (GO:0140374)

GO Molecular Function (5): transmembrane protein transporter activity (GO:0008320), protein-macromolecule adaptor activity (GO:0030674), mitochondrion targeting sequence binding (GO:0030943), protein binding (GO:0005515), molecular adaptor activity (GO:0060090)

GO Cellular Component (7): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial outer membrane translocase complex (GO:0005742), membrane (GO:0016020), mitochondrial membrane (GO:0031966), extracellular exosome (GO:0070062), TOM complex (GO:0140596)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Protein localization	1
Innate Immune System	1
Mitophagy	1
Deubiquitination	1
SARS-CoV-1-host interactions	1
SARS-CoV-2-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrial protein import pathway	2
binding	2
activation of immune response	1
positive regulation of innate immune response	1
regulation of defense response to virus by host	1
protein transmembrane import into intracellular organelle	1
protein localization to mitochondrion	1
import into the mitochondrion	1
positive regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
apoptotic process	1
regulation of programmed cell death	1
inner mitochondrial membrane organization	1
outer mitochondrial membrane organization	1
protein insertion into mitochondrial membrane	1
negative regulation of cardiac muscle hypertrophy	1
negative regulation of cell growth	1
negative regulation of striated muscle cell differentiation	1
negative regulation of cardiac muscle tissue growth	1
cell growth involved in cardiac muscle cell development	1
regulation of cell growth involved in cardiac muscle cell development	1
response to amino acid	1
response to thyroid hormone	1
response to oxygen-containing compound	1
response to L-phenylalanine derivative	1
response to virus	1
DNA-templated transcription	1
mRNA metabolic process	1
innate immune response	1
defense response to virus	1
macromolecule transmembrane transporter activity	1
protein transmembrane transport	1
protein transporter activity	1
protein binding	1
molecular adaptor activity	1
signal sequence receptor activity	1
molecular_function	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2250 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOMM70	TOMM22	Q9NS69	999
TOMM70	TOMM20	Q15388	999
TOMM70	TOMM40	O96008	998
TOMM70	TOMM7	Q9P0U1	997
TOMM70	HSP90AB1	P08238	996
TOMM70	HSP90AA1	P07900	995
TOMM70	TOMM5	Q8N4H5	992
TOMM70	HSPA4	P34932	985
TOMM70	TOMM6	Q96B49	984
TOMM70	ITPR3	Q14573	947
TOMM70	TIMM17A	Q99595	944
TOMM70	TIMM44	O43615	916
TOMM70	TIMM10	P62072	879
TOMM70	MFN2	O95140	875
TOMM70	SAMM50	Q9Y512	857

IntAct

124 interactions, top by confidence:

A	B	Type	Score
	TOMM70	psi-mi:“MI:0914”(association)	0.980
TOMM70		psi-mi:“MI:0915”(physical association)	0.980
TOMM70		psi-mi:“MI:0407”(direct interaction)	0.980
	TOMM70	psi-mi:“MI:0407”(direct interaction)	0.980
TOMM70		psi-mi:“MI:0403”(colocalization)	0.980
	TOMM70	psi-mi:“MI:0915”(physical association)	0.980
	TOMM70	psi-mi:“MI:0403”(colocalization)	0.980
TOMM70		psi-mi:“MI:2364”(proximity)	0.980
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TOMM70		psi-mi:“MI:0407”(direct interaction)	0.690
	TOMM70	psi-mi:“MI:0403”(colocalization)	0.690
TOMM70		psi-mi:“MI:0403”(colocalization)	0.690

BioGRID (255): TOMM70A (Two-hybrid), TOMM70A (Affinity Capture-RNA), RAB1A (Co-fractionation), TOMM70A (Co-fractionation), TOMM70A (Affinity Capture-MS), PARK2 (FRET), TOMM70A (Affinity Capture-MS), TOMM70A (Affinity Capture-MS), TOMM70A (Affinity Capture-MS), TOMM70A (Affinity Capture-MS), TOMM70A (Affinity Capture-MS), TOMM70A (Affinity Capture-MS), TOMM70A (Affinity Capture-MS), TOMM70A (Affinity Capture-MS), TOMM70A (Affinity Capture-MS)

ESM2 similar proteins: A0MQH0, A4II29, A4IIX9, E9PTA2, O94826, P24786, Q0VC93, Q13507, Q16288, Q17QS6, Q25BN1, Q3ULA2, Q502M6, Q59H18, Q5GIG6, Q5IFJ9, Q5IS37, Q5IS82, Q5U5A6, Q5ZLX4, Q6DFV5, Q6GPR5, Q6GQW0, Q6TUI4, Q75Q39, Q7T3X9, Q7T3Y0, Q7TQP6, Q7Z6K4, Q7Z713, Q862Z2, Q8BPU7, Q8K4Q0, Q8N122, Q8VBX0, Q8WWX0, Q8WXK3, Q91987, Q91YD4, Q91ZA8

Diamond homologs: A4K2V0, A6HD62, A6ZRW3, D7REX8, F1RBN2, F4IRM4, F4JTI1, F4K487, F4KCL7, O13754, O14217, O16259, O35814, O48802, O54981, O94826, O95801, P07213, P23231, P25638, P31948, P33313, P38825, P53041, P53042, Q07617, Q12118, Q13451, Q15785, Q32PZ3, Q3KRD5, Q3ZBR5, Q43207, Q4R8N7, Q5EA11, Q5PPS5, Q5R8D8, Q5RAP0, Q5U2X2, Q5VJS5

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
TOMM70	“form complex”	“TOM40 complex”	binding
DYRK1A	“up-regulates activity”	TOMM70	phosphorylation
TOMM70	“up-regulates activity”	HSP90AA1	binding
TOMM70	“up-regulates activity”	HSPA1A	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Attenuation phase	6	38.2×	4e-06
HSF1-dependent transactivation	6	29.7×	7e-06
HSF1 activation	5	29.7×	8e-05
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	7	21.2×	7e-06
Mitochondrial protein degradation	6	10.7×	2e-03
ESR-mediated signaling	5	10.0×	6e-03
Estrogen-dependent gene expression	6	7.1×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to heat	5	19.1×	1e-03
response to unfolded protein	5	16.7×	1e-03
mitochondrion organization	6	10.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	11
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1591 predictions. Top by Δscore:

Variant	Effect	Δscore
3:100368039:GTTAC:G	donor_loss	1.0000
3:100368040:TTAC:T	donor_loss	1.0000
3:100368041:TACC:T	donor_loss	1.0000
3:100368043:C:CT	donor_loss	1.0000
3:100368053:T:TA	donor_gain	1.0000
3:100368162:GTAAA:G	acceptor_gain	1.0000
3:100368163:TAAA:T	acceptor_gain	1.0000
3:100368164:AAA:A	acceptor_gain	1.0000
3:100368165:AA:A	acceptor_gain	1.0000
3:100368166:AC:A	acceptor_loss	1.0000
3:100368167:C:CC	acceptor_gain	1.0000
3:100368168:T:G	acceptor_loss	1.0000
3:100368173:A:AC	acceptor_gain	1.0000
3:100368173:A:C	acceptor_gain	1.0000
3:100369036:AC:A	donor_gain	1.0000
3:100369037:CC:C	donor_gain	1.0000
3:100372603:TACC:T	donor_loss	1.0000
3:100372605:C:T	donor_loss	1.0000
3:100372718:CGGTA:C	acceptor_gain	1.0000
3:100372719:GGTA:G	acceptor_gain	1.0000
3:100372720:GTA:G	acceptor_gain	1.0000
3:100372721:TA:T	acceptor_gain	1.0000
3:100372723:C:CC	acceptor_gain	1.0000
3:100372725:A:C	acceptor_gain	1.0000
3:100373533:CCT:C	donor_loss	1.0000
3:100373534:CTACC:C	donor_loss	1.0000
3:100373535:TACC:T	donor_loss	1.0000
3:100373536:A:AC	donor_gain	1.0000
3:100373537:C:CC	donor_gain	1.0000
3:100373641:TTCAG:T	acceptor_gain	1.0000

AlphaMissense

4015 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:100365614:C:G	A593P	1.000
3:100365619:G:T	A591D	1.000
3:100365620:C:G	A591P	1.000
3:100365622:G:T	A590D	1.000
3:100365623:C:G	A590P	1.000
3:100365631:A:G	L587P	1.000
3:100365631:A:T	L587H	1.000
3:100365635:A:G	S586P	1.000
3:100365640:A:G	L584P	1.000
3:100365647:C:G	A582P	1.000
3:100365667:G:T	A575D	1.000
3:100365670:A:G	L574P	1.000
3:100365680:C:G	A571P	1.000
3:100365687:G:C	F568L	1.000
3:100365687:G:T	F568L	1.000
3:100365688:A:G	F568S	1.000
3:100365689:A:G	F568L	1.000
3:100365701:C:G	A564P	1.000
3:100368062:C:A	G552V	1.000
3:100368062:C:T	G552E	1.000
3:100368063:C:G	G552R	1.000
3:100368063:C:T	G552R	1.000
3:100368077:G:T	A547D	1.000
3:100368080:A:C	F546C	1.000
3:100368085:A:C	C544W	1.000
3:100368087:A:G	C544R	1.000
3:100368095:T:A	D541V	1.000
3:100368096:C:G	D541H	1.000
3:100368108:C:G	A537P	1.000
3:100368129:C:G	G530R	1.000

dbSNP variants (sampled 300 via entrez): RS1000111890 (3:100388461 G>A), RS1000165746 (3:100388491 C>A,G), RS1000243281 (3:100367773 T>C), RS1000431382 (3:100395489 G>A), RS1000521171 (3:100400805 G>A), RS1000582698 (3:100367079 G>A,C), RS1000595112 (3:100367514 A>G,T), RS1000717511 (3:100380472 G>A,T), RS1000773164 (3:100374315 G>A), RS1000836586 (3:100387268 G>A), RS1000888741 (3:100387469 T>C), RS1000938789 (3:100379470 C>A), RS1001010883 (3:100394036 T>C), RS1001389529 (3:100379816 T>C), RS1001391695 (3:100367975 C>G,T)

Disease associations

OMIM: gene MIM:606081 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
leukodystrophy	Moderate	Autosomal dominant
mitochondrial disease	Moderate	Autosomal recessive
combined oxidative phosphorylation deficiency	Limited	Autosomal recessive
nervous system disorder	Limited	Autosomal dominant

Mondo (4): combined oxidative phosphorylation deficiency (MONDO:0000732), nervous system disorder (MONDO:0005071), leukodystrophy (MONDO:0019046), mitochondrial disease (MONDO:0044970)

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_434	Refractive error	5.000000e-25

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009422	Nervous System Diseases	C10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066210 (SINGLE PROTEIN)

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

ChEMBL bioactivities

5 potent at pChembl≥5 of 5 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.75	Kd	1.79	nM	CHEMBL5653589
8.75	ED50	1.79	nM	CHEMBL5653589
5.92	IC50	1200	nM	CHEMBL5558181
5.82	IC50	1500	nM	CHEMBL5561795
5.30	IC50	5000	nM	CHEMBL5558644

PubChem BioAssay actives

4 with measured affinity, of 5 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149634: Binding affinity to human TOMM70A incubated for 45 mins by Kinobead based pull down assay	kd	0.0018	uM
N,N’-bis(3-carbamoyl-4,5-dimethylthiophen-2-yl)pentanediamide	2084035: Inhibition of GST-tagged human TOM70 expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	ic50	1.2000	uM
N,N’-bis(3-carbamoyl-6-ethyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)pentanediamide	2084035: Inhibition of GST-tagged human TOM70 expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	ic50	1.5000	uM
methyl 2-[[2-[[5,6-bis(furan-2-yl)-1,2,4-triazin-3-yl]sulfanyl]acetyl]amino]-4,5-dimethylthiophene-3-carboxylate	2084035: Inhibition of GST-tagged human TOM70 expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	ic50	5.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
sodium arsenite	increases expression, affects cotreatment, increases abundance	1
cobaltous chloride	increases expression	1
zinc chromate	increases abundance, increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ochratoxin A	decreases expression	1
coumarin	increases phosphorylation	1
chromium hexavalent ion	increases abundance, increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Atrazine	increases expression	1
Cadmium	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Furaldehyde	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Phenobarbital	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5524508	Binding	Inhibition of GST-tagged human TOM70 expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	Structure-based discovery of small molecule inhibitors of FKBP51-Hsp90 protein-protein interaction. — Eur J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2JB	Abcam HeLa TOMM70A KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00560157	PHASE4	COMPLETED	Nutritional and Metabolic Evaluation of a Tube Feeding Immune Enhancing Diet in ICU Patients
NCT01319643	PHASE4	UNKNOWN	Normal Oxygenation Versus Hyperoxia in the Intensive Care Unit (ICU)
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04289142	PHASE4	RECRUITING	Cognitive Outcomes After Dexmedetomidine Sedation in Cardiac Surgery Patients
NCT04386525	PHASE4	UNKNOWN	Omega 3 and Ischemic Stroke; Fish Oil as an Option
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT04970667	PHASE4	COMPLETED	Flupentixol and Melitracen Tablets in the Treatment of Emotional Disorder
NCT05068349	PHASE4	UNKNOWN	For Patients With Ischemic Stroke, Clinically Study the Effectiveness and Safety of Butylphthalide.
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT06382467	PHASE4	UNKNOWN	Comparison of Remimazolam and Propofol Combination vs. Propofol in IOM
NCT06406127	PHASE4	RECRUITING	Effect of Alpha Lipoic Acid on Chemotherapy Induced Neurological Changes in Breast Cancer Patients
NCT00240695	PHASE3	COMPLETED	A Follow-up Study to Assess Safety and Tolerability of Galantamine Treatment in Individuals With Mild Cognitive Impairment
NCT01313299	PHASE3	COMPLETED	Dysport® Adult Upper Limb Spasticity
NCT01313312	PHASE3	COMPLETED	Dysport® Adult Upper Limb Spasticity Extension Study
NCT01425983	PHASE3	COMPLETED	Dietary Intervention of Stress-Induced Neurovegetative Disorders With a Specific Amino Acid Composition (asn01)
NCT01589289	PHASE3	COMPLETED	Rapid Diagnostic Tests and Clinical/Laboratory Predictors of Tropical Diseases in Neurological Disorders in DRC
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT01862640	PHASE3	COMPLETED	A Phase 3, 12-week, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of 2 Fixed Doses of Brexpiprazole in the Treatment of Alzheimer’s Agitation
NCT01922258	PHASE3	COMPLETED	Safety and Tolerability Study of Flexible Dosing of Brexpiprazole in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer’s Type
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02284126	PHASE3	COMPLETED	Topical Vancomycin for Neurosurgery Wound Prophylaxis
NCT02436096	PHASE3	COMPLETED	A Study to Evaluate eFFIcacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With fibRoMyalgia
NCT02770807	PHASE3	COMPLETED	Intra-Erythrocyte Dexamethasone Sodium Phosphate in Ataxia Telangiectasia Patients
NCT02829814	PHASE3	TERMINATED	Repeat of: A Study to Evaluate Efficacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With Fibromyalgia
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT03336450	PHASE3	COMPLETED	Study of Midazolam Hydrochloride Oromucosal Solution (MHOS/SHP615) in Pediatric Patients With Status Epilepticus (Convulsive) in the Community Setting
NCT03336645	PHASE3	COMPLETED	Open-label Study of Midazolam Hydrochloride Oromucosal Solution (MHOS/SHP615) in Children With Status Epilepticus (Convulsive) in a Healthcare Setting in Japan
NCT04639310	PHASE3	TERMINATED	XEN496 (Ezogabine) in Children With KCNQ2 Developmental and Epileptic Encephalopathy
NCT04912856	PHASE3	TERMINATED	An Open-Label Extension of the Study XEN496 (Ezogabine) in Children With KCNQ2-DEE
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05508789	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Donanemab (LY3002813) in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ 5)
NCT05738486	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer’s Disease (TRAILBLAZER-ALZ 6)
NCT05834855	PHASE3	RECRUITING	Non-inferiority Study of Rituximab Compared to Ocrelizumab in Relapsing MS
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT06819592	PHASE3	RECRUITING	PRophylaxis Against Early VENTilator-associated Infections in Acute Brain Injury
NCT07587242	PHASE3	NOT_YET_RECRUITING	A Phase 3 Study to Evaluate the Safety and Efficacy of AOC 1044 (Also Referred to as Delpacibart Zotadirsen) in Participants With DMD With Gene Mutations Amenable to Exon 44 Skipping
NCT00659776	PHASE2	TERMINATED	MR, Histologic And EM Imaging Of Intravenous Ferumoxytol In Central Nervous System (CNS) Inflammation
NCT01059149	PHASE2	TERMINATED	Safety and Long-term Effectiveness of High Frequency Repetitive Transcranial Magnetic Stimulation of Stroke (RAICup)
NCT01255358	PHASE2	COMPLETED	Intra-Erythrocyte Dexamethasone Sodium Phosphate in Ataxia Teleangiectasia Patients