TOMM40

Summary

TOMM40 (translocase of outer mitochondrial membrane 40, HGNC:18001) is a protein-coding gene on chromosome 19q13.32, encoding Mitochondrial import receptor subunit TOM40 homolog (O96008). Channel-forming protein that forms part of the translocase of the outer mitochondrial membrane (TOM) complex essential for the recognition and translocation of cytosolically synthesized mitochondrial preproteins. It is a common-essential gene (DepMap: required in 99.6% of cancer cell lines).

The protein encoded by this gene is localized in the outer membrane of the mitochondria. It is the channel-forming subunit of the translocase of the mitochondrial outer membrane (TOM) complex that is essential for import of protein precursors into mitochondria. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 10452 — RefSeq curated summary.

At a glance

• GWAS associations: 193
• Clinical variants (ClinVar): 45 total
• Phenotypes (HPO): 26
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_001128917

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18001
Approved symbol	TOMM40
Name	translocase of outer mitochondrial membrane 40
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Aliases	PEREC1, D19S1177E, C19orf1, TOM40, PER-EC1
Ensembl gene	ENSG00000130204
Ensembl biotype	protein_coding
OMIM	608061
Entrez	10452

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 13 protein_coding, 1 nonsense_mediated_decay

ENST00000252487, ENST00000405636, ENST00000426677, ENST00000589253, ENST00000589649, ENST00000592041, ENST00000592434, ENST00000927372, ENST00000927373, ENST00000927374, ENST00000927375, ENST00000947713, ENST00000947714, ENST00000947715

RefSeq mRNA: 3 — MANE Select: NM_001128917 NM_001128916, NM_001128917, NM_006114

CCDS: CCDS12646

Canonical transcript exons

ENST00000426677 — 9 exons

Exon	Start	End
ENSE00000893936	44892393	44892460
ENSE00000893938	44892837	44892929
ENSE00000893940	44893780	44893881
ENSE00000893942	44893961	44894066
ENSE00000893943	44900730	44900852
ENSE00000893944	44901028	44901104
ENSE00000893946	44901208	44901310
ENSE00001561858	44891254	44891689
ENSE00002770357	44903030	44903689

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 96.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.9214 / max 65.5115, expressed in 1746 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176322	7.4536	1713
176323	2.5217	1220
176321	0.9462	682

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	96.47	silver quality
type B pancreatic cell	CL:0000169	95.88	silver quality
mucosa of transverse colon	UBERON:0004991	95.19	gold quality
cervix squamous epithelium	UBERON:0006922	94.23	gold quality
tongue squamous epithelium	UBERON:0006919	94.13	gold quality
right adrenal gland	UBERON:0001233	93.98	gold quality
left adrenal gland	UBERON:0001234	93.92	gold quality
endometrium epithelium	UBERON:0004811	93.87	gold quality
left adrenal gland cortex	UBERON:0035825	93.69	gold quality
adrenal cortex	UBERON:0001235	93.63	gold quality
right adrenal gland cortex	UBERON:0035827	93.63	gold quality
tendon of biceps brachii	UBERON:0008188	93.62	gold quality
gastrocnemius	UBERON:0001388	93.45	gold quality
adrenal gland	UBERON:0002369	93.05	gold quality
apex of heart	UBERON:0002098	92.92	gold quality
pharyngeal mucosa	UBERON:0000355	92.91	gold quality
lower esophagus mucosa	UBERON:0035834	92.84	gold quality
muscle of leg	UBERON:0001383	92.77	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.50	gold quality
prefrontal cortex	UBERON:0000451	92.38	gold quality
body of tongue	UBERON:0011876	92.34	gold quality
esophagus mucosa	UBERON:0002469	92.29	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.13	gold quality
right atrium auricular region	UBERON:0006631	92.12	gold quality
pancreatic ductal cell	CL:0002079	92.08	silver quality
triceps brachii	UBERON:0001509	91.99	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.88	gold quality
muscle organ	UBERON:0001630	91.86	gold quality
heart left ventricle	UBERON:0002084	91.86	gold quality
cardiac ventricle	UBERON:0002082	91.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7407	yes	169.73
E-GEOD-125970	yes	22.46
E-HCAD-13	yes	20.38
E-MTAB-8271	yes	9.06
E-CURD-112	yes	8.10
E-ANND-3	yes	6.13
E-MTAB-7008	no	432.27

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

41 targeting TOMM40, 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-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-7113-3P	98.75	65.71	1120

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• examined by immunohistochemical and molecular methods the expression of Haymaker in gynecologic organs with and without tumor; significant differences in Haymaker expression between malignant and normal gynecologic tissues were not observed (PMID:16495475)
• occurrence of an unusual TG 3’ splice site in intron 1 (PMID:17672918)
• In two independent clinical cohorts, longer lengths of rs10524523 of TOMM40 are associated with a higher risk for LOAD. (PMID:20029386)
• Analysis revealed a dominant beta-sheet structure and a short alpha-helical part for both proteins together with a high thermal stability. Two secondary structure elements can be denatured independently (PMID:21717124)
• Poly-T variants of TOMM40 may modulate the negative effects of lorazepam on memory in healthy, cognitively intact, elderly individuals, in the absence of APOEepsilon4. (PMID:21720235)
• This study demonistrated taht among APOE epsilon3/epsilon3 late middle-aged adults suggest that a subgroup with VL TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes. (PMID:21784354)
• increase in CSF cortisol associated with the presence of the APOE e4 allele was only detected when a short TOMM40 poly-T variant, shown to associate with later age of onset of AD in e4 carriers, was not present. (PMID:21803501)
• There is no association of TOMM40 poly-T repeat length with age of onset of Alzheimer’s disease (AD) nor with risk of psychosis in AD. (PMID:21820212)
• No association is found between polyT polymorphisms and TOMM40 gene expression (PMID:21825236)
• The authors propose that the identified weakly stable beta-strands 1, 2 and 9 of human Tom40A play an important role in quaternary protein-protein interactions within the mammalian TOM machinery. (PMID:21835183)
• variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits (PMID:21943158)
• Subjects with APOE epsilon4 have higher CSF NFL levels than non-epsilon4 carriers, only when they do not carry a short poly-T variant of TOMM40, which is associated with later age of onset of AD (PMID:21983493)
• This study identi fi ed TOMM40alleles, genotypes,as well asTOMM40-E4haplotypes that in fl uencelongevity. (PMID:22008263)
• The main novel finding of this investigation was that multiple APOE locus cis-elements influence both APOE and TOMM40 promoter activity according to haplotype and cell type. (PMID:22089642)
• the poly-T, rs10524523 allele frequencies in different ethnicities. (PMID:22359560)
• This study demonistrated that Downregulation of TOMM40 expression in the blood of Alzheimer disease. (PMID:22472643)
• Expression levels of TOMM40 protein in mitochondria do not reveal any differences related to the very long or short poly-T variant associated with the risk of late onset Alzheimer’s disease. (PMID:22596268)
• Three SNPs of TOMM40 and APOC1 representating linkage disequilibrium at the 19q13-q13.2 chromosomal region suggest the presence of a different genetic background underlying primary progressive aphasia and the behavioral variant of frontotemporal dementia. (PMID:22710912)
• The results of this study suggested important APOE-independent associations between the TOMM40 ‘523’ polymorphism and specific cognitive domains of memory and executive control that are preferentially affected in early-stage Alzheimer’s disease. (PMID:22863908)
• In chronic hepatitis C, genetic heterogeneity in the APOE/TOMM40 genomic region is significantly associated with variation in serum ApoE and ApoB levels, and also with fibrosis suggesting a pleiotropic attribute of this genomic region. (PMID:22898894)
• Both TOMM40 and APOE significantly influence age-related memory performance, but they appear to do so independently of each other (PMID:23102119)
• TOMM40 intron 6 poly-T length may explain some of the variation in age at onset in PSEN2 familial mouseclick Alzheimer’s disease (PMID:23183136)
• TOMM40 gene expression remains significantly lower in Alzheimer’s disease patients compared to controls. (PMID:23234877)
• 3 SNPs (rs157580, rs2075650, and rs11556505)were studied in late-onset Alzheimer disease after adjustment for risk factors. Haplotypes derived from SNPs in rs2075650, rs11556505, and rs1160985 were associated with either risk or protective effects. (PMID:23288655)
• we report data from two independent Caucasian samples (242 U.S. women and men; 466 Danish men) showing that chronic family stress moderates the association between TOMM40 SNP rs157580 and triglyceride levels. (PMID:23435269)
• TOMM40 and APOE common genetic variants are not Parkinson’s disease risk factors. (PMID:23522842)
• This study demonstrated that the TOMM40 gene does not have an APOE-independent role in the risk of developing LOAD and FTLD. (PMID:23546992)
• This study associating theTOMM40rs10524523 genotype with clinical characteristics ofpatients carrying thePSEN1M146L mutation belong-ing to the same kindred. (PMID:23792692)
• The results of this study suggested that Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms. (PMID:24103330)
• These data provide no evidence to support an association of rs2075650 in TOMM40 with neovascular age-related macular degeneration or polypoidal choroidal vasculopathy. (PMID:24146538)
• Blockade of mitochondrial protein import triggers the recruitment of PARK2, by PINK1, to the TOMM machinery. (PMID:24149440)
• in a large community-dwelling sample of older adults, we found no effects of APOE epsilon or TOMM40 523 genotypes on hippocampal volumes. (PMID:24260406)
• Elevated levels of TOMM40 and APOE transcripts found in the brains of late-onset Alzheimer’s disease-affected individuals compared with unaffected control brains (PMID:24439168)
• It is an Alzheimer-disease susceptibility gene. (PMID:24508314)
• This study development of depression characterized by reduced extraversion, impaired executive function, and decreased positive emotional recall, and reduced top-down cortical control during sad emotion processing. (PMID:24549102)
• The present study shows for the first time that TOMM40 rs157581 polymorphism may modulate regional spontaneous brain activity and related to the progression of amnestic mild cognitive impairment. (PMID:24838536)
• PVRL2, TOMM40 and APOE might be associated with human longevity. (PMID:24924924)
• The results of this study suggested that previous findings of an association of the TOMM40 short allele with better cognitive performance, independently from the APOE variant status, are pertinent to elderly with diabetes. (PMID:25044051)
• Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity. (PMID:25140902)
• The findings of this study consistently lower TOMM40 expression on longitudinal 2-year sampling support its potential role as a diagnostic blood AD biomarker. (PMID:25201778)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	tomm40l	ENSDARG00000036721
danio_rerio	tomm40	ENSDARG00000092112
mus_musculus	Tomm40	ENSMUSG00000002984
rattus_norvegicus	Tomm40	ENSRNOG00000018556
drosophila_melanogaster	Tom40	FBGN0016041
drosophila_melanogaster	tomboy40	FBGN0033074
caenorhabditis_elegans		WBGENE00007686

Paralogs (1): TOMM40L (ENSG00000158882)

Protein

Protein identifiers

Mitochondrial import receptor subunit TOM40 homolog — O96008 (reviewed: O96008)

Alternative names: Protein Haymaker, Translocase of outer membrane 40 kDa subunit homolog, p38.5

All UniProt accessions (4): O96008, K7EJ57, K7EKG4, K7EKG6

UniProt curated annotations — full annotation on UniProt →

Function. Channel-forming protein that forms part of the translocase of the outer mitochondrial membrane (TOM) complex essential for the recognition and translocation of cytosolically synthesized mitochondrial preproteins. The TOM complex associates with the ion channel VDAC2 and PINK1 kinase at depolarized mitochondria, this interaction stabilizes PINK1 at the outer mitochondrial membrane and triggers downstream mitophagy by the recruitment of the E3 ubiquitin ligase PRKN. Plays a role in the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) by forming a complex with BCAP31 and mediating the translocation of Complex I components from the cytosol to the mitochondria.

Subunit / interactions. Part of the translocase of the outer mitochondrial membrane (TOM) complex consisting of at least TOMM5, TOMM6, TOMM7, TOMM20, TOMM22 and TOMM40; within the complex there are two copies of TOMM40 and they form the channel for the import of unfolded precursor protein. TOMM70 may also be found in the TOM complex. The TOM complex interacts with the VDAC2 homodimer. Upon mitochondrial depolarization, the TOM-VDAC assembly interacts with PINK1; the interaction stabilizes PINK1 at the outer mitochondrial membrane and triggers downstream mitophagy. Interacts with mitochondrial targeting sequences. Interacts with TIMM29; linking the TIM22 complex to the TOM complex. Forms a complex with BCAP31 (via C-terminus) which mediates the translocation of components of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) from the cytosol to the mitochondria. Interacts (via N-terminus) with CYP1A1 (via mitochondrial targeting signal); this interaction is required for CYP1A1 translocation across the mitochondrial outer membrane.

Subcellular location. Mitochondrion outer membrane.

Similarity. Belongs to the Tom40 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O96008-1	1	yes
O96008-2	2

RefSeq proteins (3): NP_001122388, NP_001122389, NP_006105 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR023614	Porin_dom_sf	Homologous_superfamily
IPR027246	Porin_Euk/Tom40	Family
IPR037930	Tom40	Family

Pfam: PF01459

UniProt features (81 total): topological domain 20, transmembrane region 19, strand 19, sequence conflict 6, turn 5, compositionally biased region 4, helix 3, splice variant 2, chain 1, intramembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
7VD2	ELECTRON MICROSCOPY	2.53
7VBY	ELECTRON MICROSCOPY	2.54
9EII	ELECTRON MICROSCOPY	2.75
9JXV	ELECTRON MICROSCOPY	2.89
8XDN	ELECTRON MICROSCOPY	2.93
7CP9	ELECTRON MICROSCOPY	3
9EIH	ELECTRON MICROSCOPY	3.1
9EIJ	ELECTRON MICROSCOPY	3.3
7CK6	ELECTRON MICROSCOPY	3.4
7VC4	ELECTRON MICROSCOPY	3.74
7VDD	ELECTRON MICROSCOPY	3.74
8XVA	ELECTRON MICROSCOPY	5.92

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O96008-F1	80.28	0.62

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-5205685	PINK1-PRKN Mediated Mitophagy

MSigDB gene sets: 276 (showing top): BASSO_B_LYMPHOCYTE_NETWORK, ROVERSI_GLIOMA_COPY_NUMBER_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_PROTEIN_TARGETING, TGACCTY_ERR1_Q2, MODULE_16, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, PUJANA_CHEK2_PCC_NETWORK, BROWNE_HCMV_INFECTION_24HR_UP, GROSS_HYPOXIA_VIA_HIF1A_DN, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, GOCC_MITOCHONDRIAL_ENVELOPE, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE

GO Biological Process (6): obsolete protein targeting to mitochondrion (GO:0006626), monoatomic ion transport (GO:0006811), protein import into mitochondrial matrix (GO:0030150), protein insertion into mitochondrial outer membrane (GO:0045040), protein transport (GO:0015031), transmembrane transport (GO:0055085)

GO Molecular Function (3): transmembrane protein transporter activity (GO:0008320), porin activity (GO:0015288), protein binding (GO:0005515)

GO Cellular Component (9): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial outer membrane translocase complex (GO:0005742), mitochondrial inner membrane (GO:0005743), cytosol (GO:0005829), membrane (GO:0016020), mitochondria-associated endoplasmic reticulum membrane contact site (GO:0044233), pore complex (GO:0046930), TOM complex (GO:0140596)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Protein localization	1
Mitophagy	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	3
cytoplasm	2
mitochondrial membrane	2
cellular anatomical structure	2
protein transmembrane import into intracellular organelle	1
protein localization to mitochondrion	1
import into the mitochondrion	1
mitochondrial protein import pathway	1
outer mitochondrial membrane organization	1
protein insertion into mitochondrial membrane	1
intracellular protein localization	1
establishment of protein localization	1
cellular process	1
macromolecule transmembrane transporter activity	1
protein transmembrane transport	1
protein transporter activity	1
wide pore channel activity	1
binding	1
intracellular membrane-bounded organelle	1
organelle outer membrane	1
outer mitochondrial membrane protein complex	1
organelle inner membrane	1
organelle membrane contact site	1
membrane protein complex	1
mitochondrial outer membrane translocase complex	1

Protein interactions and networks

STRING

2654 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOMM40	TOMM22	Q9NS69	999
TOMM40	TOMM20	Q15388	999
TOMM40	TOMM70	O94826	998
TOMM40	TOMM7	Q9P0U1	997
TOMM40	TOMM6	Q96B49	996
TOMM40	TOMM5	Q8N4H5	996
TOMM40	SAMM50	Q9Y512	986
TOMM40	VPS39	Q96JC1	925
TOMM40	APP	P05067	898
TOMM40	APOE	P02649	894
TOMM40	NECTIN2	Q92692	890
TOMM40	TIMM23	O14925	884
TOMM40	TIMM44	O43615	867
TOMM40	TIMM17A	Q99595	865
TOMM40	IMMT	Q16891	810

IntAct

142 interactions, top by confidence:

A	B	Type	Score
TOMM22	TOMM40	psi-mi:“MI:0915”(physical association)	0.740
TOMM22	TOMM40	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TOMM22	XRCC3	psi-mi:“MI:0914”(association)	0.640
TOMM40	ATG2A	psi-mi:“MI:0915”(physical association)	0.610
ATG2A	TOMM40	psi-mi:“MI:0915”(physical association)	0.610
ATG2A	TOMM40	psi-mi:“MI:0914”(association)	0.610
SLC16A3	CASK	psi-mi:“MI:0914”(association)	0.590
BTN3A3	BTN3A1	psi-mi:“MI:0914”(association)	0.560
NCR3LG1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
CYP2C9	TOMM40	psi-mi:“MI:0914”(association)	0.530
WNT4	TOMM40	psi-mi:“MI:0914”(association)	0.530
FOXRED2	TOMM40	psi-mi:“MI:0914”(association)	0.530
NDUFB8	NDUFS4	psi-mi:“MI:0914”(association)	0.530
DNAJC30	NDUFS8	psi-mi:“MI:0914”(association)	0.530
TRABD	FCN1	psi-mi:“MI:0914”(association)	0.530
TRAK2	OGT	psi-mi:“MI:0914”(association)	0.530
SFXN5	TOMM40	psi-mi:“MI:0914”(association)	0.530
TOMM20	TPP1	psi-mi:“MI:0914”(association)	0.480
env	FLOT1	psi-mi:“MI:0914”(association)	0.460
Dlg4	TOMM40	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (414): TOMM40 (Affinity Capture-MS), TOMM40 (Affinity Capture-MS), TOMM40 (Affinity Capture-MS), TOMM40 (Affinity Capture-MS), TOMM40 (Affinity Capture-MS), TOMM40 (Affinity Capture-MS), TOMM40 (Affinity Capture-MS), TOMM40 (Affinity Capture-MS), TOMM40 (Affinity Capture-MS), AIFM1 (Co-fractionation), ANXA11 (Co-fractionation), CAB39 (Co-fractionation), CHCHD2 (Co-fractionation), CISD1 (Co-fractionation), COX5B (Co-fractionation)

ESM2 similar proteins: A1Z6L1, A4QTI8, A5DCL4, A7F1G7, A8NWS6, B0DK33, B6K463, B8P366, C4XVQ6, C5DG70, O13498, O13656, O13814, O96008, P04840, P23644, P24391, P40478, Q0JJV1, Q0TWV0, Q10S27, Q18090, Q1LZB5, Q21752, Q2H740, Q2NL21, Q39079, Q5RC70, Q5U458, Q61Z83, Q6CAG4, Q6L5I5, Q6P825, Q758T7, Q75Q40, Q7SBE0, Q7ZTM6, Q84P97, Q8J0L4, Q9FHQ9

Diamond homologs: A1Z6L1, A4F267, A6QR22, O96008, Q18090, Q1LZB5, Q61Z83, Q6P825, Q75Q40, Q7ZTM6, Q969M1, Q9CZR3, Q9QYA2, Q9U4L6, Q9LHE5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TOMM40	“form complex”	“TOM40 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 166 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
PINK1-PRKN Mediated Mitophagy	7	23.1×	8e-06
Mitochondrial protein import	8	12.4×	6e-05
RAB geranylgeranylation	7	11.2×	5e-04
Complex I biogenesis	6	9.2×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein import into mitochondrial matrix	5	24.1×	5e-04
mitochondrial electron transport, NADH to ubiquinone	7	17.2×	6e-05
proton motive force-driven mitochondrial ATP synthesis	6	10.8×	4e-03
aerobic respiration	6	10.2×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1179 predictions. Top by Δscore:

Variant	Effect	Δscore
19:44891315:G:GG	donor_gain	1.0000
19:44891679:G:GT	donor_gain	1.0000
19:44891679:G:T	donor_gain	1.0000
19:44891688:GG:G	donor_gain	1.0000
19:44891689:GG:G	donor_gain	1.0000
19:44892391:A:AG	acceptor_gain	1.0000
19:44892392:G:GG	acceptor_gain	1.0000
19:44892392:GAGCT:G	acceptor_gain	1.0000
19:44892832:TCCA:T	acceptor_loss	1.0000
19:44892833:CCA:C	acceptor_loss	1.0000
19:44892835:A:AG	acceptor_gain	1.0000
19:44892835:A:AT	acceptor_loss	1.0000
19:44892836:G:GG	acceptor_gain	1.0000
19:44892915:C:G	donor_gain	1.0000
19:44892927:GAG:G	donor_gain	1.0000
19:44892930:G:GG	donor_gain	1.0000
19:44892930:GT:G	donor_loss	1.0000
19:44893770:T:A	acceptor_gain	1.0000
19:44893775:CACA:C	acceptor_loss	1.0000
19:44893777:C:G	acceptor_gain	1.0000
19:44893777:CA:C	acceptor_loss	1.0000
19:44893778:A:AC	acceptor_loss	1.0000
19:44893778:A:AG	acceptor_gain	1.0000
19:44893778:AG:A	acceptor_gain	1.0000
19:44893778:AGGC:A	acceptor_gain	1.0000
19:44893779:G:GC	acceptor_gain	1.0000
19:44893779:GG:G	acceptor_gain	1.0000
19:44893779:GGC:G	acceptor_gain	1.0000
19:44893779:GGCG:G	acceptor_gain	1.0000
19:44893779:GGCGT:G	acceptor_gain	1.0000

AlphaMissense

2334 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:44892416:G:C	G100R	1.000
19:44892432:T:A	V105D	1.000
19:44892903:G:T	G137W	1.000
19:44892904:G:A	G137E	1.000
19:44893828:G:C	A162P	1.000
19:44901081:T:G	Y274D	1.000
19:44901271:T:G	Y303D	1.000
19:44901310:G:C	G316R	1.000
19:44892420:T:A	V101D	0.999
19:44892426:T:C	L103P	0.999
19:44892439:A:C	K107N	0.999
19:44892439:A:T	K107N	0.999
19:44892446:A:C	S110R	0.999
19:44892448:T:A	S110R	0.999
19:44892448:T:G	S110R	0.999
19:44892456:T:C	F113S	0.999
19:44892838:T:A	V115D	0.999
19:44892843:C:G	H117D	0.999
19:44892897:T:G	Y135D	0.999
19:44892903:G:A	G137R	0.999
19:44892903:G:C	G137R	0.999
19:44892904:G:T	G137V	0.999
19:44893783:T:C	F147L	0.999
19:44893785:C:A	F147L	0.999
19:44893785:C:G	F147L	0.999
19:44893798:G:C	G152R	0.999
19:44893799:G:A	G152D	0.999
19:44893823:T:C	L160P	0.999
19:44893829:C:A	A162D	0.999
19:44893989:A:C	Q189P	0.999

dbSNP variants (sampled 300 via entrez): RS1000117006 (19:44890572 G>A,C), RS1000280246 (19:44895061 C>T), RS1000311363 (19:44891239 C>A,G,T), RS1000428942 (19:44891349 C>G,T), RS1000633301 (19:44896094 A>G,T), RS1000679583 (19:44901597 G>A), RS1000837703 (19:44900474 G>T), RS1000855968 (19:44897790 A>G), RS1001698421 (19:44895427 G>T), RS1002106848 (19:44898986 G>A), RS1002160098 (19:44890926 C>A,T), RS1002248447 (19:44901237 C>A), RS1002353271 (19:44894207 C>A,G,T), RS1002630423 (19:44898405 C>G), RS1002682488 (19:44903619 A>C)

Disease associations

OMIM: gene MIM:608061 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000504	Abnormality of vision
HP:0000657	Oculomotor apraxia
HP:0000713	Agitation
HP:0000726	Dementia
HP:0000734	Disinhibition
HP:0000738	Hallucinations
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001276	Hypertonia
HP:0001289	Confusion
HP:0001300	Parkinsonism
HP:0001336	Myoclonus
HP:0002120	Cerebral cortical atrophy
HP:0002185	Neurofibrillary tangles
HP:0002186	Apraxia
HP:0002354	Memory impairment
HP:0002381	Aphasia
HP:0002463	Language impairment
HP:0003791	Deposits immunoreactive to beta-amyloid protein
HP:0010525	Finger agnosia
HP:0010526	Dysgraphia
HP:0011446	Abnormality of mental function
HP:0012433	Abnormal social behavior
HP:0012759	Neurodevelopmental abnormality
HP:0030219	Semantic dementia

GWAS associations

193 associations (top):

Study	Trait	p-value
GCST000237_1	Alzheimer’s disease	6.000000e-14
GCST000282_9	LDL cholesterol	2.000000e-19
GCST000285_7	Cholesterol, total	3.000000e-19
GCST000288_4	HDL cholesterol	4.000000e-07
GCST000289_3	Triglycerides	2.000000e-09
GCST000313_1	Alzheimer’s disease	1.000000e-40
GCST000337_15	Quantitative traits	5.000000e-06
GCST000337_19	Quantitative traits	3.000000e-07
GCST000337_29	Quantitative traits	2.000000e-06
GCST000479_3	Alzheimer’s disease	2.000000e-157
GCST000484_5	Alzheimer’s disease	3.000000e-11
GCST000573_3	Brain imaging	1.000000e-07
GCST000808_2	Alzheimer’s disease (late onset)	5.000000e-36
GCST000827_7	Cerebrospinal fluid AB1-42 levels	3.000000e-07
GCST000900_2	Alzheimer’s disease biomarkers	1.000000e-06
GCST000900_5	Alzheimer’s disease biomarkers	1.000000e-06
GCST001013_1	Longevity	3.000000e-17
GCST001237_6	HDL cholesterol	8.000000e-11
GCST001247_13	Cardiovascular disease risk factors	2.000000e-14
GCST001247_14	Cardiovascular disease risk factors	4.000000e-08
GCST001280_7	Alzheimer’s disease (age of onset)	1.000000e-12
GCST001311_1	Cognitive decline	4.000000e-27
GCST001436_10	Metabolic syndrome	1.000000e-08
GCST001529_1	Alzheimer’s disease	8.000000e-149
GCST001571_6	Age-related macular degeneration	8.000000e-08
GCST001650_3	C-reactive protein	4.000000e-13
GCST001761_1	Cognitive decline	2.000000e-08
GCST001814_22	Age-related macular degeneration	1.000000e-06
GCST001814_31	Age-related macular degeneration	1.000000e-06
GCST001814_8	Age-related macular degeneration	3.000000e-06

EFO canonical traits (34, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0004458	C-reactive protein measurement
EFO:0004346	neuroimaging measurement
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0004760	t-tau measurement
EFO:0004763	p-tau measurement
EFO:0004847	age at onset
EFO:0004362	psychomotor performance
EFO:0000195	metabolic syndrome
EFO:0005194	amyloid-beta measurement
EFO:0004874	memory performance
EFO:0006806	paragraph delayed recall measurement
EFO:0004337	intelligence
EFO:0004340	body mass index
EFO:0007707	cerebral amyloid deposition measurement
EFO:0007800	body fat percentage
EFO:0004343	waist-hip ratio
EFO:0007708	t-tau:beta-amyloid 1-42 ratio measurement
EFO:0004318	smoking behavior
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0007998	cognitive impairment measurement
EFO:0007709	p-tau:beta-amyloid 1-42 ratio measurement
EFO:0005035	hippocampal volume
EFO:0009268	family history of Alzheimer’s disease
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0010130	health study participation

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523158 (SINGLE PROTEIN)

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs429358	APOC1, APOE, TOMM40	3	3.00	5	acenocoumarol;warfarin;simvastatin;Antivirals for treatment of HIV infections;combinations;ritonavir;warfarin;HMG-CoA reductase inhibitors
rs2075650	TOMM40		0.00	0
rs71352238	APOE, TOMM40		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	3
Arsenic	affects cotreatment, increases abundance, increases expression, affects expression	2
Valproic Acid	increases methylation, increases expression	2
Particulate Matter	increases abundance, increases expression	2
afuresertib	decreases expression	1
deoxynivalenol	decreases expression	1
afimoxifene	decreases reaction, increases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
beta-methylcholine	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	affects expression, decreases reaction	1
chloropicrin	decreases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	decreases expression	1
indioside D	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
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
bisphenol B	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
bisphenol S	affects expression	1
jinfukang	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Atrazine	decreases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Cadmium	increases abundance, increases expression	1
Cisplatin	decreases expression, affects cotreatment	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Diazinon	increases methylation	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4341387	Binding	Binding affinity to TOMM40 in human A549 cells lysates grown on SILAC media at 10 uM incubated for 1 hr by LC-MS/MS analysis	Profiling withanolide A for therapeutic targets in neurodegenerative diseases. — Bioorg Med Chem

Clinical trials (associated diseases)

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