ACAD9

Summary

ACAD9 (acyl-CoA dehydrogenase family member 9, HGNC:21497) is a protein-coding gene on chromosome 3q21.3, encoding Complex I assembly factor ACAD9, mitochondrial (Q9H845). Together with NDUFAF1 and ECSIT, forms part of the mitochondrial complex I (MCIA),which is required for the biogenesis of respiratory Complex I (CI) and is therefore crucial for the activation of the oxidative phosphorylation system. It is a selective cancer dependency (DepMap: 10.8% of cell lines).

This gene encodes a member of the acyl-CoA dehydrogenase family. Members of this family of proteins localize to the mitochondria and catalyze the rate-limiting step in the beta-oxidation of fatty acyl-CoA. The encoded protein is specifically active toward palmitoyl-CoA and long-chain unsaturated substrates. Mutations in this gene cause acyl-CoA dehydrogenase family member type 9 deficiency. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 28976 — RefSeq curated summary.

At a glance

• Gene–disease (curated): acyl-CoA dehydrogenase 9 deficiency (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 1,181 total — 47 pathogenic, 99 likely-pathogenic
• Phenotypes (HPO): 40
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 10.8% of screened cell lines
• MANE Select transcript: NM_014049

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21497
Approved symbol	ACAD9
Name	acyl-CoA dehydrogenase family member 9
Location	3q21.3
Locus type	gene with protein product
Status	Approved
Aliases	NPD002, MGC14452
Ensembl gene	ENSG00000177646
Ensembl biotype	protein_coding
OMIM	611103
Entrez	28976

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 16 protein_coding, 16 nonsense_mediated_decay, 6 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000308982, ENST00000505192, ENST00000505602, ENST00000505867, ENST00000508971, ENST00000511227, ENST00000511325, ENST00000511526, ENST00000512801, ENST00000514336, ENST00000514643, ENST00000515429, ENST00000679399, ENST00000679431, ENST00000679613, ENST00000679715, ENST00000679824, ENST00000679990, ENST00000680636, ENST00000680638, ENST00000680744, ENST00000680764, ENST00000681319, ENST00000681367, ENST00000681552, ENST00000681583, ENST00000681585, ENST00000681589, ENST00000681784, ENST00000681886, ENST00000897729, ENST00000897730, ENST00000897731, ENST00000897732, ENST00000897733, ENST00000897734, ENST00000926996, ENST00000926997, ENST00000959715, ENST00000959716

RefSeq mRNA: 2 — MANE Select: NM_014049 NM_001410805, NM_014049

CCDS: CCDS3053, CCDS93369

Canonical transcript exons

ENST00000308982 — 18 exons

Exon	Start	End
ENSE00002032118	128912507	128913114
ENSE00002075968	128879620	128879841
ENSE00003461249	128897632	128897710
ENSE00003463821	128906121	128906249
ENSE00003468618	128884653	128884746
ENSE00003511926	128909344	128909421
ENSE00003543353	128908185	128908264
ENSE00003547393	128899287	128899461
ENSE00003551482	128904386	128904505
ENSE00003552663	128910021	128910149
ENSE00003559245	128901276	128901349
ENSE00003582093	128896436	128896536
ENSE00003600670	128908973	128909099
ENSE00003631720	128910741	128910813
ENSE00003637000	128902553	128902628
ENSE00003650148	128893555	128893656
ENSE00003660117	128904062	128904132
ENSE00003671677	128895310	128895416

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 97.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.9866 / max 325.4298, expressed in 1823 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38491	25.7708	1823
38490	0.1111	42
38492	0.0549	19
202924	0.0498	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	97.95	gold quality
skin of abdomen	UBERON:0001416	95.41	gold quality
left ventricle myocardium	UBERON:0006566	95.33	gold quality
tibialis anterior	UBERON:0001385	94.61	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.52	gold quality
skin of leg	UBERON:0001511	94.41	gold quality
ileal mucosa	UBERON:0000331	94.31	gold quality
zone of skin	UBERON:0000014	93.93	gold quality
upper leg skin	UBERON:0004262	91.68	gold quality
kidney epithelium	UBERON:0004819	91.41	gold quality
right adrenal gland cortex	UBERON:0035827	91.17	gold quality
right adrenal gland	UBERON:0001233	91.07	gold quality
apex of heart	UBERON:0002098	91.04	gold quality
esophagus mucosa	UBERON:0002469	90.87	gold quality
sural nerve	UBERON:0015488	90.83	gold quality
left adrenal gland	UBERON:0001234	90.72	gold quality
muscle of leg	UBERON:0001383	90.66	gold quality
gastrocnemius	UBERON:0001388	90.58	gold quality
lower esophagus mucosa	UBERON:0035834	90.35	gold quality
heart left ventricle	UBERON:0002084	90.28	gold quality
deltoid	UBERON:0001476	90.24	silver quality
left adrenal gland cortex	UBERON:0035825	90.24	gold quality
nipple	UBERON:0002030	90.22	gold quality
adrenal gland	UBERON:0002369	90.22	gold quality
cardiac atrium	UBERON:0002081	90.21	gold quality
esophagus	UBERON:0001043	90.08	gold quality
right atrium auricular region	UBERON:0006631	90.08	gold quality
bone marrow cell	CL:0002092	89.98	gold quality
cardiac ventricle	UBERON:0002082	89.94	gold quality
adrenal cortex	UBERON:0001235	89.89	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.29
E-CURD-112	no	2.76

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting ACAD9, 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-3646	100.00	73.56	5283
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-1237-3P	98.55	67.65	1423
HSA-MIR-758-3P	98.42	68.60	1122
HSA-MIR-147A	98.33	66.40	795
HSA-MIR-4468	98.01	66.85	1187
HSA-MIR-490-3P	97.79	65.54	606
HSA-MIR-764	94.16	64.85	656

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 17)

• Very high activity of CPT2 and VCLAD, involved in the metabolism of long-chain fatty acids. Fatty acid oxidation may play role in energy generation in placenta, and deficiency in may result in placental dysfunction and gestational complications. (PMID:12971426)
• ACAD9 may play a role in the turnover of lipid membrane unsaturated fatty acids that are essential for membrane integrity and structure (PMID:16020546)
• acyl-CoA dehydrogenase 9 (ACAD 9)was identified as the long-chain ACAD in human embryonic and fetal brain and central nervous tissue, using in situ hybridization as well as enzymatic studies (PMID:16750164)
• We now report three cases of ACAD9 deficiency. (PMID:17564966)
• Validated occurrence of an unusual TG 3’ splice site in intron 10. (PMID:17672918)
• Accumulation of 3-hydroxylated intermediates of long-chain fatty acids may contribute to the pathogenesis of retinopathy in MTP deficiencies. (PMID:18385088)
• Data show that two closely related metabolic enzymes, ACAD9 and VLCAD, diverged at the root of the vertebrate lineage to function in two separate mitochondrial metabolic pathways and have clinical implications for the diagnosis of complex I deficiency. (PMID:20816094)
• Our data support a new function for ACAD9 in complex I function, making this gene an important new candidate for patients with complex I deficiency, which could be improved by riboflavin treatment. (PMID:20929961)
• ACAD9 screening of 120 additional complex I-defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles. (PMID:21057504)
• Strong candidate gene for mitochondrial disease, based on recessive mutations detected in infantile patients (PMID:22277967)
• Our results underscore the importance of the ACAD9 protein in complex I assembly and suggest that the enzymatic activity is a rudiment of the duplication event. (PMID:24158852)
• In cells where it is strongly expressed, ACAD9 plays a physiological role in fatty acid oxidation. (PMID:25721401)
• ACAD9 mutation is the most frequent cause of cardiac hypertrophy and isolated complex I deficiency. (PMID:26669660)
• Case Report: neonatal multiorgan failure due to ACAD9 mutation and complex I deficiency with mitochondrial hyperplasia in liver, cardiac myocytes, skeletal muscle, and renal tubules. (PMID:26826406)
• Study identified new mutations in ACAD9 responsible for a wide spectrum of heart diseases in the presence of elevated serum lactate levels. (PMID:27233227)
• Mutations in the ND6, NDUFV1 or ACAD9 genes are responsible for the mitochondrial complex I deficiency. (PMID:29348607)
• Immunodeficiency with susceptibility to lymphoma with complex genotype affecting energy metabolism (FBP1, ACAD9) and vesicle trafficking (RAB27A). (PMID:37388727)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	acad9	ENSDARG00000055620
mus_musculus	Acad9	ENSMUSG00000027710
rattus_norvegicus	Acad9	ENSRNOG00000014178
caenorhabditis_elegans	acox-1.1	WBGENE00008564
caenorhabditis_elegans	acox-1.2	WBGENE00008565
caenorhabditis_elegans	acox-1.3	WBGENE00008566
caenorhabditis_elegans	acox-1.4	WBGENE00008567
caenorhabditis_elegans		WBGENE00015894
caenorhabditis_elegans	acdh-1	WBGENE00016943
caenorhabditis_elegans		WBGENE00019406
caenorhabditis_elegans		WBGENE00020366

Paralogs (14): ACADVL (ENSG00000072778), ACOX3 (ENSG00000087008), GCDH (ENSG00000105607), ACAD10 (ENSG00000111271), ACADL (ENSG00000115361), ACADM (ENSG00000117054), ACADS (ENSG00000122971), IVD (ENSG00000128928), ACAD8 (ENSG00000151498), ACOXL (ENSG00000153093), ACOX1 (ENSG00000161533), ACOX2 (ENSG00000168306), ACADSB (ENSG00000196177), ACAD11 (ENSG00000240303)

Protein

Protein identifiers

Complex I assembly factor ACAD9, mitochondrial — Q9H845 (reviewed: Q9H845)

Alternative names: Acyl-CoA dehydrogenase family member 9

All UniProt accessions (15): A0A7P0T7Z1, A0A7P0T871, A0A7P0T8U3, A0A7P0T9N9, A0A7P0TB58, A0A7P0TB68, A0A7P0Z450, D6R9Z3, D6RCD8, D6RDK9, D6RGK6, D6RJA8, Q9H845, H0Y8Z9, Q9H9W4

UniProt curated annotations — full annotation on UniProt →

Function. Together with NDUFAF1 and ECSIT, forms part of the mitochondrial complex I (MCIA),which is required for the biogenesis of respiratory Complex I (CI) and is therefore crucial for the activation of the oxidative phosphorylation system. ECSIT binding triggers a large conformational change, switching ACAD9 from a fatty acid oxidation (FAO) enzyme to a CI assembly factor. The function in CI assembly is independent of the FAO activity of the protein. As FAO enzyme, it catalyzes the first step in FAO, which consists in the proR-proR stereospecific alpha, beta-dehydrogenation of fatty acyl-CoA thioesters using the electron transfer flavoprotein (ETF) as their physiologic electron acceptor, resulting in the formation of trans-2-enoyl-CoA ((2E)-enoyl-CoA). Its preferred substrates are both saturated and unsaturated long-chain acyl-CoA substrates, with optimum activity toward the latter. Among the different mitochondrial acyl-CoA dehydrogenases, its FAO activity overlaps with that of ACADV and ACADL, but plays a primary role in tissues where it is the main long-chain ACAD expressed, such as the central nervous system.

Subunit / interactions. Homodimer. Interacts with NDUFAF1 and ECSIT. Part of the mitochondrial complex I assembly/MCIA complex that comprises at least the core subunits TMEM126B, NDUFAF1, ECSIT and ACAD9 and complement subunits such as COA1 and TMEM186. Interacts with TMEM70 and TMEM242.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Ubiquitously expressed in most normal human tissues and cancer cell lines with higher levels in heart, skeletal muscles, and the central nervous system (where it is the highest expressed ACAD). Highly expressed (at protein level) in the cerebellum (Purkinje neurons, dentate nucleus, and in the granular layer), where ACADV is not found.

Disease relevance. Mitochondrial complex I deficiency, nuclear type 20 (MC1DN20) [MIM:611126] An autosomal recessive metabolic disorder associated with mitochondrial complex I deficiency, resulting in multisystemic and variable manifestations. Clinical features include infantile onset of acute metabolic acidosis, Reye-like episodes (brain edema and vomiting that may rapidly progress to seizures, coma and death), exercise intolerance, hypertrophic cardiomyopathy, liver failure, muscle weakness, and neurologic dysfunction. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the acyl-CoA dehydrogenase family.

RefSeq proteins (2): NP_001397734, NP_054768* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006089	Acyl-CoA_DH_CS	Conserved_site
IPR006091	AcylCoA_DH/ox_M	Domain
IPR009075	AcylCo_DH/oxidase_C	Domain
IPR009100	AcylCoA_DH/oxidase_NM_dom_sf	Homologous_superfamily
IPR013786	AcylCoA_DH/ox_N	Domain
IPR036250	AcylCo_DH-like_C	Homologous_superfamily
IPR037069	AcylCoA_DH/ox_N_sf	Homologous_superfamily
IPR046373	Acyl-CoA_Oxase/DH_mid-dom_sf	Homologous_superfamily
IPR049448	ACAD9/ACADV-like_C	Domain

Pfam: PF00441, PF02770, PF02771, PF21343

Catalyzed reactions (Rhea), 12 shown:

• a medium-chain 2,3-saturated fatty acyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = a medium-chain (2E)-enoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:14477)
• a long-chain 2,3-saturated fatty acyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = a long-chain (2E)-enoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:17721)
• oxidized [electron-transfer flavoprotein] + hexadecanoyl-CoA + H(+) = (2E)-hexadecenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:43448)
• eicosanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-eicosenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:47236)
• octadecanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-octadecenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:47240)
• oxidized [electron-transfer flavoprotein] + (9Z)-octadecenoyl-CoA + H(+) = (2E,9Z)-octadecadienoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:47300)
• (9Z)-hexadecenoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E,9Z)-hexadecadienoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:47304)
• tetradecanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-tetradecenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:47316)
• decanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-decenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:48176)
• (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E,4Z,7Z,10Z,13Z,16Z,19Z)-docosaheptaenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:48184)
• (9Z,12Z)-octadecadienoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E,9Z,12Z)-octadecatrienoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:48188)
• (9E)-octadecenoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E,9E)-octadecadienoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:48192)

UniProt features (75 total): helix 26, sequence variant 18, strand 16, turn 5, modified residue 5, transit peptide 1, chain 1, active site 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8PHE	ELECTRON MICROSCOPY	3.1
8PHF	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H845-F1	92.09	0.85

Functional residue map

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

Catalytic / active sites (1): 426 (proton acceptor)

Post-translational modifications (5): 41, 92, 478, 521, 521

Mutagenesis-validated functional residues (1):

Position	Phenotype
426	loss of long-chain-acyl-coa dehydrogenase activity. does not affect mitochondrial complex i assembly.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-6799198	Complex I biogenesis
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-611105	Respiratory electron transport

MSigDB gene sets: 225 (showing top): GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_DN, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, DOUGLAS_BMI1_TARGETS_DN

GO Biological Process (5): long-chain fatty acid metabolic process (GO:0001676), mitochondrial respiratory chain complex I assembly (GO:0032981), medium-chain fatty acid metabolic process (GO:0051791), fatty acid metabolic process (GO:0006631), carboxylic acid metabolic process (GO:0019752)

GO Molecular Function (7): acyl-CoA dehydrogenase activity (GO:0003995), long-chain fatty acyl-CoA dehydrogenase activity (GO:0004466), flavin adenine dinucleotide binding (GO:0050660), medium-chain fatty acyl-CoA dehydrogenase activity (GO:0070991), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-CH group of donors (GO:0016627)

GO Cellular Component (6): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), dendrite (GO:0030425), mitochondrial membrane (GO:0031966), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Respiratory electron transport	1
Metabolism	1
Aerobic respiration and respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
fatty acid metabolic process	2
acyl-CoA dehydrogenase activity	2
intracellular membrane-bounded organelle	2
NADH dehydrogenase complex assembly	1
mitochondrial respiratory chain complex assembly	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
oxoacid metabolic process	1
oxidoreductase activity, acting on the CH-CH group of donors, with a flavin as acceptor	1
nucleotide binding	1
anion binding	1
binding	1
catalytic activity	1
oxidoreductase activity	1
cytoplasm	1
organelle inner membrane	1
mitochondrial membrane	1
neuron projection	1
dendritic tree	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2864 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACAD9	TMEM126B	Q8IUX1	990
ACAD9	ECSIT	Q9BQ95	989
ACAD9	NDUFAF1	Q9Y375	988
ACAD9	HADHA	P40939	875
ACAD9	FOXRED1	Q96CU9	816
ACAD9	TMEM186	Q96B77	775
ACAD9	TIMMDC1	Q9NPL8	765
ACAD9	NDUFAF4	Q9P032	733
ACAD9	NDUFAF5	Q5TEU4	694
ACAD9	NUBPL	Q8TB37	674
ACAD9	NDUFAF6	Q330K2	627
ACAD9	ETFDH	Q16134	624
ACAD9	NDUFA1	O15239	622
ACAD9	MT-ND2	P03891	614
ACAD9	COA5	Q86WW8	614

IntAct

160 interactions, top by confidence:

A	B	Type	Score
NDUFAF1	NDUFS3	psi-mi:“MI:0914”(association)	0.790
NDUFAF4	NDUFS7	psi-mi:“MI:0914”(association)	0.790
NDUFAF5	NDUFAF8	psi-mi:“MI:0914”(association)	0.750
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
HRAS	MTHFD2	psi-mi:“MI:0914”(association)	0.730
TIMMDC1	ECSIT	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
FAF2	UBB	psi-mi:“MI:0914”(association)	0.640
ASPH	STXBP3	psi-mi:“MI:0914”(association)	0.640
NDUFA13	NDUFS8	psi-mi:“MI:0914”(association)	0.640
NDUFB5	NDUFB3	psi-mi:“MI:0914”(association)	0.640
NDUFAF4	NDUFS8	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
NDUFS5	NDUFS8	psi-mi:“MI:0914”(association)	0.530
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530

BioGRID (576): ACAD9 (Affinity Capture-MS), ACAD9 (Affinity Capture-MS), ACAD9 (Affinity Capture-MS), ACAD9 (Affinity Capture-MS), ACAD9 (Affinity Capture-MS), ACAD9 (Affinity Capture-MS), ACAD9 (Affinity Capture-MS), ACAD9 (Affinity Capture-MS), ECSIT (Affinity Capture-MS), PDSS1 (Affinity Capture-MS), NDUFAF1 (Affinity Capture-MS), TMEM126B (Affinity Capture-MS), RPL26L1 (Affinity Capture-MS), ABCF2 (Affinity Capture-MS), TIMMDC1 (Affinity Capture-MS)

ESM2 similar proteins: B1WC61, B3DMA2, O32176, O64894, O65201, P07872, P12007, P15650, P26440, P28330, P45953, P45954, P48818, P49748, P50544, P51174, P70584, P79273, P79274, Q0NXR6, Q15067, Q3SZI8, Q3SZP5, Q47146, Q54IM8, Q54RR5, Q5EAD4, Q5R778, Q5RBD5, Q5RC19, Q5RF40, Q5ZHT1, Q60HI0, Q64428, Q6JQN1, Q709F0, Q80XL6, Q8HXY7, Q8JZN5, Q8X7R2

Diamond homologs: A1A789, A7ZHD0, A7ZVY9, A8ALR4, A9MQH5, A9MYJ9, B1IRD7, B1LFX2, B1WC61, B1XBG4, B4EY23, B4T6J8, B4TIH2, B4TWR6, B5BL57, B5F752, B5FHG7, B5R1R2, B5RGA6, B5YYD3, B6HYZ0, B7L4G2, B7LWN0, B7M0D6, B7MAG2, B7MNP6, B7N7R4, B7NHE3, B7UI85, C0Q4L5, C4ZPW5, D3JV03, J7TF92, P0A9U8, P0A9U9, P0A9V0, P45857, P45953, P48818, P50544

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 162 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
Complex I biogenesis	21	31.3×	8e-24
Aerobic respiration and respiratory electron transport	21	16.8×	7e-18
Respiratory electron transport	19	16.3×	6e-16
Mitochondrial protein degradation	7	7.2×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial respiratory chain complex I assembly	16	46.6×	2e-20
mitochondrial electron transport, NADH to ubiquinone	11	28.0×	4e-11
proton motive force-driven mitochondrial ATP synthesis	13	24.3×	3e-12
aerobic respiration	12	21.1×	9e-11
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	6	9.3×	5e-03
phospholipase C-activating G protein-coupled receptor signaling pathway	8	7.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1181 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	47
Likely pathogenic	99
Uncertain significance	261
Likely benign	575
Benign	73

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1031232	NM_014049.5(ACAD9):c.1278+1G>A	Pathogenic
1069262	NM_014049.5(ACAD9):c.1218C>A (p.Tyr406Ter)	Pathogenic
1376308	NM_014049.5(ACAD9):c.1266_1270dup (p.Ile424fs)	Pathogenic
1385310	NM_014049.5(ACAD9):c.1222dup (p.Arg408fs)	Pathogenic
1387438	NM_014049.5(ACAD9):c.1017_1026del (p.Gly340fs)	Pathogenic
1393379	NM_014049.5(ACAD9):c.109C>T (p.Arg37Ter)	Pathogenic
1414842	NM_014049.5(ACAD9):c.259del (p.Ile87fs)	Pathogenic
1433050	NM_014049.5(ACAD9):c.506_507del (p.Leu169fs)	Pathogenic
1451006	NM_014049.5(ACAD9):c.3G>A (p.Met1Ile)	Pathogenic
1455070	NM_014049.5(ACAD9):c.504del (p.Lys168fs)	Pathogenic
1456248	NM_014049.5(ACAD9):c.187G>T (p.Glu63Ter)	Pathogenic
1905941	NM_014049.5(ACAD9):c.138del (p.Ile48fs)	Pathogenic
2010027	NM_014049.5(ACAD9):c.1276G>T (p.Glu426Ter)	Pathogenic
2015294	NM_014049.5(ACAD9):c.92_93dup (p.Thr32fs)	Pathogenic
2059270	NM_014049.5(ACAD9):c.1807_1808insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGTGGATCATGAGGTCAGNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAAGTGTCCC (p.Gln603fs)	Pathogenic
2059581	NM_014049.5(ACAD9):c.1476_1477del (p.Leu494fs)	Pathogenic
2065147	NM_014049.5(ACAD9):c.744_747del (p.Arg249fs)	Pathogenic
2101046	NM_014049.5(ACAD9):c.1258del (p.Arg420fs)	Pathogenic
2109814	NM_014049.5(ACAD9):c.951_954ATTG[1] (p.Ile319fs)	Pathogenic
2115972	NM_014049.5(ACAD9):c.1324C>T (p.Gln442Ter)	Pathogenic
2130200	NM_014049.5(ACAD9):c.1661del (p.Ile554fs)	Pathogenic
2422054	NM_014049.5(ACAD9):c.1747_1756del (p.Leu583fs)	Pathogenic
242460	NM_014049.5(ACAD9):c.1564-6_1569del	Pathogenic
2425884	NC_000003.11:g.(?128603476)(128603609_?)del	Pathogenic
2500742	NM_014049.5(ACAD9):c.1185_1188del (p.Ser395fs)	Pathogenic
2696595	NM_014049.5(ACAD9):c.1518C>G (p.Tyr506Ter)	Pathogenic
2710589	NM_014049.5(ACAD9):c.1459_1469del (p.His487fs)	Pathogenic
2724863	NM_014049.5(ACAD9):c.686_782dup (p.Asp261_Lys262insTer)	Pathogenic
2761424	NM_014049.5(ACAD9):c.1483dup (p.Ala495fs)	Pathogenic
2808942	NM_014049.5(ACAD9):c.1236C>G (p.Tyr412Ter)	Pathogenic

SpliceAI

3869 predictions. Top by Δscore:

Variant	Effect	Δscore
3:128893549:T:TA	acceptor_gain	1.0000
3:128893550:G:A	acceptor_gain	1.0000
3:128893551:GCAGT:G	acceptor_loss	1.0000
3:128893552:CAG:C	acceptor_loss	1.0000
3:128893553:A:AG	acceptor_gain	1.0000
3:128893553:AGT:A	acceptor_gain	1.0000
3:128893553:AGTG:A	acceptor_gain	1.0000
3:128893553:AGTGG:A	acceptor_loss	1.0000
3:128893554:G:GC	acceptor_gain	1.0000
3:128893554:GT:G	acceptor_gain	1.0000
3:128893554:GTG:G	acceptor_gain	1.0000
3:128893554:GTGG:G	acceptor_gain	1.0000
3:128893554:GTGGA:G	acceptor_gain	1.0000
3:128893654:ATGG:A	donor_loss	1.0000
3:128893655:TGGT:T	donor_loss	1.0000
3:128893656:GGTAA:G	donor_loss	1.0000
3:128893657:G:GC	donor_loss	1.0000
3:128893657:G:GG	donor_gain	1.0000
3:128893658:TAAGT:T	donor_loss	1.0000
3:128896433:TA:T	acceptor_loss	1.0000
3:128896533:CCAGG:C	donor_loss	1.0000
3:128896534:CAG:C	donor_loss	1.0000
3:128896535:AGGTC:A	donor_loss	1.0000
3:128896536:GGTC:G	donor_loss	1.0000
3:128896537:G:A	donor_loss	1.0000
3:128896538:T:A	donor_loss	1.0000
3:128897630:A:AG	acceptor_gain	1.0000
3:128897630:AGT:A	acceptor_gain	1.0000
3:128897630:AGTGG:A	acceptor_gain	1.0000
3:128897631:G:GG	acceptor_gain	1.0000

AlphaMissense

4077 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:128896519:C:G	C179W	0.998
3:128904428:A:C	S358R	0.998
3:128904430:T:A	S358R	0.998
3:128904430:T:G	S358R	0.998
3:128906221:G:C	R417P	0.997
3:128896509:C:A	A176E	0.996
3:128899301:T:A	N216K	0.996
3:128899301:T:G	N216K	0.996
3:128897710:G:C	K211N	0.995
3:128897710:G:T	K211N	0.995
3:128899303:G:A	G217E	0.995
3:128910103:G:C	R549P	0.995
3:128895409:G:A	G149D	0.994
3:128896514:T:C	F178L	0.994
3:128896516:C:A	F178L	0.994
3:128896516:C:G	F178L	0.994
3:128899312:C:A	A220D	0.994
3:128901285:T:A	V273D	0.994
3:128904097:T:C	F332L	0.994
3:128904099:T:A	F332L	0.994
3:128904099:T:G	F332L	0.994
3:128906127:A:C	S386R	0.994
3:128906129:C:A	S386R	0.994
3:128906129:C:G	S386R	0.994
3:128906223:G:C	D418H	0.994
3:128896512:C:A	A177D	0.993
3:128896517:T:C	C179R	0.993
3:128897664:C:A	A196D	0.993
3:128899290:T:A	W213R	0.993
3:128899290:T:C	W213R	0.993

dbSNP variants (sampled 300 via entrez): RS1000009694 (3:128900764 G>A,T), RS1000010254 (3:128901992 T>G), RS1000084357 (3:128899373 C>G,T), RS1000108064 (3:128899527 T>C,G), RS1000150722 (3:128882245 G>A), RS1000182185 (3:128882733 T>C), RS1000382749 (3:128905221 C>G), RS1000517602 (3:128894494 A>T), RS1000589652 (3:128894640 A>G), RS1000662663 (3:128885824 G>A,C), RS1000765533 (3:128888879 T>C), RS1000791857 (3:128891263 A>G), RS1000933043 (3:128906692 G>A), RS1001045358 (3:128912677 T>C,G), RS1001099586 (3:128888605 C>T)

Disease associations

OMIM: gene MIM:611103 | disease phenotypes: MIM:611126

GenCC curated gene-disease

Disease	Classification	Inheritance
acyl-CoA dehydrogenase 9 deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
acyl-CoA dehydrogenase 9 deficiency	Definitive	AR

Mondo (3): acyl-CoA dehydrogenase 9 deficiency (MONDO:0012624), mitochondrial complex I deficiency (MONDO:0100133), hypertrophic cardiomyopathy (MONDO:0005045)

Orphanet (3): Acyl-CoA dehydrogenase 9 deficiency (Orphanet:99901), Isolated complex I deficiency (Orphanet:2609), Rare hypertrophic cardiomyopathy (Orphanet:217569)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001252	Hypotonia
HP:0001290	Generalized hypotonia
HP:0001297	Stroke
HP:0001298	Encephalopathy
HP:0001324	Muscle weakness
HP:0001397	Hepatic steatosis
HP:0001399	Hepatic failure
HP:0001414	Microvesicular hepatic steatosis
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001645	Sudden cardiac death
HP:0001873	Thrombocytopenia
HP:0001943	Hypoglycemia
HP:0001958	Nonketotic hypoglycemia
HP:0001987	Hyperammonemia
HP:0002151	Increased circulating lactate concentration
HP:0002181	Cerebral edema
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003128	Lactic acidosis
HP:0003198	Myopathy
HP:0003215	Dicarboxylic aciduria
HP:0003234	Decreased circulating carnitine concentration
HP:0003324	Generalized muscle weakness
HP:0003326	Myalgia
HP:0003458	EMG: myopathic abnormalities
HP:0003473	Fatigable weakness

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001713_2	Dental caries	6.000000e-06
GCST007989_6	Facial morphology traits (63 three-dimensional facial segments)	1.000000e-17

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
C567006	Acyl-CoA Dehydrogenase Family, Member 9, Deficiency of (supp.)
C537475	Mitochondrial complex I deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067161 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, decreases expression, increases abundance, affects cotreatment	3
Valproic Acid	increases expression, decreases expression, decreases methylation, affects cotreatment	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
sodium arsenite	increases abundance, decreases expression, affects cotreatment	2
Smoke	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
FR900359	increases phosphorylation	1
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	affects cotreatment, decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
beta-lapachone	decreases expression	1
arsenite	decreases methylation	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
LDN 193189	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652865	Binding	Binding affinity to human ACAD9 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1IR	Abcam HeLa ACAD9 KO	Cancer cell line	Female
CVCL_C7ZC	HAP1 ACAD9 (-) 1	Cancer cell line	Male
CVCL_C7ZD	HAP1 ACAD9 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT07202897	PHASE3	NOT_YET_RECRUITING	LA-HCM Study : Rivaroxaban for Antithrombotic Prevention in Hypertrophic Cardiomyopathy Patients With Abnormal Left Atrial Strain.
NCT00001631	PHASE2	COMPLETED	Study of Blood Flow in Heart Muscle
NCT00001894	PHASE2	COMPLETED	A Comparison of Two Treatments: Pacemaker and Percutaneous Transluminal Septal Ablation for Hypertrophic Cardiomyopathy
NCT00001960	PHASE2	COMPLETED	Studying the Effectiveness of Pacemaker Therapy in Children Who Have Thickened Heart Muscle
NCT00011076	PHASE2	COMPLETED	Pirfenidone to Treat Hypertrophic Cardiomyopathy
NCT00035386	PHASE2	COMPLETED	Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy: A Pilot Study
NCT00430833	PHASE2	UNKNOWN	CHANCE - Candesartan in Hypertrophic Cardiomyopathy
NCT00500552	PHASE2	COMPLETED	Perhexiline Therapy in Patients With Hypertrophic Cardiomyopathy
NCT01150461	PHASE2	COMPLETED	Effect of Losartan in Patients With Nonobstructive Hypertrophic Cardiomyopathy
NCT01230918	PHASE2	TERMINATED	Study to Develop a Non-invasive Marker for Monitoring Myocardial Fibrosis
NCT01447654	PHASE2	COMPLETED	Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy
NCT01696370	PHASE2	UNKNOWN	Trimetazidine Therapy in Hypertrophic Cardiomyopathy
NCT01912534	PHASE2	COMPLETED	Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
NCT02590809	PHASE2	COMPLETED	Hypertrophic Cardiomyopathy Symptom Release by BX1514M
NCT03496168	PHASE2	COMPLETED	Extension Study of Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Previously Enrolled in PIONEER
NCT03532802	PHASE2	COMPLETED	The Effect of Metoprolol in Patients With Hypertrophic Obstructive Cardiomyopathy.
NCT03832660	PHASE2	COMPLETED	Sacubitril/Valsartan vs Lifestyle in Hypertrophic Cardiomyopathy
NCT04219826	PHASE2	COMPLETED	Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Hypertrophic Cardiomyopathy