ACADL

Summary

ACADL (acyl-CoA dehydrogenase long chain, HGNC:88) is a protein-coding gene on chromosome 2q34, encoding Long-chain specific acyl-CoA dehydrogenase, mitochondrial (P28330). Long-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation (FAO), breaking down fatty acids into acetyl-CoA and allowing the production of energy from fats.

The protein encoded by this gene belongs to the acyl-CoA dehydrogenase family, which is a family of mitochondrial flavoenzymes involved in fatty acid and branched chain amino-acid metabolism. This protein is one of the four enzymes that catalyze the initial step of mitochondrial beta-oxidation of straight-chain fatty acid. Defects in this gene are the cause of long-chain acyl-CoA dehydrogenase (LCAD) deficiency, leading to nonketotic hypoglycemia.

Source: NCBI Gene 33 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary pulmonary alveolar proteinosis (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 99 total
• MANE Select transcript: NM_001608

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:88
Approved symbol	ACADL
Name	acyl-CoA dehydrogenase long chain
Location	2q34
Locus type	gene with protein product
Status	Approved
Aliases	LCAD, ACAD4
Ensembl gene	ENSG00000115361
Ensembl biotype	protein_coding
OMIM	609576
Entrez	33

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000233710, ENST00000482502, ENST00000482523, ENST00000498120, ENST00000652584, ENST00000862329, ENST00000862330, ENST00000959646

RefSeq mRNA: 1 — MANE Select: NM_001608 NM_001608

CCDS: CCDS2389

Canonical transcript exons

ENST00000233710 — 11 exons

Exon	Start	End
ENSE00000785331	210210196	210210262
ENSE00000785333	210216347	210216511
ENSE00000785334	210217965	210218102
ENSE00000965179	210205632	210205796
ENSE00000965180	210204581	210204682
ENSE00000965181	210203331	210203444
ENSE00000965182	210195211	210195338
ENSE00000965183	210192804	210192890
ENSE00001002853	210187923	210189054
ENSE00001302221	210225187	210225447
ENSE00003657026	210220647	210220802

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 95.55.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0218 / max 55.5352, expressed in 314 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
33461	0.4152	165
33463	0.3400	155
33459	0.0994	49
33462	0.0883	35
33460	0.0789	41

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	95.55	gold quality
popliteal artery	UBERON:0002250	93.65	gold quality
tibial artery	UBERON:0007610	93.61	gold quality
descending thoracic aorta	UBERON:0002345	93.48	gold quality
aorta	UBERON:0000947	92.96	gold quality
right lobe of thyroid gland	UBERON:0001119	92.70	gold quality
thoracic aorta	UBERON:0001515	92.31	gold quality
left lobe of thyroid gland	UBERON:0001120	92.29	gold quality
tibial nerve	UBERON:0001323	92.11	gold quality
ascending aorta	UBERON:0001496	92.01	gold quality
calcaneal tendon	UBERON:0003701	91.36	gold quality
thyroid gland	UBERON:0002046	91.33	gold quality
blood vessel layer	UBERON:0004797	90.54	gold quality
left coronary artery	UBERON:0001626	90.01	gold quality
coronary artery	UBERON:0001621	88.83	gold quality
right lobe of liver	UBERON:0001114	88.79	gold quality
right coronary artery	UBERON:0001625	88.79	gold quality
right lung	UBERON:0002167	88.19	gold quality
left ovary	UBERON:0002119	87.37	gold quality
sperm	CL:0000019	87.01	gold quality
right ovary	UBERON:0002118	86.50	gold quality
liver	UBERON:0002107	86.48	gold quality
prostate gland	UBERON:0002367	86.26	gold quality
nephron tubule	UBERON:0001231	86.15	gold quality
sural nerve	UBERON:0015488	85.94	gold quality
metanephros cortex	UBERON:0010533	85.64	gold quality
lower lobe of lung	UBERON:0008949	85.37	silver quality
male germ cell	CL:0000015	83.86	gold quality
pancreas	UBERON:0001264	83.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	18.64

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARA, PPARD

miRNA regulators (miRDB)

91 targeting ACADL, 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-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514

Literature-anchored findings (GeneRIF, showing 13)

• The microRNA miR-33 is a pleiotropic regulator of metabolic and developmental processes in Drosophila melanogaster. (PMID:33840153)
• gp33 attaches to the flap domain of the Escherichia coli RNA polymerase beta-subunit and that this interaction is essential for activation (PMID:15574501)
• The 3.0 A-resolution X-ray crystal structure of gp33 complexed with its RNA polymerase binding determinant, the beta-flap domain, was determined. (PMID:22135460)
• studies shed new light on the unique structural malleability of gp33 that might be important in its transition from a repressor to a late transcription co-activator (PMID:28807826)
• LCAD is minimally expressed in human skeletal muscle and likely does not play a significant role in long-chain fatty acid oxidation. (PMID:20363655)
• Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site. (PMID:24121500)
• the fatty acid oxidation pathway and LCAD are factors contributing to the pathophysiology of pulmonary disease (PMID:24591516)
• Long-chain acyl-CoA dehydrogenase can be a source of mitochondrial hydrogen peroxide. (PMID:31234015)
• The common K333Q polymorphism in long-chain acyl-CoA dehydrogenase (LCAD) reduces enzyme stability and function. (PMID:32389575)
• Clinical outcomes in a series of 18 patients with long chain fatty acids oxidation disorders treated with triheptanoin for a median duration of 22 months. (PMID:33610471)
• ACADL suppresses PD-L1 expression to prevent cancer immune evasion by targeting Hippo/YAP signaling in lung adenocarcinoma. (PMID:36929466)
• Bulk and single-cell transcriptome profiling reveal extracellular matrix mechanical regulation of lipid metabolism reprograming through YAP/TEAD4/ACADL axis in hepatocellular carcinoma. (PMID:37151879)
• Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51. (PMID:38594588)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	acadl	ENSDARG00000088357
mus_musculus	Acadl	ENSMUSG00000026003
rattus_norvegicus	Acadl	ENSRNOG00000012966
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), ACADM (ENSG00000117054), ACADS (ENSG00000122971), IVD (ENSG00000128928), ACAD8 (ENSG00000151498), ACOXL (ENSG00000153093), ACOX1 (ENSG00000161533), ACOX2 (ENSG00000168306), ACAD9 (ENSG00000177646), ACADSB (ENSG00000196177), ACAD11 (ENSG00000240303)

Protein

Protein identifiers

Long-chain specific acyl-CoA dehydrogenase, mitochondrial — P28330 (reviewed: P28330)

Alternative names: Medium-chain acyl-CoA dehydrogenase, mitochondrial

All UniProt accessions (1): P28330

UniProt curated annotations — full annotation on UniProt →

Function. Long-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation (FAO), breaking down fatty acids into acetyl-CoA and allowing the production of energy from fats. The first step of FAO 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). Among the different mitochondrial acyl-CoA dehydrogenases, long-chain specific acyl-CoA dehydrogenase activity overlaps with that of ACADV and ACAD9, acting on saturated and unsaturated acyl-CoAs with 6 to 24 carbons with a preference for 8 to 18 carbons long primary chains. Plays a primary role in FAO in tissues where it is the main long-chain ACAD expressed, such as the lung, specifically in type 2 alveolar cells (responsible for surfactant production). Probably responsible for beta-oxidation of bulky substrates including branched chain fatty acyl-CoAs and sterol derivatives thanks to its enlarged substrate-binding cavity.

Subunit / interactions. Homotetramer.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Expressed at mRNA and protein levels in lungs, where it localizes specifically in alveolar epithelial cells (alveolar type II pneumocytes). Also expressed at mRNA levels in prostate, thyroid gland, kidney, heart and muscle.

Post-translational modifications. Acetylation at Lys-318 and Lys-322 in proximity of the cofactor-binding sites strongly reduces catalytic activity. These sites are deacetylated by SIRT3.

Pathway. Lipid metabolism; mitochondrial fatty acid beta-oxidation.

Miscellaneous. Originally thought to be responsible for the oxidation of long-chain fatty acyl-CoAs in human, however, in contrast to other mammals, LCAD is not widely expressed in human tissues, instead ACADV is the enzyme responsible for this catalytic activity in the high energy producing tissues muscle and heart.

Similarity. Belongs to the acyl-CoA dehydrogenase family.

RefSeq proteins (1): NP_001599* (*=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
IPR034179	LCAD	Family
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
IPR050741

Pfam: PF00441, PF02770, PF02771

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)
• hexanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-hexenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:43464)
• docosanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-docosenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:47228)
• tetracosanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-tetracosenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:47232)
• 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)
• dodecanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-dodecenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:47296)
• 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)

UniProt features (36 total): modified residue 19, binding site 11, sequence variant 2, transit peptide 1, chain 1, active site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8W0Z	X-RAY DIFFRACTION	2
8W0T	X-RAY DIFFRACTION	2.5
8W0U	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P28330-F1	93.09	0.91

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): 291 (proton acceptor)

Ligand- & substrate-binding residues (11): 328; 385–389; 412–413; 414–416; 170–179; 179; 203–205; 227–228; 282; 289–292; 317

Post-translational modifications (19): 42, 54, 66, 66, 81, 81, 92, 95, 165, 240, 254, 254, 279, 279, 318, 322, 322, 358, 362

Mutagenesis-validated functional residues (1):

Position	Phenotype
291	loss of long-chain-acyl-coa dehydrogenase activity. no effect on protein abundance. no effect on solubility. no effect o

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-77285	Beta oxidation of myristoyl-CoA to lauroyl-CoA
R-HSA-77288	mitochondrial fatty acid beta-oxidation of unsaturated fatty acids
R-HSA-77310	Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA
R-HSA-1430728	Metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-77286	mitochondrial fatty acid beta-oxidation of saturated fatty acids
R-HSA-77289	Mitochondrial Fatty Acid Beta-Oxidation
R-HSA-8978868	Fatty acid metabolism

MSigDB gene sets: 243 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GOBP_LIPID_MODIFICATION, MODULE_93, BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, GOBP_FATTY_ACID_CATABOLIC_PROCESS, BENPORATH_ES_WITH_H3K27ME3, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS, GOBP_MODIFIED_AMINO_ACID_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_FATTY_ACID_BETA_OXIDATION_USING_ACYL_COA_DEHYDROGENASE

GO Biological Process (12): temperature homeostasis (GO:0001659), lipid catabolic process (GO:0016042), carnitine metabolic process, CoA-linked (GO:0019254), fatty acid beta-oxidation using acyl-CoA dehydrogenase (GO:0033539), carnitine catabolic process (GO:0042413), long-chain fatty acid catabolic process (GO:0042758), negative regulation of fatty acid biosynthetic process (GO:0045717), negative regulation of fatty acid oxidation (GO:0046322), regulation of cholesterol metabolic process (GO:0090181), positive regulation of cold-induced thermogenesis (GO:0120162), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (7): long-chain fatty acyl-CoA dehydrogenase activity (GO:0004466), protein homodimerization activity (GO:0042803), flavin adenine dinucleotide binding (GO:0050660), acyl-CoA dehydrogenase activity (GO:0003995), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-CH group of donors (GO:0016627)

GO Cellular Component (4): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
mitochondrial fatty acid beta-oxidation of saturated fatty acids	2
Mitochondrial Fatty Acid Beta-Oxidation	2
Metabolism	1
Fatty acid metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid metabolic process	2
carnitine metabolic process	2
acyl-CoA dehydrogenase activity	2
negative regulation of fatty acid metabolic process	2
mitochondrion	2
multicellular organismal-level homeostasis	1
catabolic process	1
fatty acid beta-oxidation	1
amino-acid betaine catabolic process	1
long-chain fatty acid metabolic process	1
fatty acid catabolic process	1
fatty acid biosynthetic process	1
regulation of fatty acid biosynthetic process	1
negative regulation of lipid biosynthetic process	1
fatty acid oxidation	1
regulation of fatty acid oxidation	1
cholesterol metabolic process	1
regulation of steroid metabolic process	1
regulation of small molecule metabolic process	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
primary metabolic process	1
monocarboxylic acid metabolic process	1
identical protein binding	1
protein dimerization activity	1
nucleotide binding	1
anion binding	1
oxidoreductase activity, acting on the CH-CH group of donors, with a flavin as acceptor	1
binding	1
catalytic activity	1
oxidoreductase activity	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

2206 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACADL	HADHB	P55084	903
ACADL	SIRT3	Q9NTG7	886
ACADL	HADHA	P40939	885
ACADL	ACSL1	P33121	815
ACADL	CPT2	P23786	809
ACADL	CPT1A	P50416	762
ACADL	HADH	Q16836	754
ACADL	ACOX1	Q15067	719
ACADL	PLIN2	Q99541	715
ACADL	CPT1B	Q92523	706
ACADL	PPARA	Q07869	683
ACADL	CPT1C	Q8TCG5	672
ACADL	UCP1	P25874	667
ACADL	ACAA1	P09110	644
ACADL	PPARGC1A	Q9UBK2	639

IntAct

22 interactions, top by confidence:

A	B	Type	Score
MTHFD2	HRAS	psi-mi:“MI:0914”(association)	0.730
ACADL	SYT2	psi-mi:“MI:0915”(physical association)	0.590
TGM1	ACADL	psi-mi:“MI:0915”(physical association)	0.560
GMFB	GMFG	psi-mi:“MI:0914”(association)	0.530
MTHFD2	ACADL	psi-mi:“MI:0914”(association)	0.530
ACADL	RAD50	psi-mi:“MI:0915”(physical association)	0.400
APP	ZNF724	psi-mi:“MI:0914”(association)	0.350
TMPRSS11A	PAK4	psi-mi:“MI:0914”(association)	0.350
rep	ACADL	psi-mi:“MI:0914”(association)	0.350
TTC9C	PLD2	psi-mi:“MI:0914”(association)	0.350
TNFAIP6	ZMYM6	psi-mi:“MI:0914”(association)	0.350
ZNF597	ACADL	psi-mi:“MI:0914”(association)	0.350
ZC3H7A	ACADL	psi-mi:“MI:0914”(association)	0.350
ACADL	RAP1B	psi-mi:“MI:0914”(association)	0.350
APP	CES2	psi-mi:“MI:0914”(association)	0.350
EXOC1	ACADL	psi-mi:“MI:0915”(physical association)	0.000
ACADL	TGM1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (23): ACADL (Affinity Capture-MS), SYT2 (Affinity Capture-MS), ACADL (Affinity Capture-MS), ACADL (Affinity Capture-MS), SYT2 (Affinity Capture-MS), ACADL (Affinity Capture-MS), ACADL (Affinity Capture-MS), ACADL (Two-hybrid), RAD50 (Proximity Label-MS), ACADL (Affinity Capture-MS), ACADL (Affinity Capture-MS), SYT2 (Affinity Capture-MS), ACADL (Affinity Capture-MS), ACADL (Affinity Capture-MS), ACADL (Affinity Capture-MS)

ESM2 similar proteins: A5A6I0, A8ALR4, A8WP91, A8XNF0, A9MQH5, B1XBG4, B4EY23, B7L4G2, B7UI85, B9U6P5, C3UVB0, C4ZPW5, F8GVD3, K4L7X3, P08503, P0A9U8, P0A9U9, P0A9V0, P11310, P12007, P15650, P26440, P28330, P41367, P45952, P45954, P51174, P70584, P79274, Q13PC1, Q22347, Q2LQN9, Q2LQP0, Q39QF4, Q39QF5, Q3SZB4, Q3SZI8, Q54RR5, Q5EAD4, Q5RBD5

Diamond homologs: A0R502, A8XNF0, B4EY23, C3UVB0, F8GVD3, G3KIM8, H6LGM6, I6Y3Q0, I6YCF5, J7TF92, K4L7X3, O54143, P15650, P15651, P16219, P28330, P45857, P45954, P51174, P70584, P79273, P79274, P96855, Q06319, Q07417, Q13PC1, Q22347, Q3ZBF6, Q4KCY6, Q5EAD4, Q5RAS0, Q5RF40, Q60HI0, Q75IM9, Q8GB20, Q9DBL1, Q9FS87, Q9FS88, Q9SWG0, A5A6I0

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
ACADL	“down-regulates quantity”	myristoyl-CoA(4-)	“chemical modification”
ACADL	“down-regulates quantity”	FAD(3-)	“chemical modification”
ACADL	“up-regulates quantity”	trans-tetradec-2-enoyl-CoA	“chemical modification”
ACADL	“up-regulates quantity”	FADH2(2-)	“chemical modification”
ACADL	“down-regulates quantity”	lauroyl-CoA(4-)	“chemical modification”
ACADL	“up-regulates quantity”	trans-dodec-2-enoyl-CoA(4-)	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	69
Likely benign	16
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

1771 predictions. Top by Δscore:

Variant	Effect	Δscore
2:210195335:CTGT:C	acceptor_gain	1.0000
2:210195345:T:TC	acceptor_gain	1.0000
2:210195346:T:C	acceptor_gain	1.0000
2:210195346:T:TC	acceptor_gain	1.0000
2:210203325:GCTTA:G	donor_loss	1.0000
2:210203326:CTTA:C	donor_loss	1.0000
2:210203327:TTAC:T	donor_loss	1.0000
2:210203328:TACCT:T	donor_loss	1.0000
2:210203329:A:C	donor_loss	1.0000
2:210203440:CTTTC:C	acceptor_gain	1.0000
2:210203441:TTTC:T	acceptor_gain	1.0000
2:210203442:TTCCT:T	acceptor_loss	1.0000
2:210203444:CCT:C	acceptor_loss	1.0000
2:210203445:C:CA	acceptor_loss	1.0000
2:210203445:C:CC	acceptor_gain	1.0000
2:210203446:T:A	acceptor_loss	1.0000
2:210204575:TCTGA:T	donor_loss	1.0000
2:210204576:CTGAC:C	donor_loss	1.0000
2:210204577:TGA:T	donor_loss	1.0000
2:210204578:GACC:G	donor_loss	1.0000
2:210204579:ACCT:A	donor_loss	1.0000
2:210204580:CCTGT:C	donor_loss	1.0000
2:210204692:C:CT	acceptor_gain	1.0000
2:210205627:CTCA:C	donor_loss	1.0000
2:210205628:TCA:T	donor_loss	1.0000
2:210205629:CAC:C	donor_loss	1.0000
2:210205631:C:A	donor_loss	1.0000
2:210210192:ACAC:A	donor_loss	1.0000
2:210210194:ACCT:A	donor_loss	1.0000
2:210210195:C:A	donor_loss	1.0000

AlphaMissense

2815 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:210195289:C:G	R345P	0.988
2:210220698:C:G	R61P	0.985
2:210203374:A:T	V314D	0.978
2:210205707:G:C	S231R	0.973
2:210205707:G:T	S231R	0.973
2:210205709:T:G	S231R	0.973
2:210192854:A:C	C383W	0.972
2:210192831:C:T	G391E	0.971
2:210192846:A:G	L386P	0.970
2:210195320:C:G	A335P	0.970
2:210203387:T:G	T310P	0.966
2:210192832:C:G	G391R	0.965
2:210192832:C:T	G391R	0.965
2:210203355:A:C	F320L	0.965
2:210203355:A:T	F320L	0.965
2:210203357:A:G	F320L	0.965
2:210192856:A:G	C383R	0.964
2:210210196:C:A	K201N	0.964
2:210210196:C:G	K201N	0.964
2:210195319:G:T	A335E	0.963
2:210218068:A:G	W90R	0.962
2:210218068:A:T	W90R	0.962
2:210218059:C:G	A93P	0.958
2:210189041:C:G	A405P	0.957
2:210192864:G:T	A380D	0.956
2:210203364:T:A	R317S	0.949
2:210203364:T:G	R317S	0.949
2:210216371:G:T	A171E	0.949
2:210216378:C:G	A169P	0.948
2:210195268:A:G	L352P	0.945

dbSNP variants (sampled 300 via entrez): RS1000125297 (2:210222827 A>C,G), RS1000153134 (2:210216790 C>T), RS1000157354 (2:210224517 C>T), RS1000172181 (2:210201792 A>G), RS1000448216 (2:210200421 C>T), RS1000484376 (2:210216515 A>C,G), RS1000541465 (2:210188145 A>G), RS1000652912 (2:210192366 G>A), RS1000851193 (2:210215230 C>A,T), RS1000925926 (2:210210850 G>A), RS1001212763 (2:210223819 A>C), RS1001283057 (2:210192059 T>C), RS1001304219 (2:210202987 A>G), RS1001354939 (2:210192496 A>C,G,T), RS1001433792 (2:210208052 G>A,C)

Disease associations

OMIM: gene MIM:609576 | disease phenotypes: MIM:190350

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary pulmonary alveolar proteinosis	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
long chain acyl-CoA dehydrogenase deficiency	Disputed	AR

Mondo (3): long chain acyl-CoA dehydrogenase deficiency (MONDO:0020531), trichorhinophalangeal syndrome type I (MONDO:0008596), hereditary pulmonary alveolar proteinosis (MONDO:0012580)

Orphanet (2): Trichorhinophalangeal syndrome type 1 (Orphanet:77258), Long chain acyl-CoA dehydrogenase deficiency (Orphanet:99900)

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000550_5	Metabolite levels	3.000000e-60
GCST001882_5	Metabolite levels	4.000000e-29
GCST002364_4	Urinary metabolites (H-NMR features)	3.000000e-18
GCST005648_36	Serum metabolite concentrations in chronic kidney disease	1.000000e-35
GCST006249_99	Serum metabolite levels	3.000000e-33
GCST009733_12	Urinary metabolite levels in chronic kidney disease	4.000000e-181
GCST009733_231	Urinary metabolite levels in chronic kidney disease	4.000000e-75
GCST009735_38	Urinary metabolite modules (eigenmetabolites) in chronic kidney disease	7.000000e-132

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0005116	urinary metabolite measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
C535690	Long-chain acyl-CoA dehydrogenase deficiency (supp.)
C535832	Pulmonary alveolar proteinosis, congenital (supp.)
C536820	Trichorhinophalangeal Syndrome, Type I (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	3
Fluorouracil	increases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	increases expression, decreases expression	2
Valproic Acid	decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
bisphenol E	decreases expression	1
lasiocarpine	decreases expression	1
bisphenol A	decreases expression	1
chlortoluron	decreases expression	1
4,4’-bisphenol F	increases expression	1
sodium arsenite	decreases expression	1
di-n-hexyl phthalate	decreases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression, decreases reaction	1
brequinar	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
Omacor	increases expression	1
GW 4064	decreases expression, affects cotreatment	1
GW 7647	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Arsenicals	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Glucose	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01511068	PHASE2	COMPLETED	Inhaled Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in Hereditary Pulmonary Alveolar Proteinosis (PAP)
NCT05761899	PHASE1/PHASE2	RECRUITING	Safety and Efficacy of PMT Therapy of hPAP