ACADS

Summary

ACADS (acyl-CoA dehydrogenase short chain, HGNC:90) is a protein-coding gene on chromosome 12q24.31, encoding Short-chain specific acyl-CoA dehydrogenase, mitochondrial (P16219). Short-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation, an aerobic process breaking down fatty acids into acetyl-CoA and allowing the production of energy from fats.

This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Mutations in this gene have been associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency. Alternative splicing results in two variants which encode different isoforms.

Source: NCBI Gene 35 — RefSeq curated summary.

At a glance

• Gene–disease (curated): short chain acyl-CoA dehydrogenase deficiency (Definitive, ClinGen)
• GWAS associations: 34
• Clinical variants (ClinVar): 513 total — 27 pathogenic, 47 likely-pathogenic
• Phenotypes (HPO): 40
• MANE Select transcript: NM_000017

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:90
Approved symbol	ACADS
Name	acyl-CoA dehydrogenase short chain
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	SCAD, ACAD3
Ensembl gene	ENSG00000122971
Ensembl biotype	protein_coding
OMIM	606885
Entrez	35

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 retained_intron

ENST00000242592, ENST00000411593, ENST00000539690, ENST00000893619, ENST00000893620, ENST00000893621, ENST00000893622, ENST00000893623, ENST00000936844, ENST00000936845, ENST00000946559, ENST00000946560, ENST00000946561

RefSeq mRNA: 2 — MANE Select: NM_000017 NM_000017, NM_001302554

CCDS: CCDS76610, CCDS9207

Canonical transcript exons

ENST00000242592 — 10 exons

Exon	Start	End
ENSE00001191782	120738820	120738915
ENSE00001191801	120736986	120737135
ENSE00001191811	120739296	120740008
ENSE00001245827	120739140	120739196
ENSE00001245837	120738533	120738670
ENSE00001245843	120738280	120738450
ENSE00001245851	120737837	120737988
ENSE00001245859	120737356	120737467
ENSE00002226541	120725826	120725931
ENSE00003654770	120727026	120727189

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 98.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.9105 / max 348.8940, expressed in 1730 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128383	11.8084	1728
128382	0.1022	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.37	gold quality
mucosa of transverse colon	UBERON:0004991	98.22	gold quality
apex of heart	UBERON:0002098	97.75	gold quality
gastrocnemius	UBERON:0001388	97.00	gold quality
muscle of leg	UBERON:0001383	95.72	gold quality
transverse colon	UBERON:0001157	95.61	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.48	gold quality
heart left ventricle	UBERON:0002084	95.04	gold quality
cardiac ventricle	UBERON:0002082	94.85	gold quality
right adrenal gland	UBERON:0001233	94.51	gold quality
right adrenal gland cortex	UBERON:0035827	94.47	gold quality
liver	UBERON:0002107	94.37	gold quality
tendon of biceps brachii	UBERON:0008188	94.21	silver quality
left adrenal gland	UBERON:0001234	94.05	gold quality
muscle organ	UBERON:0001630	93.89	gold quality
left adrenal gland cortex	UBERON:0035825	93.85	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.79	gold quality
duodenum	UBERON:0002114	93.63	gold quality
adrenal cortex	UBERON:0001235	93.40	gold quality
small intestine	UBERON:0002108	92.75	gold quality
right atrium auricular region	UBERON:0006631	92.16	gold quality
triceps brachii	UBERON:0001509	92.07	gold quality
omental fat pad	UBERON:0010414	91.80	gold quality
peritoneum	UBERON:0002358	91.76	gold quality
heart	UBERON:0000948	91.62	gold quality
body of stomach	UBERON:0001161	91.60	gold quality
adrenal gland	UBERON:0002369	91.43	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.38	gold quality
colon	UBERON:0001155	91.20	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.11

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting ACADS, 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-4319	99.76	69.83	2586
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-4704-3P	98.28	69.33	1300
HSA-MIR-3928-3P	97.61	66.53	1096
HSA-MIR-3918	96.13	64.65	1300
HSA-MIR-6821-3P	95.21	66.79	578
HSA-MIR-6790-3P	88.15	62.55	113

Literature-anchored findings (GeneRIF, showing 25)

• Reduction of catalytic activity and stability in polymorphic variant of SCAD (Gly185Ser) is caused by decreased flexibility in the tertiary conformation of the mutant enzyme. (PMID:12220177)
• Replacement of the catalytic glutamate in either short-chain acyl-CoA dehydrogenase (SCAD) or isovaleryl-CoA dehydrogenase (IVD)with glycine resulted in a several-fold reduction in affinity for substrate. (PMID:16376132)
• One of 220 SIDs cases was homozygous for the prevalent MCAD A985G mutation. (PMID:18045290)
• The c.319C>T mutation can lead to wide clinical and biochemical phenotypic variability, suggesting a complex multifactorial/polygenic condition. This should be screened for in individuals with multicore myopathy, particularly among the Ashkenazim. (PMID:18054510)
• A homozygous variant allele of the SCAD gene, 625G>A, was detected in new case of short-chain acyl-CoA dehydrogenase deficiency. (PMID:18175080)
• Extensive laboratory investigations indicate that the short-chain acyl-CoA dehydrogenase gene variant is likely preventing or delaying the normal expression of the Prader-Willi syndrome phenotype. (PMID:18184946)
• SCAD deficiency should be considered as a disorder of protein folding that can lead to clinical disease in combination with other genetic and environmental factors. (PMID:18523805)
• A deoxyribonucleic analysis revealed the presence of a 625G>A (G-to-A substitution at nucleotide 625) variant short-chain acyl-coenzyme A dehydrogenase gene polymorphism. (PMID:18539996)
• SCAD deficiency cause a disorder that leads to the accumulation of butyrylcarnitine and ethylmalonic acid in blood and urine. (PMID:18977676)
• We therefore propose that SCAD misfolding leads to production of ROS, which in turn leads to fission and a grain-like structure of the mitochondrial reticulum. This finding indicates a toxic response elicited by misfolded p.Arg83Cys SCAD proteins (PMID:20371198)
• Molecular pathogenesis of a novel mutation, G108D, in ACADS identified in subjects with ACADS deficiency. (PMID:20376488)
• In glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS was associated with reduced measures of glucose-stimulated insulin release during an oral glucose tolerance test. (PMID:21211036)
• physiological concentrations of flavin adenine dinucleotide resulted in a spectacular enhancement of the thermal stabilities of SCAD and prevented enzymatic activity loss (PMID:21968293)
• IVD mutations in Asian populations are distinct from these in Western populations. (PMID:22004070)
• Thirteen proteins had significant alteration in protein levels in patients carrying variation c.319C>T in ACADS compared to controls and they belonged to various pathways, such as the antioxidant system and amino acid metabolism. (PMID:24485985)
• Results show significant upregulation of LASP1 and SCAD protein levels in acute psychotic bipolar disorder samples. (PMID:24554194)
• Korean patients with Short-chain acyl-CoA dehydrogenase deficiency showed heterogenous clinical features and ACADS genotype. (PMID:27466294)
• a link between ACADS susceptibility variants and abnormal beta-oxidation consistent with known altered kinetics of these variants (PMID:28532786)
• Study discovered a high occurrence of two rare pathogenic variants-the deletion c.310_312delGAG and the substitution c.1138C>T, with allelic frequencies of 64% and 31%, respectively especially in the Roma ethnic group. (PMID:29678161)
• ACADS acts as a potential methylation biomarker associated with the proliferation and metastasis of hepatocellular carcinomas. (PMID:31652420)
• Effects of genetic variations in Acads gene on the risk of chronic obstructive pulmonary disease. (PMID:32593204)
• The minor C-allele of the rs2014355 variant in ACADS gene is associated with exercise-induced increase in HDL cholesterol levels in Taiwanese adults. (PMID:33429745)
• Screening and follow-up results of fatty acid oxidative metabolism disorders in 608 818 newborns in Jining, Shandong province. (PMID:34704412)
• Integrated Analysis of Expression and Prognostic Values of Acyl-CoA Dehydrogenase short-chain in Colorectal Cancer. (PMID:34790035)
• Short-chain acyl-CoA dehydrogenase is a potential target for the treatment of vascular remodelling. (PMID:36883465)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	acads	ENSDARG00000030781
mus_musculus	Acads	ENSMUSG00000029545
rattus_norvegicus	Acads	ENSRNOG00000001177
drosophila_melanogaster	Arc42	FBGN0038742
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), IVD (ENSG00000128928), ACAD8 (ENSG00000151498), ACOXL (ENSG00000153093), ACOX1 (ENSG00000161533), ACOX2 (ENSG00000168306), ACAD9 (ENSG00000177646), ACADSB (ENSG00000196177), ACAD11 (ENSG00000240303)

Protein

Protein identifiers

Short-chain specific acyl-CoA dehydrogenase, mitochondrial — P16219 (reviewed: P16219)

Alternative names: Butyryl-CoA dehydrogenase

All UniProt accessions (3): E5KSD5, E9PE82, P16219

UniProt curated annotations — full annotation on UniProt →

Function. Short-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation, an aerobic process breaking down fatty acids into acetyl-CoA and allowing the production of energy from fats. The first step of fatty acid beta-oxidation consists in the removal of one hydrogen from C-2 and C-3 of the straight-chain fatty acyl-CoA thioester, resulting in the formation of trans-2-enoyl-CoA. Among the different mitochondrial acyl-CoA dehydrogenases, short-chain specific acyl-CoA dehydrogenase acts specifically on acyl-CoAs with saturated 4 to 6 carbons long primary chains.

Subunit / interactions. Homotetramer.

Subcellular location. Mitochondrion matrix.

Disease relevance. Acyl-CoA dehydrogenase short-chain deficiency (ACADSD) [MIM:201470] An inborn error of mitochondrial fatty acid beta-oxidation resulting in acute acidosis and muscle weakness in infants, and a form of lipid-storage myopathy in adults. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 FAD per subunit.

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

Similarity. Belongs to the acyl-CoA dehydrogenase family.

RefSeq proteins (2): NP_000008, NP_001289483 (=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

Pfam: PF00441, PF02770, PF02771

Catalyzed reactions (Rhea), 4 shown:

• butanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-butenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:24004)
• pentanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-pentenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:43456)
• hexanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-hexenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:43464)
• a short-chain 2,3-saturated fatty acyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = a short-chain (2E)-enoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:47196)

UniProt features (74 total): helix 18, sequence variant 14, strand 13, modified residue 11, binding site 9, turn 6, transit peptide 1, chain 1, active site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2VIG	X-RAY DIFFRACTION	1.9
7Y0B	X-RAY DIFFRACTION	2.08
7Y0A	X-RAY DIFFRACTION	2.32
8SGS	ELECTRON MICROSCOPY	3.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16219-F1	93.58	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): 392 (proton acceptor)

Ligand- & substrate-binding residues (9): 393; 394–396 (in other chain); 152–161 (in other chain); 161; 185–187 (in other chain); 269–272; 297; 308 (in other chain); 365–369

Post-translational modifications (11): 27, 51, 51, 72, 129, 129, 208, 262, 262, 306, 306

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-77350	Beta oxidation of hexanoyl-CoA to butanoyl-CoA
R-HSA-77352	Beta oxidation of butanoyl-CoA to acetyl-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: 208 (showing top): GOBP_LIPID_MODIFICATION, GOBP_FATTY_ACID_CATABOLIC_PROCESS, JI_RESPONSE_TO_FSH_UP, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, GOBP_FATTY_ACID_BETA_OXIDATION_USING_ACYL_COA_DEHYDROGENASE, GOBP_SHORT_CHAIN_FATTY_ACID_METABOLIC_PROCESS, KESHELAVA_MULTIPLE_DRUG_RESISTANCE, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, BLALOCK_ALZHEIMERS_DISEASE_UP, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, MODULE_294, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, CAIRO_HEPATOBLASTOMA_DN

GO Biological Process (5): fatty acid beta-oxidation (GO:0006635), fatty acid beta-oxidation using acyl-CoA dehydrogenase (GO:0033539), butyrate catabolic process (GO:0046359), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (6): acyl-CoA dehydrogenase activity (GO:0003995), short-chain fatty acyl-CoA dehydrogenase activity (GO:0016937), flavin adenine dinucleotide binding (GO:0050660), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-CH group of donors (GO:0016627)

GO Cellular Component (3): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-5 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
acyl-CoA dehydrogenase activity	2
intracellular membrane-bounded organelle	2
fatty acid catabolic process	1
fatty acid ligase activity	1
fatty acid oxidation	1
fatty acid beta-oxidation	1
butyrate metabolic process	1
short-chain fatty acid catabolic process	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid 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
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2274 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACADS	CPT2	P23786	899
ACADS	HADHA	P40939	822
ACADS	DHRS4	Q9BTZ2	819
ACADS	HADHB	P55084	756
ACADS	ETFB	P38117	750
ACADS	ECHS1	P30084	743
ACADS	SLC25A20	O43772	741
ACADS	HADH	Q16836	709
ACADS	ETHE1	O95571	697
ACADS	ACAA1	P09110	697
ACADS	SIRT3	Q9NTG7	694
ACADS	ACAA2	P42765	672
ACADS	ETFDH	Q16134	658
ACADS	ETFA	P13804	644
ACADS	EHHADH	Q08426	624

IntAct

35 interactions, top by confidence:

A	B	Type	Score
LYRM2	NDUFAB1	psi-mi:“MI:0914”(association)	0.730
ESS2	ACADS	psi-mi:“MI:0914”(association)	0.640
ACADS	DPEP1	psi-mi:“MI:0915”(physical association)	0.590
SUN2	POTEF	psi-mi:“MI:0914”(association)	0.530
ESS2	HSPA8	psi-mi:“MI:0914”(association)	0.530
ACADS	GGT7	psi-mi:“MI:0915”(physical association)	0.400
UTP6	ACADS	psi-mi:“MI:0915”(physical association)	0.400
IRF7	ACADS	psi-mi:“MI:0915”(physical association)	0.370
STX5	HMMR	psi-mi:“MI:0914”(association)	0.350
RING1	FGA	psi-mi:“MI:0914”(association)	0.350
KIF6	ACADS	psi-mi:“MI:0914”(association)	0.350
SEC22C	ACADS	psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
	NUDT19	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
CCN2	ACADS	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
FECH	GTPBP10	psi-mi:“MI:0914”(association)	0.350
ESS2	CDC40	psi-mi:“MI:0914”(association)	0.350
IFNG	MMP3	psi-mi:“MI:0914”(association)	0.350
MRPS23	MYH7B	psi-mi:“MI:0914”(association)	0.350
SLC2A12	TRAFD1	psi-mi:“MI:0914”(association)	0.350

BioGRID (34): ACADS (Affinity Capture-MS), ACADS (Co-fractionation), ACADS (Co-fractionation), CLIC4 (Co-fractionation), DPEP1 (Affinity Capture-MS), ACADS (Affinity Capture-MS), ACADS (Affinity Capture-MS), ACADS (Affinity Capture-MS), ACADS (Affinity Capture-MS), ACADS (Affinity Capture-MS), ACADS (Affinity Capture-MS), ACADS (Affinity Capture-MS), ACADS (Affinity Capture-MS), ACADS (Affinity Capture-MS), ACADS (Affinity Capture-MS)

ESM2 similar proteins: A5A6I0, A8XNF0, C3UVB0, G3KIM8, H6LGM6, J7TF92, O34421, P08503, P0A9V0, P11310, P12007, P15651, P16219, P26440, P41367, P45857, P45867, P45952, P45954, P46703, P52042, P63428, P70584, P79273, P9WQG0, P9WQG1, Q06319, Q07417, Q22347, Q2LQN9, Q2LQP0, Q39QF4, Q39QF5, Q3SZB4, Q3SZI8, Q3ZBF6, Q54IM8, Q54RR5, Q5EAD4, Q5P5Z9

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

8 interactions.

A	Effect	B	Mechanism
ACADS	“down-regulates quantity”	hexanoyl-CoA(4-)	“chemical modification”
ACADS	“down-regulates quantity”	FAD(3-)	“chemical modification”
ACADS	“up-regulates quantity”	trans-hex-2-enoyl-CoA(4-)	“chemical modification”
ACADS	“up-regulates quantity”	FADH2(2-)	“chemical modification”
ACADS	“down-regulates quantity”	butyryl-CoA(4-)	“chemical modification”
ACADS	“up-regulates quantity”	crotonoyl-CoA(4-)	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	47
Uncertain significance	209
Likely benign	125
Benign	26

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1060209	NM_000017.4(ACADS):c.812del (p.Gly271fs)	Pathogenic
1485321	NM_000017.4(ACADS):c.937A>G (p.Lys313Glu)	Pathogenic
1509542	NC_000012.11:g.(?121172765)(121176235_?)del	Pathogenic
189087	NM_000017.4(ACADS):c.409C>T (p.Gln137Ter)	Pathogenic
189093	NM_000017.4(ACADS):c.682_683del (p.Glu228fs)	Pathogenic
1948098	NM_000017.4(ACADS):c.1086+2T>G	Pathogenic
2039130	NM_000017.4(ACADS):c.88C>T (p.Gln30Ter)	Pathogenic
2422134	NC_000012.11:g.(?121174454)(121176447_?)del	Pathogenic
2631279	NM_000017.4(ACADS):c.826del (p.Ala276fs)	Pathogenic
2709405	NM_000017.4(ACADS):c.3G>A (p.Met1Ile)	Pathogenic
3010236	NM_000017.4(ACADS):c.931C>T (p.Gln311Ter)	Pathogenic
3244257	NC_000012.11:g.(?121163689)(121438995_?)del	Pathogenic
3646036	NM_000017.4(ACADS):c.105dup (p.Glu36fs)	Pathogenic
3648925	NM_000017.4(ACADS):c.762_911del150 (p.Gly255_Leu304del)	Pathogenic
370099	NM_000017.4(ACADS):c.1084C>T (p.Gln362Ter)	Pathogenic
370351	NM_000017.4(ACADS):c.1164_1165del (p.Glu389fs)	Pathogenic
370525	NM_000017.4(ACADS):c.369C>G (p.Tyr123Ter)	Pathogenic
370891	NM_000017.4(ACADS):c.527C>A (p.Ser176Ter)	Pathogenic
3727600	NM_000017.4(ACADS):c.561_568del (p.Asn188fs)	Pathogenic
3826	NM_000017.4(ACADS):c.319C>T (p.Arg107Cys)	Pathogenic
3833	NM_000017.4(ACADS):c.307GAG[1] (p.Glu104del)	Pathogenic
419056	NM_000017.4(ACADS):c.238del (p.Leu80fs)	Pathogenic
421618	NM_000017.4(ACADS):c.319_321delinsTGC (p.Arg107Cys)	Pathogenic
4682807	GRCh37/hg19 12q24.31(chr12:120829779-121489188)x1	Pathogenic
4704035	NM_000017.4(ACADS):c.226_229dup (p.Leu77fs)	Pathogenic
4753128	NM_000017.4(ACADS):c.701G>A (p.Arg234Gln)	Pathogenic
860547	NM_000017.4(ACADS):c.514dup (p.Ala172fs)	Pathogenic
1002010	NM_000017.4(ACADS):c.137G>A (p.Arg46Gln)	Likely pathogenic
1415577	NM_000017.4(ACADS):c.47-2A>C	Likely pathogenic
1525913	NM_000017.4(ACADS):c.1139G>A (p.Arg380Gln)	Likely pathogenic

SpliceAI

1575 predictions. Top by Δscore:

Variant	Effect	Δscore
12:120725929:GAG:G	donor_gain	1.0000
12:120725929:GAGGT:G	donor_loss	1.0000
12:120725930:AGGTG:A	donor_loss	1.0000
12:120725932:G:C	donor_loss	1.0000
12:120727186:TCAG:T	donor_loss	1.0000
12:120727187:CAGGT:C	donor_loss	1.0000
12:120727188:AG:A	donor_loss	1.0000
12:120727189:GGT:G	donor_loss	1.0000
12:120727190:G:C	donor_loss	1.0000
12:120736977:T:TA	acceptor_gain	1.0000
12:120736982:CCA:C	acceptor_loss	1.0000
12:120736983:CA:C	acceptor_loss	1.0000
12:120736984:A:AG	acceptor_gain	1.0000
12:120736984:A:AT	acceptor_loss	1.0000
12:120736985:G:GG	acceptor_gain	1.0000
12:120736985:GGT:G	acceptor_gain	1.0000
12:120737131:ACAAC:A	donor_gain	1.0000
12:120737134:AC:A	donor_gain	1.0000
12:120737136:G:GG	donor_gain	1.0000
12:120737835:AG:A	acceptor_gain	1.0000
12:120737836:GG:G	acceptor_gain	1.0000
12:120738278:A:AG	acceptor_gain	1.0000
12:120738278:AG:A	acceptor_gain	1.0000
12:120738278:AGG:A	acceptor_gain	1.0000
12:120738278:AGGG:A	acceptor_loss	1.0000
12:120738279:G:GT	acceptor_gain	1.0000
12:120738279:GG:G	acceptor_gain	1.0000
12:120738279:GGG:G	acceptor_gain	1.0000
12:120738279:GGGC:G	acceptor_gain	1.0000
12:120738279:GGGCA:G	acceptor_gain	1.0000

AlphaMissense

2690 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:120737458:A:C	S155R	0.999
12:120737460:C:A	S155R	0.999
12:120737460:C:G	S155R	0.999
12:120737912:A:T	K183I	0.999
12:120737913:A:C	K183N	0.999
12:120737913:A:T	K183N	0.999
12:120737917:T:A	W185R	0.999
12:120737917:T:C	W185R	0.999
12:120737906:G:A	G181E	0.998
12:120737906:G:T	G181V	0.998
12:120738446:C:A	A264D	0.998
12:120739386:G:C	G393R	0.998
12:120737459:G:T	S155I	0.997
12:120737911:A:G	K183E	0.997
12:120737924:C:T	T187I	0.997
12:120738552:G:C	R272P	0.997
12:120737444:G:A	G150D	0.996
12:120737448:C:G	C151W	0.996
12:120737449:T:C	F152L	0.996
12:120737451:T:A	F152L	0.996
12:120737451:T:G	F152L	0.996
12:120737453:C:A	A153D	0.996
12:120737456:T:A	L154H	0.996
12:120737845:A:C	S161R	0.996
12:120737847:T:A	S161R	0.996
12:120737847:T:G	S161R	0.996
12:120737873:C:A	A170D	0.996
12:120737960:C:A	A199D	0.996
12:120738290:C:A	A212D	0.996
12:120738293:T:C	F213S	0.996

dbSNP variants (sampled 300 via entrez): RS1000329500 (12:120733209 G>A), RS1000442246 (12:120733745 G>A), RS1000573160 (12:120735579 T>A,C), RS1000626538 (12:120739004 C>T), RS1000910458 (12:120724264 CAAAT>C), RS1001085460 (12:120729202 C>T), RS1001232381 (12:120725169 G>A), RS1001298373 (12:120737077 C>T), RS1001538185 (12:120729353 G>A), RS1001648164 (12:120736882 A>T), RS1001819769 (12:120730588 C>T), RS1002073893 (12:120731308 G>A,T), RS1002105029 (12:120731590 G>A), RS1002191456 (12:120736770 CG>C), RS1002704924 (12:120738139 C>G,T)

Disease associations

OMIM: gene MIM:606885 | disease phenotypes: MIM:201470, MIM:125853

GenCC curated gene-disease

Disease	Classification	Inheritance
short chain acyl-CoA dehydrogenase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
short chain acyl-CoA dehydrogenase deficiency	Definitive	AR

Mondo (2): short chain acyl-CoA dehydrogenase deficiency (MONDO:0008722), type 2 diabetes mellitus (MONDO:0005148)

Orphanet (1): Short chain acyl-CoA dehydrogenase deficiency (Orphanet:26792)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000544	External ophthalmoplegia
HP:0000648	Optic atrophy
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001332	Dystonia
HP:0001371	Flexion contracture
HP:0001397	Hepatic steatosis
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001638	Cardiomyopathy
HP:0001942	Metabolic acidosis
HP:0001999	Abnormal facial shape
HP:0002098	Respiratory distress
HP:0002500	Abnormal cerebral white matter morphology
HP:0002650	Scoliosis
HP:0003198	Myopathy
HP:0003219	Ethylmalonic aciduria
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0004911	Episodic metabolic acidosis
HP:0006929	Hypoglycemic encephalopathy

GWAS associations

34 associations (top):

Study	Trait	p-value
GCST000550_4	Metabolite levels	5.000000e-96
GCST001217_11	Metabolic traits	4.000000e-305
GCST002364_31	Urinary metabolites (H-NMR features)	2.000000e-22
GCST004601_167	Red blood cell count	6.000000e-23
GCST004621_59	Red cell distribution width	4.000000e-24
GCST005648_24	Serum metabolite concentrations in chronic kidney disease	4.000000e-27
GCST005650_1	Serum metabolite ratios in chronic kidney disease	2.000000e-33
GCST005650_2	Serum metabolite ratios in chronic kidney disease	6.000000e-37
GCST005650_3	Serum metabolite ratios in chronic kidney disease	3.000000e-40
GCST006011_38	Mean corpuscular volume	2.000000e-08
GCST006249_30	Serum metabolite levels	4.000000e-177
GCST006409_12	Allergic rhinitis	4.000000e-11
GCST007205_3	Schizophrenia	1.000000e-08
GCST007327_139	Smoking status (ever vs never smokers)	4.000000e-09
GCST009600_128	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	5.000000e-08
GCST009600_52	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	4.000000e-08
GCST009698_102	Metabolite levels	2.000000e-08
GCST009698_75	Metabolite levels	3.000000e-14
GCST009698_76	Metabolite levels	1.000000e-38
GCST009698_77	Metabolite levels	2.000000e-17
GCST009733_132	Urinary metabolite levels in chronic kidney disease	8.000000e-169
GCST009733_43	Urinary metabolite levels in chronic kidney disease	3.000000e-11
GCST009735_17	Urinary metabolite modules (eigenmetabolites) in chronic kidney disease	7.000000e-25
GCST010002_176	Refractive error	8.000000e-11
GCST012020_190	Serum metabolite levels	8.000000e-11
GCST012020_328	Serum metabolite levels	9.000000e-54
GCST012020_329	Serum metabolite levels	4.000000e-184
GCST012020_373	Serum metabolite levels	1.000000e-128
GCST012020_374	Serum metabolite levels	9.000000e-121
GCST012020_375	Serum metabolite levels	8.000000e-12

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0005116	urinary metabolite measurement
EFO:0004305	erythrocyte count
EFO:0009188	Red cell distribution width
EFO:0004318	smoking behavior
EFO:0005059	acylcarnitine measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
C537596	Short chain Acyl CoA dehydrogenase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects cotreatment, decreases methylation, increases expression	4
Benzo(a)pyrene	affects methylation, increases methylation	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
bisphenol F	increases expression	1
bisphenol E	decreases expression	1
lasiocarpine	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	affects expression, increases expression	1
beta-hexachlorocyclohexane	decreases expression	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
cyproconazole	decreases expression	1
PCB 180	affects expression	1
GW 4064	affects cotreatment, decreases expression, increases expression	1
GW 7647	affects cotreatment, increases expression	1
6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
perfluorobutanesulfonic acid	decreases expression	1
bisphenol S	increases expression	1
jinfukang	increases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Cadmium	increases expression, increases abundance	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Farnesol	affects cotreatment, increases expression	1
Gold	affects binding, decreases expression	1

Cellosaurus cell lines

8 cell lines: 4 finite cell line, 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_4F77	GM17470	Finite cell line	Male
CVCL_4F78	GM17471	Finite cell line	Male
CVCL_4F79	GM17472	Finite cell line	Male
CVCL_4F80	GM17473	Finite cell line	Male
CVCL_A2VT	GM26153	Transformed cell line	Female
CVCL_E1P9	HAP1 ACADS (-) 1	Cancer cell line	Male
CVCL_E1PA	HAP1 ACADS (-) 2	Cancer cell line	Male
CVCL_E1PB	HAP1 ACADS (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06759272	PHASE4	NOT_YET_RECRUITING	Impact of CYP2C19 Genotype-guided Approach in Antiplatelet Therapy on Platelet Reactivity Index Among Coronary Artery Disease (CAD) Patients
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes