ACADSB

Summary

ACADSB (acyl-CoA dehydrogenase short/branched chain, HGNC:91) is a protein-coding gene on chromosome 10q26.13, encoding Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial (P45954). Short and branched chain specific acyl-CoA dehydrogenase that catalyzes 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….

Short/branched chain acyl-CoA dehydrogenase(ACADSB) is a member of the acyl-CoA dehydrogenase family of enzymes that catalyze the dehydrogenation of acyl-CoA derivatives in the metabolism of fatty acids or branch chained amino acids. Substrate specificity is the primary characteristic used to define members of this gene family. The ACADSB gene product has the greatest activity towards the short branched chain acyl-CoA derivative, (S)-2-methylbutyryl-CoA, but also reacts significantly with other 2-methyl branched chain substrates and with short straight chain acyl-CoAs. The cDNA encodes for a mitochondrial precursor protein which is cleaved upon mitochondrial import and predicted to yield a mature peptide of approximately 43.7-KDa.

Source: NCBI Gene 36 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 2-methylbutyryl-CoA dehydrogenase deficiency (Definitive, ClinGen)
• GWAS associations: 5
• Clinical variants (ClinVar): 367 total — 15 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 19
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001609

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:91
Approved symbol	ACADSB
Name	acyl-CoA dehydrogenase short/branched chain
Location	10q26.13
Locus type	gene with protein product
Status	Approved
Aliases	SBCAD, ACAD7
Ensembl gene	ENSG00000196177
Ensembl biotype	protein_coding
OMIM	600301
Entrez	36

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000358776, ENST00000368869, ENST00000411816, ENST00000541070, ENST00000908750, ENST00000908751, ENST00000908752, ENST00000908753, ENST00000908754

RefSeq mRNA: 2 — MANE Select: NM_001609 NM_001330174, NM_001609

CCDS: CCDS7634, CCDS81518

Canonical transcript exons

ENST00000358776 — 11 exons

Exon	Start	End
ENSE00001399396	123053695	123058290
ENSE00001448198	123009006	123009071
ENSE00001661123	123051049	123051186
ENSE00001724008	123047209	123047298
ENSE00001766561	123053061	123053160
ENSE00003481818	123044393	123044485
ENSE00003489237	123040466	123040672
ENSE00003518328	123037747	123037847
ENSE00003571649	123043046	123043171
ENSE00003597543	123034356	123034515
ENSE00003637107	123041209	123041379

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 97.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.9649 / max 422.5005, expressed in 1691 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107475	10.4418	1688
107474	0.3575	183
107473	0.1655	79

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	97.69	gold quality
liver	UBERON:0002107	97.54	gold quality
biceps brachii	UBERON:0001507	94.57	gold quality
renal medulla	UBERON:0000362	94.13	gold quality
heart right ventricle	UBERON:0002080	93.58	gold quality
duodenum	UBERON:0002114	93.43	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.12	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.61	gold quality
jejunal mucosa	UBERON:0000399	91.17	gold quality
adult mammalian kidney	UBERON:0000082	90.22	gold quality
gastrocnemius	UBERON:0001388	89.71	gold quality
muscle of leg	UBERON:0001383	89.52	gold quality
jejunum	UBERON:0002115	89.20	gold quality
right adrenal gland cortex	UBERON:0035827	88.56	gold quality
kidney	UBERON:0002113	88.55	gold quality
adrenal tissue	UBERON:0018303	88.43	gold quality
body of tongue	UBERON:0011876	88.19	gold quality
endothelial cell	CL:0000115	88.01	gold quality
left adrenal gland	UBERON:0001234	87.95	gold quality
rectum	UBERON:0001052	87.91	gold quality
middle temporal gyrus	UBERON:0002771	87.74	gold quality
adrenal cortex	UBERON:0001235	87.67	gold quality
myocardium	UBERON:0002349	87.64	gold quality
muscle organ	UBERON:0001630	87.56	gold quality
left adrenal gland cortex	UBERON:0035825	87.49	gold quality
right adrenal gland	UBERON:0001233	87.47	gold quality
adrenal gland	UBERON:0002369	87.44	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.35	gold quality
nephron tubule	UBERON:0001231	87.32	gold quality
cardiac ventricle	UBERON:0002082	87.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1

miRNA regulators (miRDB)

180 targeting ACADSB, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3148	99.97	75.06	6478

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 10)

• Differences between the rat and human enzyme at positions 383, 222, and 220 alter substrate specificity without affecting substrate binding. (PMID:12855692)
• Identification and characterization of an IVS3+3A>G mutation (c.303+3A>G) in the SBCAD gene, and provide evidence that this mutation is disease-causing. (PMID:16317551)
• Results examine the mechanistic basis for dysfunction of the common variant short-chain acyl-CoA dehydrogenases and demonstrate that mutations can have a large impact on the redox properties of the enzyme. (PMID:16331963)
• Results indicate that substrate redox activation occurs in short-chain acyl-CoA dehydrogenase leading to a large enzyme midpoint potential shift. (PMID:16331964)
• These findings confirm that SBCAD deficiency can be identified through newborn screening by acylcarnitine analysis. (PMID:20547083)
• Strong candidate gene for mitochondrial disease, based on recessive mutations detected in infantile patients (PMID:22277967)
• the c.1165 A>G mutation before knowing whether the optimal screening cut-off would minimize true positives or false negatives for SBCADD associated with this mutation. (PMID:23712021)
• ACADSB mutation is associated with short/branched-chain acyl-CoA dehydrogenase deficiency. (PMID:30730842)
• ACADSB regulates ferroptosis and affects the migration, invasion, and proliferation of colorectal cancer cells. (PMID:32776663)
• Lipid Metabolism Pathway Genes and Lung Cancer: ACADSB rs12220683G>C Is Associated with Better Survival Outcome in Patients with Non-Small Cell Lung Cancer. (PMID:37527640)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	acadsb	ENSDARG00000076780
		ENSDARG00000098174
mus_musculus	Acadsb	ENSMUSG00000030861
rattus_norvegicus	Acadsb	ENSRNOG00000020624
drosophila_melanogaster	CG3902	FBGN0036824
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), ACAD9 (ENSG00000177646), ACAD11 (ENSG00000240303)

Protein

Protein identifiers

Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial — P45954 (reviewed: P45954)

Alternative names: 2-methyl branched chain acyl-CoA dehydrogenase, 2-methylbutyryl-coenzyme A dehydrogenase

All UniProt accessions (2): A0A0S2Z3P9, P45954

UniProt curated annotations — full annotation on UniProt →

Function. Short and branched chain specific acyl-CoA dehydrogenase that catalyzes 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, acts specifically on short and branched chain acyl-CoA derivatives such as (S)-2-methylbutyryl-CoA as well as short straight chain acyl-CoAs such as butyryl-CoA (butanoyl-CoA). Plays an important role in the metabolism of L-isoleucine by catalyzing the dehydrogenation of 2-methylbutyryl-CoA, one of the steps of the L-isoleucine catabolic pathway. Can also act on valproyl-CoA, a metabolite of valproic acid, an antiepileptic drug.

Subunit / interactions. Homotetramer.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Ubiquitously expressed, with highest levels in heart, muscle and liver.

Disease relevance. Short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD) [MIM:610006] Autosomal recessive disorder and consists of a defect in catabolism of L-isoleucine which is characterized by an increase of 2-methylbutyrylglycine and 2-methylbutyrylcarnitine in blood and urine. Affected individuals have seizures and psychomotor delay as the main clinical features. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Competitively inhibited by valproyl-CoA.

Pathway. Lipid metabolism; mitochondrial fatty acid beta-oxidation. Amino-acid degradation; L-isoleucine degradation.

Similarity. Belongs to the acyl-CoA dehydrogenase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P45954-1	1	yes
P45954-2	2

RefSeq proteins (2): NP_001317103, NP_001600* (*=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), 9 shown:

• butanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-butenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:24004)
• hexanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-hexenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:43464)
• 2-methylbutanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-2-methylbut-2-enoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:43780)
• 2-methylpropanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = 2-methylpropenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:44180)
• 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)
• (2S)-2-methylbutanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-2-methylbut-2-enoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:48256)
• 2-methylhexanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = 2-methylhexenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:48272)
• (2R)-2-methylbutanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = ethylacryloyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:65296)
• valproyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-2-propylpent-2-enoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:65344)

UniProt features (63 total): helix 20, strand 11, binding site 10, modified residue 6, sequence variant 5, mutagenesis site 4, turn 3, transit peptide 1, chain 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2JIF	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P45954-F1	91.47	0.88

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): 414 (proton acceptor)

Ligand- & substrate-binding residues (10): 330; 387–391; 416–418 (in other chain); 174–183 (in other chain); 183; 207–209 (in other chain); 229; 283; 291–294; 319

Post-translational modifications (6): 70, 70, 183, 284, 284, 426

Mutagenesis-validated functional residues (4):

Position	Phenotype
137	decreased acyl-coa dehydrogenase activity.
138	increased acyl-coa dehydrogenase activity. no effect on substrate specificity.
210	increased acyl-coa dehydrogenase activity. changed substrate specificity.
416	increased acyl-coa dehydrogenase activity. no effect on substrate specificity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-70895	Branched-chain amino acid catabolism
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-1430728	Metabolism
R-HSA-392499	Metabolism of proteins
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 257 (showing top): MODULE_93, YAATNRNNNYNATT_UNKNOWN, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, SP3_Q3, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, LEE_LIVER_CANCER_CIPROFIBRATE_DN, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, PAX2_01, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, SMID_BREAST_CANCER_LUMINAL_B_UP

GO Biological Process (4): L-isoleucine catabolic process (GO:0006550), fatty acid metabolic process (GO:0006631), lipid metabolic process (GO:0006629), carboxylic acid catabolic process (GO:0046395)

GO Molecular Function (7): short-chain 2-methyl fatty acyl-CoA dehydrogenase activity (GO:0003853), acyl-CoA dehydrogenase activity (GO:0003995), short-chain fatty acyl-CoA dehydrogenase activity (GO:0016937), identical protein binding (GO:0042802), flavin adenine dinucleotide binding (GO:0050660), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-CH group of donors (GO:0016627)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Metabolism of proteins	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
branched-chain amino acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
primary metabolic process	1
carboxylic acid metabolic process	1
small molecule catabolic process	1
short-chain fatty acyl-CoA dehydrogenase activity	1
oxidoreductase activity, acting on the CH-CH group of donors, with a flavin as acceptor	1
acyl-CoA dehydrogenase activity	1
protein binding	1
nucleotide binding	1
anion binding	1
catalytic activity	1
oxidoreductase activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2122 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACADSB	HADHB	P55084	768
ACADSB	HADHA	P40939	694
ACADSB	ETHE1	O95571	689
ACADSB	ACAA1	P09110	685
ACADSB	ECHS1	P30084	668
ACADSB	ECHDC1	Q9NTX5	650
ACADSB	ALDH6A1	Q02252	637
ACADSB	HIBCH	Q6NVY1	597
ACADSB	EHHADH	Q08426	562
ACADSB	HADH	Q16836	562
ACADSB	ACAA2	P42765	544
ACADSB	BCKDHB	P21953	544
ACADSB	HSPE1	P61604	543
ACADSB	BCKDHA	P12694	521
ACADSB	ECI2	O75521	506

IntAct

46 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
ACADSB	PXDN	psi-mi:“MI:0915”(physical association)	0.400
ACADSB	GOLGA4	psi-mi:“MI:0915”(physical association)	0.400
THOC2		psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
MS4A4A	MON2	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
USP19		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
SLC16A11	ESYT2	psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
SAR1B	UBA6	psi-mi:“MI:0914”(association)	0.350
PCSK1	HS6ST1	psi-mi:“MI:0914”(association)	0.350
SNTG1	RNASEH1	psi-mi:“MI:0914”(association)	0.350
MFSD4A	UBXN8	psi-mi:“MI:0914”(association)	0.350
AURKB	VWA8	psi-mi:“MI:0914”(association)	0.350
CD80	RIMOC1	psi-mi:“MI:0914”(association)	0.350
GPR17	C1QTNF9B	psi-mi:“MI:0914”(association)	0.350
PIM1	IDH3B	psi-mi:“MI:0914”(association)	0.350
SLC18A2	MGST3	psi-mi:“MI:0914”(association)	0.350
UPK2	IFT56	psi-mi:“MI:0914”(association)	0.350
MFSD9	PGRMC1	psi-mi:“MI:0914”(association)	0.350
SLC35A3	STXBP3	psi-mi:“MI:0914”(association)	0.350
SLC38A10	XPOT	psi-mi:“MI:0914”(association)	0.350
SLC7A11	PSMD9	psi-mi:“MI:0914”(association)	0.350
SLCO4A1	RAB29	psi-mi:“MI:0914”(association)	0.350

BioGRID (91): ACADSB (Affinity Capture-MS), YTHDF1 (Affinity Capture-MS), ACADSB (Co-fractionation), ACADSB (Co-fractionation), ACTR1A (Co-fractionation), KDSR (Co-fractionation), ACADSB (Proximity Label-MS), ACADSB (Proximity Label-MS), ACADSB (Proximity Label-MS), ACADSB (Proximity Label-MS), ACADSB (Affinity Capture-MS), ACADSB (Affinity Capture-MS), PXDN (Affinity Capture-MS), ACADSB (Affinity Capture-MS), ACADSB (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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	21
Uncertain significance	151
Likely benign	68
Benign	70

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
150986	GRCh38/hg38 10q26.13(chr10:122143176-124358013)x1	Pathogenic
1527606	GRCh37/hg19 10q25.3-26.13(chr10:117019650-125217066)	Pathogenic
2153596	NM_001609.4(ACADSB):c.275C>G (p.Ser92Ter)	Pathogenic
2632051	NM_001609.4(ACADSB):c.1116C>A (p.Tyr372Ter)	Pathogenic
2828858	NM_001609.4(ACADSB):c.356del (p.Leu119fs)	Pathogenic
2828859	NM_001609.4(ACADSB):c.878dup (p.Gly293_Arg294insTer)	Pathogenic
2899530	NM_001609.4(ACADSB):c.1172del (p.Gly391fs)	Pathogenic
3682850	NM_001609.4(ACADSB):c.548G>A (p.Ser183Asn)	Pathogenic
4278338	NM_001609.4(ACADSB):c.1128+2T>G	Pathogenic
4806895	NM_001609.4(ACADSB):c.653T>C (p.Leu218Pro)	Pathogenic
4814191	NM_001609.4(ACADSB):c.454A>T (p.Lys152Ter)	Pathogenic
57088	GRCh38/hg38 10q26.11-26.13(chr10:119273012-123117390)x3	Pathogenic
583673	NC_000010.11:g.(?123034356)(123041379_?)del	Pathogenic
664690	NM_001609.4(ACADSB):c.1165A>G (p.Met389Val)	Pathogenic
9200	NM_001609.4(ACADSB):c.763C>T (p.Leu255Phe)	Pathogenic
1032758	NM_001609.4(ACADSB):c.1228+1G>A	Likely pathogenic
1066905	NM_001609.4(ACADSB):c.1128+1G>A	Likely pathogenic
1068211	NM_001609.4(ACADSB):c.1128+1_1128+3del	Likely pathogenic
1698867	NM_001609.4(ACADSB):c.824del (p.Ile275fs)	Likely pathogenic
2572604	NM_001609.4(ACADSB):c.746del (p.Pro249fs)	Likely pathogenic
2628744	NM_001609.4(ACADSB):c.1053C>A (p.Tyr351Ter)	Likely pathogenic
2786901	NM_001609.4(ACADSB):c.901-2A>G	Likely pathogenic
2991398	NM_001609.4(ACADSB):c.202+1G>C	Likely pathogenic
3075976	NM_001609.4(ACADSB):c.68dup (p.Leu23fs)	Likely pathogenic
3591135	NM_001609.4(ACADSB):c.18dup (p.Arg7fs)	Likely pathogenic
3591171	NM_001609.4(ACADSB):c.304-1G>T	Likely pathogenic
3591194	NM_001609.4(ACADSB):c.508A>T (p.Lys170Ter)	Likely pathogenic
3591201	NM_001609.4(ACADSB):c.510+1G>A	Likely pathogenic
3591226	NM_001609.4(ACADSB):c.681+1G>A	Likely pathogenic
3591236	NM_001609.4(ACADSB):c.992del	Likely pathogenic

SpliceAI

1740 predictions. Top by Δscore:

Variant	Effect	Δscore
10:123034343:AT:A	acceptor_gain	1.0000
10:123034344:T:G	acceptor_gain	1.0000
10:123034344:T:TA	acceptor_gain	1.0000
10:123034354:A:AG	acceptor_gain	1.0000
10:123034355:G:GC	acceptor_loss	1.0000
10:123034355:G:GG	acceptor_gain	1.0000
10:123034355:GC:G	acceptor_gain	1.0000
10:123034355:GCTAA:G	acceptor_gain	1.0000
10:123034513:CAGGT:C	donor_loss	1.0000
10:123034514:AGGTA:A	donor_loss	1.0000
10:123034515:GGTA:G	donor_loss	1.0000
10:123034516:G:GG	donor_gain	1.0000
10:123034516:GTAA:G	donor_loss	1.0000
10:123034517:T:A	donor_loss	1.0000
10:123037745:A:AG	acceptor_gain	1.0000
10:123037746:G:GG	acceptor_gain	1.0000
10:123037746:GTT:G	acceptor_gain	1.0000
10:123037746:GTTAA:G	acceptor_gain	1.0000
10:123037821:G:GG	donor_gain	1.0000
10:123037831:GAT:G	donor_gain	1.0000
10:123037845:G:GT	donor_gain	1.0000
10:123037845:GGG:G	donor_gain	1.0000
10:123037846:GGG:G	donor_gain	1.0000
10:123040461:TTTA:T	acceptor_loss	1.0000
10:123040463:TAGT:T	acceptor_loss	1.0000
10:123040464:A:AC	acceptor_loss	1.0000
10:123040464:A:AG	acceptor_gain	1.0000
10:123040464:AGTT:A	acceptor_gain	1.0000
10:123040465:G:A	acceptor_loss	1.0000
10:123040465:G:GG	acceptor_gain	1.0000

AlphaMissense

2803 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:123053094:T:A	W388R	0.987
10:123053094:T:C	W388R	0.987
10:123053085:T:C	C385R	0.986
10:123053146:G:C	R405P	0.986
10:123041215:A:C	S173R	0.985
10:123041217:T:A	S173R	0.985
10:123041217:T:G	S173R	0.985
10:123041223:C:G	C175W	0.984
10:123041323:A:C	S209R	0.983
10:123041325:C:A	S209R	0.983
10:123041325:C:G	S209R	0.983
10:123041221:T:C	C175R	0.979
10:123043068:T:C	F235S	0.979
10:123047232:T:G	C308W	0.979
10:123041317:T:A	W207R	0.978
10:123041317:T:C	W207R	0.978
10:123041313:G:C	K205N	0.977
10:123041313:G:T	K205N	0.977
10:123041245:A:C	S183R	0.974
10:123041247:T:A	S183R	0.974
10:123041247:T:G	S183R	0.974
10:123047230:T:C	C308R	0.973
10:123051166:G:C	A370P	0.973
10:123053739:G:C	A425P	0.973
10:123041273:C:A	A192D	0.972
10:123047216:G:A	G303E	0.971
10:123051068:C:A	A337D	0.971
10:123041306:G:A	G203E	0.970
10:123040547:G:C	A129P	0.969
10:123047215:G:A	G303R	0.968

dbSNP variants (sampled 300 via entrez): RS1000043964 (10:123046497 C>A), RS1000047771 (10:123056773 C>A,T), RS1000215168 (10:123017328 A>AT), RS1000318236 (10:123056305 A>G), RS1000328960 (10:123049795 A>G), RS1000365878 (10:123042958 A>G,T), RS1000381136 (10:123049631 G>A), RS1000446488 (10:123017735 T>A), RS1000589607 (10:123024022 C>A,G,T), RS1000643041 (10:123044852 A>G,T), RS1000707639 (10:123050845 C>G), RS1000749218 (10:123030822 C>T), RS1000843725 (10:123044806 G>C), RS1000871145 (10:123024734 A>G), RS1000931831 (10:123031299 C>A)

Disease associations

OMIM: gene MIM:600301 | disease phenotypes: MIM:610006

GenCC curated gene-disease

Disease	Classification	Inheritance
2-methylbutyryl-CoA dehydrogenase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
2-methylbutyryl-CoA dehydrogenase deficiency	Definitive	AR

Mondo (2): 2-methylbutyryl-CoA dehydrogenase deficiency (MONDO:0012392), microcephaly (MONDO:0001149)

Orphanet (1): 2-methylbutyryl-CoA dehydrogenase deficiency (Orphanet:79157)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000577	Exotropia
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001531	Failure to thrive in infancy
HP:0001943	Hypoglycemia
HP:0002045	Hypothermia
HP:0003593	Infantile onset
HP:0003700	Generalized amyotrophy
HP:0005949	Apneic episodes in infancy
HP:0011463	Childhood onset
HP:0033220	2-ethylhydracylic aciduria
HP:0035019	Elevated circulating C5 acylcarnitine concentration

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004493_5	Lower body strength	6.000000e-06
GCST007355_1	Antidepressant treatment resistance (> 2 drugs prescribed)	3.000000e-07
GCST007356_2	Antidepressant treatment resistance (number of drugs prescribed)	4.000000e-07
GCST007356_3	Antidepressant treatment resistance (number of drugs prescribed)	5.000000e-07
GCST010204_81	Low density lipoprotein cholesterol levels	7.000000e-20

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007999	lower body strength measurement
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C566487	2-Methylbutyryl-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

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, decreases expression, decreases methylation	4
bisphenol A	affects expression, increases expression, increases methylation	3
Valproic Acid	decreases expression, increases expression, increases methylation	3
entinostat	increases expression, affects cotreatment	2
Acetaminophen	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
chlortoluron	decreases expression	1
deoxynivalenol	decreases expression	1
trichostatin A	affects expression	1
osteum	affects cotreatment, affects reaction, decreases expression	1
perfluorooctanoic acid	increases expression	1
indirubin	decreases expression	1
potassium chromate(VI)	increases expression	1
polyhexamethyleneguanidine	affects expression	1
perfluoro-n-nonanoic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
belinostat	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
(+)-JQ1 compound	increases expression	1
bisphenol AF	increases expression	1

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8YJ	Ubigene HEK293 ACADSB KO	Transformed cell line	Female
CVCL_IM21	GM17477	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.