ACADSB

Chr 10

acyl-CoA dehydrogenase short/branched chain

Also known as: 2-MEBCAD, ACAD7, SBCAD

NCBI Gene: 36 ENSG00000196177 UniProt: P45954

Short/branched chain acyl-CoA dehydrogenase catalyzes the dehydrogenation of short and branched chain acyl-CoA derivatives, particularly (S)-2-methylbutyryl-CoA in the L-isoleucine catabolic pathway, and also acts on short straight chain acyl-CoAs and valproyl-CoA. Mutations cause 2-methylbutyrylglycinuria (also called short/branched chain acyl-CoA dehydrogenase deficiency), an autosomal recessive organic aciduria affecting amino acid metabolism. This gene is extremely intolerant to loss-of-function variants (pLI near 0), suggesting that complete loss of function may be incompatible with normal development.

ResearchSummary from RefSeq, UniProt

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. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.17

Clinical Summary— ACADSB

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Gene-Disease Validity (ClinGen)

2-methylbutyryl-CoA dehydrogenase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

43 unique Pathogenic / Likely Pathogenic· 149 VUS of 363 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.17LOEUF

pLI 0.000

Z-score 0.91

OE 0.80 (0.56–1.17)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.07Z-score

OE missense 1.01 (0.91–1.13)

230 obs / 227.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.80 (0.56–1.17)

0≤0.351.4

Missense OE?1.01 (0.91–1.13)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 19 / 23.8Missense obs/exp: 230 / 227.0Syn Z: 0.54

This gene — mechanism propensity

0.7132th %ile

GOF

0.7127th %ile

LOF

0.3161th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

363 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic31

VUS149

Likely Benign72

Benign71

Conflicting19

Pathogenic

Likely Pathogenic

149

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	4	1	0	12
Likely Pathogenic	24	5	2	0	31
VUS	1	71	74	3	149
Likely Benign	0	1	44	27	72
Benign	0	3	62	6	71
Conflicting	—				19
Total	32	84	183	36	354

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

52 pathogenic / likely-pathogenic (of 57) ClinVar copy-number / structural variants overlap ACADSB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →