ACAD8

Chr 11AR

acyl-CoA dehydrogenase family member 8

Also known as: ACAD-8, ARC42, IBDH

NCBI Gene: 27034 ENSG00000151498 UniProt: Q9UKU7 OMIM: 604773

The protein is isobutyryl-CoA dehydrogenase, a mitochondrial enzyme that catalyzes the conversion of 2-methylpropanoyl-CoA to (2E)-2-methylpropenoyl-CoA in the valine catabolic pathway. Mutations cause isobutyryl-CoA dehydrogenase deficiency, inherited in an autosomal recessive pattern. The gene shows low constraint against loss-of-function variants (LOEUF 1.27), consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes 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. The encoded protein is a mitochondrial enzyme that functions in catabolism of the branched-chain amino acid valine. Defects in this gene are the cause of isobutyryl-CoA dehydrogenase deficiency.[provided by RefSeq, Nov 2009]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Isobutyryl-CoA dehydrogenase deficiencyMIM #611283

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · isobutyryl-CoA dehydrogenase deficiency · AR · ClinGen 2019

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.27

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.27LOEUF

pLI 0.000

Z-score 0.51

OE 0.89 (0.64–1.27)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.22Z-score

OE missense 0.96 (0.86–1.07)

221 obs / 230.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.89 (0.64–1.27)

0≤0.351.4

Missense OE?0.96 (0.86–1.07)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 22 / 24.7Missense obs/exp: 221 / 230.5Syn Z: -1.95

Background carrier burden — how many people carry a rare variant somewhere in ACAD8?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

530 rare PASS variants

Rare truncating (LoF)

1 in 1,100

101 rare PASS variants

Rare synonymous (reference)

1 in 230

211 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ACAD8. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 150	1 in 1,100
South Asian	~43k	1 in 130	1 in 1,200
Remaining (unassigned)	~30k	1 in 140	1 in 1,300
European (Finnish)	~27k	1 in 490	1 in 3,000
Admixed American	~22k	1 in 130	1 in 680
African / African American	~21k	1 in 96	1 in 740
East Asian	~20k	1 in 93	1 in 570
Ashkenazi Jewish	~13k	1 in 540	none seen
Middle Eastern	~2,884	1 in 120	≈ 1 in 960

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.