ACADL

Chr 2

acyl-CoA dehydrogenase long chain

Also known as: ACAD4, LCAD

The protein catalyzes the initial step of mitochondrial beta-oxidation of straight-chain fatty acids as one of four acyl-CoA dehydrogenases involved in fatty acid metabolism. Mutations cause long-chain acyl-CoA dehydrogenase (LCAD) deficiency, which presents with nonketotic hypoglycemia due to impaired fatty acid oxidation. The condition follows autosomal recessive inheritance with a dominant negative mechanism of pathogenicity.

OMIMResearchSummary from RefSeq, UniProt, Mechanism
MultiplemechanismLOEUF 1.16
Clinical SummaryACADL
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Gene-Disease Validity (ClinGen)
long chain acyl-CoA dehydrogenase deficiency · ARDisputed

Disputed — evidence questions this relationship

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
1.16LOEUF
pLI 0.000
Z-score 0.91
OE 0.81 (0.571.16)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.86Z-score
OE missense 0.84 (0.750.95)
196 obs / 232.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.81 (0.571.16)
00.351.4
Missense OE0.84 (0.750.95)
00.61.4
Synonymous OE0.75
01.21.6
LoF obs/exp: 21 / 26.0Missense obs/exp: 196 / 232.7Syn Z: 1.79
DN
0.7327th %ile
GOF
0.6932th %ile
LOF
0.3260th %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

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

ACADL · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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