ACADL

Chr 2

acyl-CoA dehydrogenase long chain

Also known as: ACAD4, LCAD

NCBI Gene: 33 ENSG00000115361 UniProt: P28330 OMIM: 609576

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.

OMIM ResearchSummary from RefSeq, UniProt, Mechanism

The protein encoded by this gene belongs to the acyl-CoA dehydrogenase family, which is a family of mitochondrial flavoenzymes involved in fatty acid and branched chain amino-acid metabolism. This protein is one of the four enzymes that catalyze the initial step of mitochondrial beta-oxidation of straight-chain fatty acid. Defects in this gene are the cause of long-chain acyl-CoA dehydrogenase (LCAD) deficiency, leading to nonketotic hypoglycemia. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.16

Clinical Summary— ACADL

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Gene-Disease Validity (ClinGen)

long chain acyl-CoA dehydrogenase deficiency · ARDisputed

Disputed — evidence questions this relationship

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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

65 VUS of 94 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.16LOEUF

pLI 0.000

Z-score 0.91

OE 0.81 (0.57–1.16)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.86Z-score

OE missense 0.84 (0.75–0.95)

196 obs / 232.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.81 (0.57–1.16)

0≤0.351.4

Missense OE?0.84 (0.75–0.95)

0≤0.61.4

Synonymous OE?0.75

0≤1.21.6

LoF obs/exp: 21 / 26.0Missense obs/exp: 196 / 232.7Syn Z: 1.79

This gene — mechanism propensity

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

94 submitted variants in ClinVar

ClinVar

Classification Summary

VUS65

Likely Benign15

Benign6

Conflicting3

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	3	61	1	0	65
Likely Benign	1	3	4	7	15
Benign	0	2	2	2	6
Conflicting	—				3
Total	4	66	7	9	89

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap ACADL — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →