ACOX1

Chr 17ADAR

acyl-CoA oxidase 1

Also known as: ACOX, AOX, MITCH, PALMCOX, SCOX

NCBI Gene: 51 ENSG00000161533 UniProt: Q15067 OMIM: 609751

The protein catalyzes the first step of peroxisomal fatty acid beta-oxidation, converting acyl-CoAs to 2-trans-enoyl-CoAs while producing hydrogen peroxide. Mutations cause peroxisomal acyl-CoA oxidase deficiency and Mitchell syndrome through both autosomal recessive loss-of-function and autosomal dominant gain-of-function mechanisms, leading to accumulation of very long chain fatty acids. The phenotype resembles pseudoneonatal adrenoleukodystrophy with neurological deterioration and white matter abnormalities.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is the first enzyme of the fatty acid beta-oxidation pathway, which catalyzes the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs. It donates electrons directly to molecular oxygen, thereby producing hydrogen peroxide. Defects in this gene result in pseudoneonatal adrenoleukodystrophy, a disease that is characterized by accumulation of very long chain fatty acids. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.462 OMIM phenotypes

Clinical Summary— ACOX1

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Gene-Disease Validity (ClinGen)

peroxisomal acyl-CoA oxidase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

93 unique Pathogenic / Likely Pathogenic· 352 VUS of 949 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.46LOEUF

pLI 0.062

Z-score 3.97

OE 0.26 (0.16–0.46)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.98Z-score

OE missense 0.71 (0.64–0.79)

258 obs / 364.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.16–0.46)

0≤0.351.4

Missense OE?0.71 (0.64–0.79)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 9 / 34.0Missense obs/exp: 258 / 364.5Syn Z: 0.22

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveACOX1-related adrenoleukodystrophy pseudoneonatalLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7327th %ile

GOF

0.71top 25%

LOF

0.2189th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

GOFHowever, treatment of flies and primary Schwann cells with an antioxidant suppressed the p.N237S-induced neurodegeneration. In summary, both loss and gain of ACOX1 lead to glial and neuronal loss, but different mechanisms are at play and require different treatments.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 32169171 ↗

ClinVar Variant Classifications

949 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44

Likely Pathogenic49

VUS352

Likely Benign410

Benign53

Conflicting26

Pathogenic

Likely Pathogenic

352

VUS

410

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	30	4	10	0	44
Likely Pathogenic	42	4	3	0	49
VUS	1	231	113	7	352
Likely Benign	1	3	162	244	410
Benign	0	2	48	3	53
Conflicting	—				26
Total	74	244	336	254	934

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap ACOX1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →