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…

Primary Disease Associations & Inheritance

Mitchell syndromeMIM #618960

Peroxisomal acyl-CoA oxidase deficiencyMIM #264470

UniProtAdrenoleukodystrophy, pseudoneonatal

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

212

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.46

LOEUF

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in ACOX1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 88

720 rare PASS variants

Rare truncating (LoF)

1 in 2,300

104 rare PASS variants

Rare synonymous (reference)

1 in 130

332 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ACOX1. 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 80	1 in 3,300
South Asian	~43k	1 in 100	1 in 1,400
Remaining (unassigned)	~30k	1 in 77	≈ 1 in 7,500
European (Finnish)	~27k	1 in 630	1 in 3,700
Admixed American	~22k	1 in 89	1 in 2,000
African / African American	~21k	1 in 83	1 in 1,400
East Asian	~20k	1 in 84	1 in 1,800
Ashkenazi Jewish	~13k	1 in 310	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 100	none seen

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.

Exome coverage (gnomAD): All 14 coding exons well covered in gnomAD exomes and genomes.? see exons ↓