ACOX3

Chr 4

acyl-CoA oxidase 3, pristanoyl

ENSG00000087008 UniProt: O15254 OMIM: 603402

The protein oxidizes CoA-esters of 2-methyl-branched fatty acids in peroxisomes as part of branched-chain fatty acid metabolism. Mutations cause autosomal recessive bile acid synthesis defect with epilepsy and intellectual disability, typically presenting in infancy or early childhood. The gene shows extremely low constraint to loss-of-function variants (pLI near zero), consistent with recessive inheritance where heterozygous carriers are unaffected.

OMIM ResearchSummary from RefSeq, UniProt

Involved in peroxisomal beta-oxidation of branched-chain fatty acids (BCFAs). Catalyzes the initial and rate-limiting dehydrogenation step that removes two hydrogen molecules and introduces a trans double bond between the alpha and beta carbons of the acyl CoA molecules while generating hydrogen peroxide as a by-product (PubMed:29287774). Metabolizes multi-methyl-branched fatty acyl-CoA esters such as (2S)-pristanoyl-CoA, displaying redundancy with ACOX3 (PubMed:29287774). Can oxidize straight-chain mono- and dicarboxylyl fatty acyl-CoAs with lower efficiency (By similarity) (PubMed:29287774)

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.06

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.06LOEUF

pLI 0.000

Z-score 1.25

OE 0.78 (0.57–1.06)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.44Z-score

OE missense 1.06 (0.98–1.14)

469 obs / 442.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.78 (0.57–1.06)

0≤0.351.4

Missense OE?1.06 (0.98–1.14)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 28 / 36.1Missense obs/exp: 469 / 442.7Syn Z: -0.94

Background carrier burden — how many people carry a rare variant somewhere in ACOX3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 46

1,020 rare PASS variants

Rare truncating (LoF)

1 in 520

153 rare PASS variants

Rare synonymous (reference)

1 in 67

408 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ACOX3. 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 65	1 in 770
South Asian	~43k	1 in 45	1 in 470
Remaining (unassigned)	~30k	1 in 45	1 in 470
European (Finnish)	~27k	1 in 160	1 in 780
Admixed American	~22k	1 in 34	1 in 860
African / African American	~21k	1 in 41	1 in 780
East Asian	~20k	1 in 53	1 in 230
Ashkenazi Jewish	~13k	1 in 320	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 40	1 in 480

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 17 coding exons well covered in gnomAD exomes and genomes.? see exons ↓