ACAA2

Chr 18

acetyl-CoA acyltransferase 2

Also known as: DSAEC, T1

NCBI Gene: 10449 ENSG00000167315 UniProt: P42765 OMIM: 604770

The encoded protein catalyzes the final step of mitochondrial fatty acid beta-oxidation, breaking down medium- to long-chain fatty acids into acetyl-CoA for energy production. Mutations cause autosomal recessive 3-methylglutaconicaciduria with early-onset neurodegeneration, developmental delay, and metabolic dysfunction affecting the central nervous system and energy metabolism. This gene is highly intolerant to loss-of-function variants, indicating its critical role in cellular energy production.

OMIM ResearchSummary from RefSeq, UniProt

The encoded protein catalyzes the last step of the mitochondrial fatty acid beta-oxidation spiral. Unlike most mitochondrial matrix proteins, it contains a non-cleavable amino-terminal targeting signal. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.31

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.31LOEUF

pLI 0.000

Z-score 0.56

OE 0.86 (0.58–1.31)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.27Z-score

OE missense 1.05 (0.94–1.18)

220 obs / 209.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.86 (0.58–1.31)

0≤0.351.4

Missense OE?1.05 (0.94–1.18)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 16 / 18.6Missense obs/exp: 220 / 209.0Syn Z: 0.90

Background carrier burden — how many people carry a rare variant somewhere in ACAA2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

500 rare PASS variants

Rare truncating (LoF)

1 in 1,100

97 rare PASS variants

Rare synonymous (reference)

1 in 150

154 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ACAA2. 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 160	1 in 1,200
South Asian	~43k	1 in 130	1 in 1,300
Remaining (unassigned)	~30k	1 in 110	1 in 1,200
European (Finnish)	~27k	1 in 240	1 in 4,400
Admixed American	~22k	1 in 110	1 in 830
African / African American	~21k	1 in 77	1 in 2,200
East Asian	~20k	1 in 170	1 in 930
Ashkenazi Jewish	~13k	1 in 300	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 84	≈ 1 in 2,900

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): 8 of 10 coding exons well covered in gnomAD exomes; exons 1, 8 marginal. Genomes: all 10.? see exons ↓