ACAT1

Chr 11

acetyl-CoA acetyltransferase 1

Also known as: ACAT, MAT, T2, THIL

NCBI Gene: 38 ENSG00000075239 UniProt: P24752

The protein is a mitochondrial enzyme that catalyzes the reversible formation of acetoacetyl-CoA from two molecules of acetyl-CoA in isoleucine catabolism. Mutations cause 3-ketothiolase deficiency (alpha-methylacetoacetic aciduria), an autosomal recessive disorder characterized by urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and butanone. The pathogenic mechanism involves loss of enzyme function leading to accumulation of these metabolic intermediates.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a mitochondrially localized enzyme that catalyzes the reversible formation of acetoacetyl-CoA from two molecules of acetyl-CoA. Defects in this gene are associated with 3-ketothiolase deficiency, an inborn error of isoleucine catabolism characterized by urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and butanone. [provided by RefSeq, Feb 2009]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProt3-ketothiolase deficiency

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · beta-ketothiolase deficiency · AR · ClinGen 2018

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

103

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.05

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.05LOEUF

pLI 0.000

Z-score 1.39

OE 0.67 (0.44–1.05)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.91Z-score

OE missense 0.83 (0.74–0.94)

193 obs / 231.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.67 (0.44–1.05)

0≤0.351.4

Missense OE?0.83 (0.74–0.94)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 14 / 20.8Missense obs/exp: 193 / 231.8Syn Z: -0.65

Background carrier burden — how many people carry a rare variant somewhere in ACAT1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

533 rare PASS variants

Rare truncating (LoF)

1 in 1,400

123 rare PASS variants

Rare synonymous (reference)

1 in 240

198 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ACAT1. 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 150	1 in 1,400
South Asian	~43k	1 in 120	1 in 1,800
Remaining (unassigned)	~30k	1 in 140	1 in 2,500
European (Finnish)	~27k	1 in 500	1 in 2,300
Admixed American	~22k	1 in 130	1 in 1,100
African / African American	~21k	1 in 110	1 in 950
East Asian	~20k	1 in 150	1 in 930
Ashkenazi Jewish	~13k	1 in 170	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 180	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): 10 of 12 coding exons well covered in gnomAD exomes; exons 2, 10 marginal. Genomes: 11 of 12 (exon 10 below).? see exons ↓