ACAT1

Chr 11AR

acetyl-CoA acetyltransferase 1

Also known as: ACAT, MAT, T2, THIL

NCBI Gene: 38ENSG00000075239UniProt: P35610

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]

Primary Disease Associations & Inheritance

Alpha-methylacetoacetic aciduriaMIM #203750
AR
0
Active trials
55
Pathogenic / LP
286
ClinVar variants
72
Pubs (1 yr)
0.9
Missense Z
1.05
LOEUF
Clinical Summary— ACAT1
🧬
Gene-Disease Validity (ClinGen)
beta-ketothiolase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
55 Pathogenic / Likely Pathogenic· 79 VUS of 286 total submissions

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 OE0.67 (0.44–1.05)
0≤0.351.4
Missense OE0.83 (0.74–0.94)
0≤0.61.4
Synonymous OE1.09
0≤1.21.6
LoF obs/exp: 14 / 20.8Missense obs/exp: 193 / 231.8Syn Z: -0.65
DN
DN
0.76top 25%
GOF
0.5954th %ile
LOF
0.3939th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

286 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35
Likely Pathogenic20
VUS79
Likely Benign145
Benign5
Conflicting2
35
Pathogenic
20
Likely Pathogenic
79
VUS
145
Likely Benign
5
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
3
19
1
35
Likely Pathogenic
13
4
3
0
20
VUS
2
66
10
1
79
Likely Benign
2
7
74
62
145
Benign
0
0
5
0
5
Conflicting
—2
Total298011164286

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

View in ClinVar →

ACAT1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ACAT1-related alpha-methylacetoacetic aciduria

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Exosomal circUBR5 drives metastasis and chemoresistance in gastric signet-ring cell carcinoma by reprogramming cholesterol metabolism through the hsa-miR-1208/CYP19A1 axis and ACAT1 upregulation.
Jiang Y et al.·Cancer Lett
2026
ACAT1 inhibitor Avasimibe suppresses osteoclastogenesis and alleviates ovariectomy-induced bone loss via CKB/PI3K-AKT signaling.
Zhao X et al.·Int Immunopharmacol
2026
TRIM8-dependent K63-ubiquitinated PGK1 promotes glycolysis and angiogenesis in gastric cancer via interaction with ACAT1.
Feng A et al.·Cell Death Dis
2025Open Access
Jianpi-Huogu Prescription Repairs Nontraumatic Osteonecrosis of the Femoral Head by Inhibiting NAMPT/STK11/HMGCR/ACAT1 Axis-Mediated Lipid Production.
Li T et al.·J Cell Mol Med
2025Open Access
TRIM59 suppresses mitochondrial-associated apoptosis to facilitate progression in papillary renal cell carcinoma via the ACAT1-cardiolipin pathway.
Weng H et al.·Cell Death Dis
2025Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients