ACSS1

Chr 20

acyl-CoA synthetase short chain family member 1

Also known as: ACAS2L, ACECS1, AceCS2L

NCBI Gene: 84532ENSG00000154930UniProt: Q9NUB1

This gene encodes a mitochondrial acetyl-CoA synthetase that catalyzes the conversion of acetate to acetyl-CoA for the tricarboxylic acid cycle and provides fuel for thermogenesis under ketogenic conditions when carbohydrate availability is insufficient. The gene is tolerant to loss-of-function variants (pLI near 0, LOEUF 0.759), and no established Mendelian diseases have been definitively linked to ACSS1 mutations in current clinical practice.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
19
Pubs (1 yr)
17
P/LP submissions
0%
P/LP missense
0.76
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— ACSS1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
17 unique Pathogenic / Likely Pathogenic· 73 VUS of 114 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.76LOEUF
pLI 0.000
Z-score 2.62
OE 0.50 (0.34–0.76)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
1.83Z-score
OE missense 0.75 (0.68–0.82)
313 obs / 418.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.50 (0.34–0.76)
0≤0.351.4
Missense OE0.75 (0.68–0.82)
0≤0.61.4
Synonymous OE1.06
0≤1.21.6
LoF obs/exp: 16 / 32.0Missense obs/exp: 313 / 418.6Syn Z: -0.62
DN
0.7228th %ile
GOF
0.6541th %ile
LOF
0.3164th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction 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

114 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14
Likely Pathogenic3
VUS73
Likely Benign5
Benign2
14
Pathogenic
3
Likely Pathogenic
73
VUS
5
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
14
0
14
Likely Pathogenic
0
0
3
0
3
VUS
0
68
5
0
73
Likely Benign
0
3
0
2
5
Benign
0
1
0
1
2
Total07222397

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

View in ClinVar →

Protein Context — Lollipop Plot

ACSS1 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Utilizing integrated bioinformatics and machine learning approaches to elucidate biomarkers linking sepsis to fatty acid metabolism-associated genes
Tan Y et al.·Sci Rep
2024
Identifying Acss1, Mtfp1 and Oxct1 as key regulators and promising biomarkers of sarcopenia in various models.
Cui H et al.·Gene
2023Functional
Acetyl-CoA synthetases ACSS1 and ACSS2 are 4-hydroxytamoxifen responsive factors that promote survival in tamoxifen treated and estrogen deprived cells
Calhoun S et al.·Transl Oncol
2022
Acetyl-CoA synthases are essential for maintaining histone acetylation under metabolic stress during zygotic genome activation in pigs.
Zhou W et al.·J Cell Physiol
2021
Mitochondrial ACSS1-K635 acetylation knock-in mice exhibit altered metabolism, cell senescence, and nonalcoholic fatty liver disease.
Xu G et al.·Sci Adv
2024
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
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