ACSF3

Chr 16AR

acyl-CoA synthetase family member 3

NCBI Gene: 197322ENSG00000176715UniProt: Q4G176

This gene encodes a member of the acyl-CoA synthetase family of enzymes that activate fatty acids by catalyzing the formation of a thioester linkage between fatty acids and coenzyme A. The encoded protein is localized to mitochondria, has high specificity for malonate and methylmalonate and possesses malonyl-CoA synthetase activity. Mutations in this gene are a cause of combined malonic and methylmalonic aciduria. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Sep 2013]

Primary Disease Associations & Inheritance

Combined malonic and methylmalonic aciduriaMIM #614265
AR
1
Active trials
121
Pathogenic / LP
484
ClinVar variants
3
Pubs (1 yr)
-1.3
Missense Z
1.77
LOEUF
Clinical Summary— ACSF3
🧬
Gene-Disease Validity (ClinGen)
combined malonic and methylmalonic acidemia · 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
121 Pathogenic / Likely Pathogenic· 136 VUS of 484 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
📖
GeneReview available — ACSF3
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.77LOEUF
pLI 0.000
Z-score -1.62
OE 1.35 (1.02–1.77)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-1.30Z-score
OE missense 1.19 (1.10–1.29)
426 obs / 356.9 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.35 (1.02–1.77)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.19 (1.10–1.29)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.28
0≤1.21.6
LoF obs/exp: 34 / 25.2Missense obs/exp: 426 / 356.9Syn Z: -2.81

ClinVar Variant Classifications

484 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic48
Likely Pathogenic73
VUS136
Likely Benign221
Benign3
Conflicting3
48
Pathogenic
73
Likely Pathogenic
136
VUS
221
Likely Benign
3
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
0
36
0
48
Likely Pathogenic
47
3
23
0
73
VUS
0
109
16
11
136
Likely Benign
0
4
84
133
221
Benign
0
0
3
0
3
Conflicting
—3
Total59116162144484

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

View in ClinVar →

Protein Context — Lollipop Plot

ACSF3 · protein map & ClinVar variants

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

Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Dysregulated mitochondrial fission and neurodegeneration proteomic signature in ACSF3-deficient cells.
Alatibi K et al.·Biochim Biophys Acta Mol Cell Biol Lipids
2024
Combined Malonic and Methylmalonic Aciduria Due to ACSF3 Variants Results in Benign Clinical Course in Three Chinese Patients
Wang P et al.·Front Pediatr
2021Cohort
Genome-wide analysis of the acyl-coenzyme A synthetase family and their association with the formation of goat milk flavour
Zhang F et al.·Front Genet
2022
Altered Metabolic Flexibility in Inherited Metabolic Diseases of Mitochondrial Fatty Acid Metabolism
Tucci S et al.·Int J Mol Sci
2021
Combined Malonic and Methylmalonic Aciduria Diagnosed by Recurrent and Severe Infections Mimicking a Primary Immunodeficiency Disease: A Case Report
Lee JK et al.·J Korean Med Sci
2023Case report
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Value of genetic analysis for confirming inborn errors of metabolism detected through the Spanish neonatal screening program.
Navarrete R et al.·Eur J Hum Genet
2019
An ancient regulatory variant of ACSF3 influences the coevolution of increased human height and basal metabolic rate via metabolic homeostasis.
Zhang Y et al.·Cell Genom
2025
KBG syndrome: report and follow-up on three unrelated patients observed at different ages.
Serra G et al.·Ital J Pediatr
2025Cohort
Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort.
Levtova A et al.·J Inherit Metab Dis
2019Cohort
Biallelic ACSF3 variants with combined malonic and methylmalonic acidemia and associated developmental epileptic encephalopathy phenotype: A novel genotype-phenotype correlation.
Curry J et al.·Seizure
2025Case report
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