ACSL4

Chr XXLD

acyl-CoA synthetase long chain family member 4

Also known as: ACS4, FACL4, LACS4, MRX63, MRX68, XLID63

NCBI Gene: 2182ENSG00000068366UniProt: O60488

The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation. This isozyme preferentially utilizes arachidonate as substrate. The absence of this enzyme may contribute to the cognitive disability or Alport syndrome. Alternative splicing of this gene generates multiple transcript variants. [provided by RefSeq, Jan 2016]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked 63MIM #300387
XLD
UniProtAMME complex
256
ClinVar variants
78
Pathogenic / LP
0.98
pLI score· haploinsufficient
0
Active trials
Clinical Summary— ACSL4
🧬
Gene-Disease Validity (ClinGen)
non-syndromic X-linked intellectual disability · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
78 Pathogenic / Likely Pathogenic· 128 VUS of 256 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.31LOEUF
pLI 0.981
Z-score 4.11
OE 0.12 (0.05–0.31)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
2.59Z-score
OE missense 0.55 (0.48–0.63)
143 obs / 260.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.12 (0.05–0.31)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.55 (0.48–0.63)
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.0.99
0≤1.21.6
LoF obs/exp: 3 / 25.3Missense obs/exp: 143 / 260.7Syn Z: 0.07

ClinVar Variant Classifications

256 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic69
Likely Pathogenic9
VUS128
Likely Benign31
Benign13
Conflicting6
69
Pathogenic
9
Likely Pathogenic
128
VUS
31
Likely Benign
13
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
67
0
69
Likely Pathogenic
4
2
3
0
9
VUS
11
101
14
2
128
Likely Benign
0
13
6
12
31
Benign
0
1
7
5
13
Conflicting
—6
Total171179719256

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

View in ClinVar →

Protein Context — Lollipop Plot

ACSL4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ACSL4-related intellectual developmental disorder

strong
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, X-linked 63

MIM #300387

Molecular basis of disorder known

X-linked dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Histone lactylation-regulated METTL3 promotes ferroptosis via m6A-modification on ACSL4 in sepsis-associated lung injury.
Wu D et al.·Redox Biol
2024
Protosappanin A Protects DOX-Induced Myocardial Injury and Cardiac Dysfunction by Targeting ACSL4/FTH1 Axis-Dependent Ferroptosis.
Cui J et al.·Adv Sci (Weinh)
2024
Ferroptosis-Mediated Inflammation Promotes Pulmonary Hypertension.
Kazmirczak F et al.·Circ Res
2024
Copper metabolism in cell death and autophagy.
Xue Q et al.·Autophagy
2023Review
eIF3f promotes tumour malignancy by remodelling fatty acid biosynthesis in hepatocellular carcinoma.
Zhou S et al.·J Hepatol
2025Functional
Integrative clinical and preclinical studies identify FerroTerminator1 as a potent therapeutic drug for MASH.
Tao L et al.·Cell Metab
2024
Recommendations for robust and reproducible research on ferroptosis.
Mishima E et al.·Nat Rev Mol Cell Biol
2025Review
FTO deficiency in older livers exacerbates ferroptosis during ischaemia/reperfusion injury by upregulating ACSL4 and TFRC.
Li R et al.·Nat Commun
2024
The role of ferroptosis and its mechanism in ischemic stroke.
Hu X et al.·Exp Neurol
2024Review
Mechanism of Ferroptosis and Its Role in Type 2 Diabetes Mellitus.
Sha W et al.·J Diabetes Res
2021Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Ultrasound targeted microbubble destruction-assisted mesoporous silicon delivery of dexamethasone inhibits ulcerative colitis by regulating the MTDH/ACSL4/NF-κB pathway.
Kang K et al.·Life Sci
2026
ACSL4-mediated astrocyte ferroptosis augments neuroinflammation and exacerbates NMOSD pathology.
Wen H et al.·Cell Death Differ
2026
Concentrated Angelica sinensis pills ameliorate ovarian insufficiency by promoting vascular remodeling via inhibiting CYP1B1/ACSL4-mediated ferroptosis.
Ling C et al.·Phytomedicine
2026Functional
DPP4 suppresses pancreatic cancer growth by enhancing ferroptosis sensitivity through stabilization of ACSL4.
Zhou X et al.·Cell Signal
2026
Prognostic Relevance of ACSL4 as a Serological Marker and Its Mediating Roles in Acute Supratentorial Intracerebral Hemorrhage: An Observational Analytical Study.
Li M et al.·Int J Gen Med
2026🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools