ACSL4

Chr XXLD

acyl-CoA synthetase long chain family member 4

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

NCBI Gene: 2182ENSG00000068366UniProt: O60488OMIM: 300157

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]

OMIMResearchGenerating clinical summary…
LOFmechanismXLDLOEUF 0.311 OMIM phenotype
Clinical Summary— ACSL4
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Gene-Disease Validity (ClinGen)
non-syndromic X-linked intellectual disability · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.
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ClinVar Variants
13 unique Pathogenic / Likely Pathogenic· 119 VUS of 328 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?
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?
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?
LoF OE?0.12 (0.05–0.31)
0≤0.351.4
Missense OE?0.55 (0.48–0.63)
0≤0.61.4
Synonymous OE?0.99
0≤1.21.6
LoF obs/exp: 3 / 25.3Missense obs/exp: 143 / 260.7Syn Z: 0.07

ClinVar Variant Classifications

328 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5
Likely Pathogenic8
VUS119
Likely Benign30
Benign13
Conflicting9
5
Pathogenic
8
Likely Pathogenic
119
VUS
30
Likely Benign
13
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
1
0
0
5
Likely Pathogenic
5
3
0
0
8
VUS
13
102
2
2
119
Likely Benign
0
12
6
12
30
Benign
0
1
7
5
13
Conflicting
—9
Total221191519184

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

View in ClinVar →

80 pathogenic / likely-pathogenic (of 90) ClinVar copy-number / structural variants overlap ACSL4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

ACSL4 · protein map & ClinVar variants

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

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