ACSL4

Chr XXLD

acyl-CoA synthetase long chain family member 4

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

NCBI Gene: 2182 ENSG00000068366 UniProt: O60488 OMIM: 300157

The ACSL4 protein converts long-chain fatty acids (particularly arachidonate) to acyl-CoA esters for lipid biosynthesis and fatty acid degradation, and plays a role in insulin secretion and ferroptosis regulation. Mutations cause X-linked intellectual disability and may contribute to Alport syndrome with sensorineural hearing loss. This gene shows high constraint against loss-of-function variants, indicating that complete loss of protein function is likely deleterious.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked 63MIM #300387

XLD

UniProtAMME complex

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · non-syndromic X-linked intellectual disability · XL · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.31

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

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

Background carrier burden — how many people carry a rare variant somewhere in ACSL4?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 240

389 rare PASS variants

Rare truncating (LoF)

1 in 12,000

21 rare PASS variants

Rare synonymous (reference)

1 in 290

216 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ACSL4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 240	1 in 14,000
South Asian	~36k	1 in 190	≈ 1 in 18,000
Remaining (unassigned)	~31k	1 in 240	none seen
European (Finnish)	~27k	1 in 1,300	≈ 1 in 26,000
Admixed American	~23k	1 in 230	none seen
African / African American	~21k	1 in 210	≈ 1 in 6,500
East Asian	~20k	1 in 290	none seen
Ashkenazi Jewish	~13k	1 in 480	≈ 1 in 13,000
Middle Eastern	~2,758	1 in 200	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.