ACSF3

Chr 16AR

acyl-CoA synthetase family member 3

NCBI Gene: 197322 ENSG00000176715 UniProt: Q4G176 OMIM: 614245

This mitochondrial enzyme catalyzes the formation of CoA thioesters from malonate and methylmalonate, serving as the initial step in intramitochondrial fatty acid synthesis. Mutations cause combined malonic and methylmalonic aciduria, a metabolic disorder affecting fatty acid metabolism. The gene shows low constraint to loss-of-function variants and inheritance follows an autosomal recessive pattern.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

ARLOEUF 1.771 OMIM phenotype

Clinical Summary— ACSF3

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Gene-Disease Validity (ClinGen)

combined malonic and methylmalonic acidemia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

209 unique Pathogenic / Likely Pathogenic· 297 VUS of 1143 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — ACSF3

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

-1.30Z-score

OE missense 1.19 (1.10–1.29)

426 obs / 356.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.35 (1.02–1.77)

0≤0.351.4

Missense OE?1.19 (1.10–1.29)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 34 / 25.2Missense obs/exp: 426 / 356.9Syn Z: -2.81

ClinVar Variant Classifications

1143 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic50

Likely Pathogenic159

VUS297

Likely Benign515

Benign82

Conflicting24

Pathogenic

159

Likely Pathogenic

297

VUS

515

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	31	1	18	0	50
Likely Pathogenic	145	9	5	0	159
VUS	2	255	25	15	297
Likely Benign	0	12	159	344	515
Benign	0	3	66	13	82
Conflicting	—				24
Total	178	280	273	372	1,127

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

View in ClinVar →

73 pathogenic / likely-pathogenic (of 112) ClinVar copy-number / structural variants overlap ACSF3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →