ACSM3

Chr 16

acyl-CoA synthetase medium chain family member 3

Also known as: SA, SAH

NCBI Gene: 6296 ENSG00000005187 UniProt: Q53FZ2 OMIM: 145505

ACSM3 encodes a mitochondrial enzyme that catalyzes the activation of medium-chain fatty acids by CoA, representing the first step in fatty acid metabolism with particular preference for isobutyrate and other 2-6 carbon fatty acids. The gene is not constrained against loss-of-function variants and currently has no established Mendelian disease associations in pediatric neurology. While implicated in IgA glomerulonephritis and as a biomarker for ulcerative colitis, pathogenic variants causing neurological phenotypes have not been reported.

OMIM ResearchSummary from RefSeq, UniProt

Enables medium-chain fatty acid-CoA ligase activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid biosynthetic process. Located in mitochondrion. Implicated in IgA glomerulonephritis. Biomarker of ulcerative colitis. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.05

Clinical Summary— ACSM3

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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

8 unique Pathogenic / Likely Pathogenic· 164 VUS of 214 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.05LOEUF

pLI 0.000

Z-score 1.30

OE 0.76 (0.56–1.05)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.46Z-score

OE missense 0.93 (0.84–1.02)

290 obs / 312.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.76 (0.56–1.05)

0≤0.351.4

Missense OE?0.93 (0.84–1.02)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 26 / 34.2Missense obs/exp: 290 / 312.7Syn Z: 1.14

This gene — mechanism propensity

0.76top 25%

GOF

0.5661th %ile

LOF

0.3551th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

214 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic1

VUS164

Likely Benign14

Benign1

Conflicting1

Pathogenic

Likely Pathogenic

164

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	1	0	0	7
Likely Pathogenic	0	1	0	0	1
VUS	1	163	0	0	164
Likely Benign	0	9	0	5	14
Benign	0	0	1	0	1
Conflicting	—				1
Total	7	174	1	5	188

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap ACSM3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →