ACSM3

Chr 16

acyl-CoA synthetase medium chain family member 3

Also known as: SA, SAH

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.

OMIMResearchSummary from RefSeq, UniProt
DNmechanismLOEUF 1.05
Clinical SummaryACSM3
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
21 unique Pathogenic / Likely Pathogenic· 80 VUS of 134 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
1.05LOEUF
pLI 0.000
Z-score 1.30
OE 0.76 (0.561.05)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.46Z-score
OE missense 0.93 (0.841.02)
290 obs / 312.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.76 (0.561.05)
00.351.4
Missense OE0.93 (0.841.02)
00.61.4
Synonymous OE0.86
01.21.6
LoF obs/exp: 26 / 34.2Missense obs/exp: 290 / 312.7Syn Z: 1.14
DN
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

134 submitted variants in ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic1
VUS80
Likely Benign5
Benign1
Conflicting1
20
Pathogenic
1
Likely Pathogenic
80
VUS
5
Likely Benign
1
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
1
14
0
20
Likely Pathogenic
0
1
0
0
1
VUS
1
73
6
0
80
Likely Benign
0
3
0
2
5
Benign
0
0
1
0
1
Conflicting
1
Total678212108

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

View in ClinVar →

Protein Context — Lollipop Plot

ACSM3 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
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