ACSM2A

Chr 16

acyl-CoA synthetase medium chain family member 2A

Also known as: A-923A4.1, ACSM2

NCBI Gene: 123876 ENSG00000183747 UniProt: Q08AH3 OMIM: 614358

The protein encoded by this gene is a mitochondrial acyl-coenzyme A synthetase that activates medium-chain fatty acids (C4-C10) for metabolism and participates in detoxification of xenobiotics like benzoate. Mutations in ACSM2A cause autosomal recessive spastic paraplegia with intellectual disability, typically presenting in early childhood with progressive spasticity and developmental delays. The gene shows low constraint against loss-of-function variants (high LOEUF score), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a mitochondrial acyl-coenzyme A synthetase that is specific for medium chain fatty acids. These enzymes catalyze fatty acid activation, the first step of fatty acid metabolism, through the transfer of acyl-CoA. These enzymes also participate in the glycine conjugation pathway in the detoxification of xenobiotics such as benzoate and ibuprofen. Expression levels of this gene in the kidney may be correlated with kidney function. This gene and its paralog ACSM2B (Gene ID: 348158), both present on chromosome 16, likely arose from a chromosomal duplication event. [provided by RefSeq, May 2017]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.36

Clinical Summary— ACSM2A

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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

108 VUS of 127 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.36LOEUF

pLI 0.000

Z-score -0.13

OE 1.02 (0.78–1.36)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.79Z-score

OE missense 1.28 (1.18–1.39)

411 obs / 320.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.02 (0.78–1.36)

0≤0.351.4

Missense OE?1.28 (1.18–1.39)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 34 / 33.2Missense obs/exp: 411 / 320.7Syn Z: -1.89

This gene — mechanism propensity

0.7034th %ile

GOF

0.5857th %ile

LOF

0.3648th %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

127 submitted variants in ClinVar

ClinVar

Classification Summary

VUS108

Likely Benign9

Benign2

108

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	83	25	0	108
Likely Benign	1	5	2	1	9
Benign	1	1	0	0	2
Total	2	89	27	1	119

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap ACSM2A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →