ACADM

Chr 1AR

acyl-CoA dehydrogenase medium chain

Also known as: ACAD1, MCAD, MCADH

NCBI Gene: 34 ENSG00000117054 UniProt: P11310 OMIM: 607008

The encoded protein functions as a mitochondrial acyl-CoA dehydrogenase that catalyzes the initial step of medium-chain fatty acid beta-oxidation (C4-C12). Biallelic mutations cause medium-chain acyl-CoA dehydrogenase deficiency, an autosomal recessive disorder characterized by hepatic dysfunction, fasting hypoglycemia, and encephalopathy that can result in infantile death. The pathogenic mechanism involves loss of enzymatic function leading to impaired fatty acid oxidation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes the medium-chain specific (C4 to C12 straight chain) acyl-Coenzyme A dehydrogenase. The homotetramer enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Defects in this gene cause medium-chain acyl-CoA dehydrogenase deficiency, a disease characterized by hepatic dysfunction, fasting hypoglycemia, and encephalopathy, which can result in infantile death. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.151 OMIM phenotype

Clinical Summary— ACADM

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Gene-Disease Validity (ClinGen)

medium chain acyl-CoA dehydrogenase deficiency · 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

393 unique Pathogenic / Likely Pathogenic· 264 VUS of 1097 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ACADM

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.15LOEUF

pLI 0.000

Z-score 0.95

OE 0.80 (0.57–1.15)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.54Z-score

OE missense 0.90 (0.80–1.01)

205 obs / 228.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.80 (0.57–1.15)

0≤0.351.4

Missense OE?0.90 (0.80–1.01)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 21 / 26.2Missense obs/exp: 205 / 228.1Syn Z: 0.16

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveACADM-related medium chain acyl-CoA dehydrogenase deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7326th %ile

GOF

0.6931th %ile

LOF

0.3453th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

1097 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic117

Likely Pathogenic276

VUS264

Likely Benign311

Benign50

Conflicting66

117

Pathogenic

276

Likely Pathogenic

264

VUS

311

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	76	22	19	0	117
Likely Pathogenic	140	125	10	1	276
VUS	7	204	40	13	264
Likely Benign	1	6	160	144	311
Benign	0	1	44	5	50
Conflicting	—				66
Total	224	358	273	163	1,084

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap ACADM — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →