ACAD9

Chr 3AR

acyl-CoA dehydrogenase family member 9

Also known as: MC1DN20, NPD002

NCBI Gene: 28976 ENSG00000177646 UniProt: Q9H845 OMIM: 611103

This protein functions as both a fatty acid oxidation enzyme that catalyzes the first step in mitochondrial beta-oxidation of long-chain fatty acids and as an assembly factor required for mitochondrial respiratory complex I biogenesis. Mutations cause mitochondrial complex I deficiency with autosomal recessive inheritance, affecting energy metabolism through dual impairment of fatty acid oxidation and oxidative phosphorylation. The gene shows low constraint to loss-of-function variants, consistent with recessive disease requiring biallelic mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the acyl-CoA dehydrogenase family. Members of this family of proteins localize to the mitochondria and catalyze the rate-limiting step in the beta-oxidation of fatty acyl-CoA. The encoded protein is specifically active toward palmitoyl-CoA and long-chain unsaturated substrates. Mutations in this gene cause acyl-CoA dehydrogenase family member type 9 deficiency. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2010]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Mitochondrial complex I deficiency, nuclear type 20MIM #611126

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · acyl-CoA dehydrogenase 9 deficiency · AR · ClinGen 2018

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.81

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.000

Z-score 2.37

OE 0.54 (0.37–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.18Z-score

OE missense 1.03 (0.94–1.12)

367 obs / 357.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.54 (0.37–0.81)

0≤0.351.4

Missense OE?1.03 (0.94–1.12)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 17 / 31.3Missense obs/exp: 367 / 357.5Syn Z: -0.17

Background carrier burden — how many people carry a rare variant somewhere in ACAD9?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 64

948 rare PASS variants

Rare truncating (LoF)

1 in 410

186 rare PASS variants

Rare synonymous (reference)

1 in 140

314 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ACAD9. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 69	1 in 580
South Asian	~43k	1 in 61	1 in 630
Remaining (unassigned)	~30k	1 in 59	1 in 210
European (Finnish)	~27k	1 in 200	1 in 1,900
Admixed American	~22k	1 in 51	1 in 290
African / African American	~21k	1 in 56	1 in 1,000
East Asian	~20k	1 in 79	1 in 1,300
Ashkenazi Jewish	~13k	1 in 150	1 in 1,200
Middle Eastern	~2,884	1 in 40	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 18 coding exons well covered in gnomAD exomes and genomes.? see exons ↓