IVD

Chr 15AR

isovaleryl-CoA dehydrogenase

Also known as: ACAD2, IVDH

NCBI Gene: 3712 ENSG00000128928 UniProt: P26440 OMIM: 607036

Isovaleryl-CoA dehydrogenase catalyzes the third step in leucine catabolism within the mitochondrial matrix. Mutations cause isovaleric acidemia, an autosomal recessive disorder characterized by accumulation of toxic isovaleric acid that damages the central nervous system. The pathogenic mechanism involves loss of enzyme function leading to substrate accumulation and metabolic toxicity.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Isovaleryl-CoA dehydrogenase (IVD) is a mitochondrial matrix enzyme that catalyzes the third step in leucine catabolism. The genetic deficiency of IVD results in an accumulation of isovaleric acid, which is toxic to the central nervous system and leads to isovaleric acidemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Isovaleric acidemiaMIM #243500

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · isovaleric acidemia · AR · ClinGen 2019

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

710

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.35

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — IVD

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?

1.35LOEUF

pLI 0.000

Z-score 0.24

OE 0.95 (0.68–1.35)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.35Z-score

OE missense 0.94 (0.84–1.04)

231 obs / 246.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.95 (0.68–1.35)

0≤0.351.4

Missense OE?0.94 (0.84–1.04)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 22 / 23.3Missense obs/exp: 231 / 246.4Syn Z: 0.22

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 63

736 rare PASS variants

Rare truncating (LoF)

1 in 1,000

132 rare PASS variants

Rare synonymous (reference)

1 in 160

264 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for IVD. 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 100	1 in 1,200
South Asian	~43k	1 in 65	1 in 600
Remaining (unassigned)	~30k	1 in 48	1 in 910
European (Finnish)	~27k	1 in 110	1 in 2,100
Admixed American	~22k	1 in 74	1 in 490
African / African American	~21k	1 in 58	1 in 320
East Asian	~20k	1 in 81	1 in 370
Ashkenazi Jewish	~13k	1 in 270	none seen
Middle Eastern	~2,884	1 in 75	1 in 370

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 12 coding exons well covered in gnomAD exomes and genomes.? see exons ↓