IVD

Chr 15

isovaleryl-CoA dehydrogenase

Also known as: ACAD2, IVDH

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]

Primary Disease Associations & Inheritance

UniProtIsovaleric acidemia
487
ClinVar variants
97
Pathogenic / LP
0.00
pLI score
8
Active trials
Clinical SummaryIVD
🧬
Gene-Disease Validity (ClinGen)
isovaleric acidemia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
97 Pathogenic / Likely Pathogenic· 119 VUS of 487 total submissions
💊
Clinical Trials
8 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.35LOEUF
pLI 0.000
Z-score 0.24
OE 0.95 (0.681.35)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.35Z-score
OE missense 0.94 (0.841.04)
231 obs / 246.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.95 (0.681.35)
00.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.841.04)
00.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
01.21.6
LoF obs/exp: 22 / 23.3Missense obs/exp: 231 / 246.4Syn Z: 0.22

ClinVar Variant Classifications

487 submitted variants in ClinVar

Classification Summary

Pathogenic31
Likely Pathogenic66
VUS119
Likely Benign246
Benign19
Conflicting6
31
Pathogenic
66
Likely Pathogenic
119
VUS
246
Likely Benign
19
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
18
0
13
0
31
Likely Pathogenic
31
23
12
0
66
VUS
0
110
9
0
119
Likely Benign
2
6
113
125
246
Benign
2
3
14
0
19
Conflicting
6
Total53142161125487

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

View in ClinVar →

Protein Context — Lollipop Plot

IVD · protein map & ClinVar variants

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

Gene2Phenotype Curations

IVD-related isovaleric acidemia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

No OMIM entries found.

📖
GeneReview available — IVD
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

T-Cell Lymphoproliferative Disorder

Pivotal, Clinical Study for the Accuracy Evaluation of the IdentiClone Dx TRG Assay

NOT YET RECRUITING
NCT06876571Invivoscribe, Inc.Started 2025-06-02
IdentiClone Dx TRG Assay
Resistance Bacterial

Molecular Diagnostics of Bacterial Infections and Antibiotic Resistance in Blood Samples and Rectal Swabs Using Advanced NGS Sequencing Methods

RECRUITING
NCT06322173Phase NAIRCCS Sacro Cuore Don Calabria di NegrarStarted 2022-06-28
NGS Analysis
COVID-19

Phase 2a Trial to Evaluate Safety and Immunogenicity of COVID-19 Vaccine Strategies in HIV-infected/Uninfected Adults.

ACTIVE NOT RECRUITING
NCT05515042Phase PHASE2The Aurum Institute NPCStarted 2022-07-25
Ad26.COV2.S (VAC31518, JNJ-78436735) Vaccine, SARS-CoV-2 rS (CovovaxTM), BNT162b2 (Pfizer)
Solid Tumor, AdultColorectal CancerNon-Small Cell Lung

A Study to Evaluate the Safety and Efficacy of A2B395, an Allogeneic Logic-gated CAR T, in Participants With Solid Tumors That Express EGFR and Have Lost HLA-A*02 Expression

RECRUITING
NCT06682793Phase PHASE1, PHASE2A2 Biotherapeutics Inc.Started 2025-05-22
A2B395xT CDx with HLA-LOH assay
Carcinoma, Non-small Cell Lung Cancer (NSCLC)

Next Generation Sequencing Method for the Detection of EGFR Gene Mutations in the Plasma of Patients With Lung Cancer

ACTIVE NOT RECRUITING
NCT06595498Phase NAIstituto Oncologico Veneto IRCCSStarted 2024-07-01
Plasma- SeqSensei™ Solid Cancer IVD Kit (Sysmex)cobas® EGFR Mutation Test v2 (Roche)
Solid Tumor, AdultColorectal CancerNSCLC

A Study to Evaluate the Safety and Efficacy of Mesothelin-Targeting Logic-gated CAR T, in Participants With Solid Tumors That Express MSLN and Have Lost HLA-A*02 Expression

RECRUITING
NCT06051695Phase PHASE1, PHASE2A2 Biotherapeutics Inc.Started 2024-04-03
A2B694A2B543xT CDx with HLA-LOH Assay
Breast Cancer

Precision Oncology Clinical Diagnostic Study In Primary and Metastatic Breast Cancer (PRISM)

RECRUITING
NCT07425002Phase NACancer Trials IrelandStarted 2025-11-11
TSO500 Assay
Metastatic Colorectal Cancer (mCRC)

DHF-20-1839-2: Clinical Performance Study Protocol for Therascreen® KRAS RGQ PCR Kit

RECRUITING
NCT06645236Phase NAQIAGEN Gaithersburg, IncStarted 2023-12-22
therascreen® KRAS RGQ PCR Kit