IVD

Summary

IVD (isovaleryl-CoA dehydrogenase, HGNC:6186) is a protein-coding gene on chromosome 15q15.1, encoding Isovaleryl-CoA dehydrogenase, mitochondrial (P26440). A mitochondrial matrix enzyme that catalyzes the third step in leucine catabolism, where isovaleryl-CoA (3-methylbutanoyl-CoA) is metabolized to 3-methylbut-2-enoyl-CoA.

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.

Source: NCBI Gene 3712 — RefSeq curated summary.

At a glance

• Gene–disease (curated): isovaleric acidemia (Definitive, ClinGen)
• GWAS associations: 11
• Clinical variants (ClinVar): 854 total — 51 pathogenic, 93 likely-pathogenic
• Phenotypes (HPO): 42
• MANE Select transcript: NM_002225

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6186
Approved symbol	IVD
Name	isovaleryl-CoA dehydrogenase
Location	15q15.1
Locus type	gene with protein product
Status	Approved
Aliases	ACAD2, IVDH
Ensembl gene	ENSG00000128928
Ensembl biotype	protein_coding
OMIM	607036
Entrez	3712

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 18 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000466756, ENST00000473112, ENST00000479013, ENST00000481262, ENST00000484250, ENST00000487418, ENST00000491554, ENST00000497252, ENST00000497816, ENST00000558610, ENST00000559575, ENST00000560660, ENST00000610693, ENST00000650656, ENST00000651168, ENST00000868496, ENST00000868497, ENST00000868498, ENST00000868499, ENST00000868500, ENST00000868501, ENST00000966716, ENST00000966717

RefSeq mRNA: 7 — MANE Select: NM_002225 NM_001159508, NM_001354597, NM_001354598, NM_001354599, NM_001354600, NM_001354601, NM_002225

CCDS: CCDS10057, CCDS53930

Canonical transcript exons

ENST00000487418 — 12 exons

Exon	Start	End
ENSE00000883873	40407636	40407725
ENSE00002565712	40418130	40421308
ENSE00003465298	40410628	40410797
ENSE00003487920	40411260	40411353
ENSE00003531218	40412991	40413087
ENSE00003566074	40414889	40414982
ENSE00003604465	40416290	40416362
ENSE00003636998	40415401	40415482
ENSE00003655751	40411555	40411691
ENSE00003656810	40405795	40405971
ENSE00003687018	40416078	40416182
ENSE00003694034	40407939	40407990

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 98.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.3507 / max 226.3828, expressed in 1756 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146105	37.2518	1753
146107	0.0849	25
146106	0.0140	3

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of thyroid gland	UBERON:0001119	98.89	gold quality
left lobe of thyroid gland	UBERON:0001120	98.66	gold quality
thyroid gland	UBERON:0002046	98.18	gold quality
right lobe of liver	UBERON:0001114	97.13	gold quality
right adrenal gland cortex	UBERON:0035827	96.89	gold quality
adenohypophysis	UBERON:0002196	96.86	gold quality
right adrenal gland	UBERON:0001233	96.81	gold quality
left adrenal gland	UBERON:0001234	96.53	gold quality
left adrenal gland cortex	UBERON:0035825	96.42	gold quality
pituitary gland	UBERON:0000007	96.28	gold quality
adrenal cortex	UBERON:0001235	96.10	gold quality
right ovary	UBERON:0002118	96.07	gold quality
left ovary	UBERON:0002119	95.91	gold quality
adrenal gland	UBERON:0002369	95.90	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.61	gold quality
rectum	UBERON:0001052	95.53	gold quality
right uterine tube	UBERON:0001302	95.48	gold quality
body of stomach	UBERON:0001161	95.34	gold quality
apex of heart	UBERON:0002098	95.30	gold quality
heart left ventricle	UBERON:0002084	95.05	gold quality
liver	UBERON:0002107	94.98	gold quality
right atrium auricular region	UBERON:0006631	94.90	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.88	gold quality
gall bladder	UBERON:0002110	94.75	gold quality
cerebellar hemisphere	UBERON:0002245	94.74	gold quality
cardiac ventricle	UBERON:0002082	94.70	gold quality
mucosa of stomach	UBERON:0001199	94.61	gold quality
cerebellar cortex	UBERON:0002129	94.54	gold quality
tibial nerve	UBERON:0001323	94.48	gold quality
endocervix	UBERON:0000458	94.33	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.43
E-MTAB-5061	yes	4.14
E-MTAB-7606	no	344.83

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

103 targeting IVD, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4320	99.75	65.80	793
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-24-3P	99.59	69.97	1934

Literature-anchored findings (GeneRIF, showing 10)

• Replacement of the catalytic glutamate in either short-chain acyl-CoA dehydrogenase (SCAD) or isovaleryl-CoA dehydrogenase (IVD)with glycine resulted in a several-fold reduction in affinity for substrate. (PMID:16376132)
• Mutations of isovaleryl-CoA dehydrogenase gene is associated with isovaleric acidemia (PMID:17576084)
• A child with isovaleric acidemia was subsequently found to harbour a known missense mutation (c.A1199G [p.Y371C]) and a novel 4-bp duplication (c.1148_1151dupGCTA [p.Y355X]) in the IVD gene. The former may be a founder mutation in the Chinese population. (PMID:20519759)
• All were homozygous for a single c.367 G > A (p.G123R) mutation. Despite the genetic homogeneity of this South African group, the clinical presentation varied, ranging from mental handicap and episodes of metabolic derangement to an asymptomatic state (PMID:22350545)
• A heterogeneous mutation spectrum in the IVD gene was identified in isovaleric acidemia patients in the United Arab Emirates. (PMID:22960500)
• study reports the first Saudi isovaleric acidemia patients from a consanguineous family with a novel transversion (p.G362V) and briefly discuss likely phenotype-genotype correlation of the disease in the Saudi population (PMID:23063737)
• kinetics and ligand binding of isovaleryl-CoA dehydrogenase (PMID:25450250)
• Our results have illustrated the heterogeneous mutation spectrum and clinical presentation of IVA in the Japanese patients (PMID:26018748)
• Nine novel isovaleryl-CoA dehydrogenase mutations have been found in a Spanish cohort with isovaleric acidemia. (PMID:27904153)
• A Case Report of a Novel Isovaleryl-CoA Dehydrogenase Gene Mutation in a Chinese Family with Isovaleric Acidemia. (PMID:37702673)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ivd	ENSDARG00000042853
mus_musculus	Ivd	ENSMUSG00000027332
rattus_norvegicus	Ivd	ENSRNOG00000009421
drosophila_melanogaster	CG6638	FBGN0035911
caenorhabditis_elegans		WBGENE00015326

Paralogs (14): ACADVL (ENSG00000072778), ACOX3 (ENSG00000087008), GCDH (ENSG00000105607), ACAD10 (ENSG00000111271), ACADL (ENSG00000115361), ACADM (ENSG00000117054), ACADS (ENSG00000122971), ACAD8 (ENSG00000151498), ACOXL (ENSG00000153093), ACOX1 (ENSG00000161533), ACOX2 (ENSG00000168306), ACAD9 (ENSG00000177646), ACADSB (ENSG00000196177), ACAD11 (ENSG00000240303)

Protein

Protein identifiers

Isovaleryl-CoA dehydrogenase, mitochondrial — P26440 (reviewed: P26440)

Alternative names: Butyryl-CoA dehydrogenase

All UniProt accessions (10): P26440, A0A087WVD3, A0A0A0MT83, A0A0S2Z4K7, H0YKV0, H0YLC3, H0YN10, H0YNA4, H0YNT5, H7C4G6

UniProt curated annotations — full annotation on UniProt →

Function. A mitochondrial matrix enzyme that catalyzes the third step in leucine catabolism, where isovaleryl-CoA (3-methylbutanoyl-CoA) is metabolized to 3-methylbut-2-enoyl-CoA. To a lesser extent, it also participates in the first step in fatty acid beta-oxidation, in which it catalyzes the proR-proR stereospecific alpha,beta-dehydrogenation of other saturated short-chain acyl-CoA thioesters such as pentanoyl-CoA, hexanoyl-CoA and butanoyl-CoA, using the electron transfer flavoprotein (ETF) as their physiologic electron acceptor.

Subunit / interactions. Homotetramer.

Subcellular location. Mitochondrion matrix.

Disease relevance. Isovaleric acidemia (IVA) [MIM:243500] A metabolic disorder characterized by retarded psychomotor development, a peculiar odor resembling sweaty feet, an aversion to dietary protein, and pernicious vomiting, leading to acidosis and coma. The acute neonatal form leads to massive metabolic acidosis from the first days of life and rapid death. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Amino-acid degradation; L-leucine degradation; (S)-3-hydroxy-3-methylglutaryl-CoA from 3-isovaleryl-CoA: step 1/3.

Similarity. Belongs to the acyl-CoA dehydrogenase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P26440-1	1	yes
P26440-2	2

RefSeq proteins (7): NP_001152980, NP_001341526, NP_001341527, NP_001341528, NP_001341529, NP_001341530, NP_002216* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006089	Acyl-CoA_DH_CS	Conserved_site
IPR006091	AcylCoA_DH/ox_M	Domain
IPR009075	AcylCo_DH/oxidase_C	Domain
IPR009100	AcylCoA_DH/oxidase_NM_dom_sf	Homologous_superfamily
IPR013786	AcylCoA_DH/ox_N	Domain
IPR034183	IVD	Family
IPR036250	AcylCo_DH-like_C	Homologous_superfamily
IPR037069	AcylCoA_DH/ox_N_sf	Homologous_superfamily
IPR046373	Acyl-CoA_Oxase/DH_mid-dom_sf	Homologous_superfamily

Pfam: PF00441, PF02770, PF02771

Enzyme classification (BRENDA):

• EC 1.3.8.4 — isovaleryl-CoA dehydrogenase (BRENDA: 14 organisms, 68 substrates, 28 inhibitors, 55 Km, 17 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ISOVALERYL-COA	0.001–0.9	36
(S)-2-METHYLBUTYRYL-COA	0.0019–0.0035	2
BUTYRYL-COA	0.025–0.0362	2
HEXANOYL-COA	0.02–0.0338	2
ISOBUTYRYL-COA	0.5–0.79	2
N-VALERYL-COA	0.0748–0.4	2
PHENAZINE METHOSULFATE	0.51–0.833	2
VALERYL-COA	0.0105–0.0167	2
ELECTRON TRANSFER PROTEIN	0.002	1
ELECTRON-TRANSFER FLAVOPROTEIN	0.0038	1
FAD	0.0004	1

Catalyzed reactions (Rhea), 5 shown:

• 3-methylbutanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = 3-methylbut-2-enoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:12276)
• butanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-butenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:24004)
• pentanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-pentenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:43456)
• hexanoyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = (2E)-hexenoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:43464)
• a short-chain 2,3-saturated fatty acyl-CoA + oxidized [electron-transfer flavoprotein] + H(+) = a short-chain (2E)-enoyl-CoA + reduced [electron-transfer flavoprotein] (RHEA:47196)

UniProt features (85 total): helix 21, sequence variant 19, binding site 11, strand 11, modified residue 10, mutagenesis site 4, turn 4, transit peptide 1, chain 1, active site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9JQ3	ELECTRON MICROSCOPY	2.45
1IVH	X-RAY DIFFRACTION	2.6
8SGR	ELECTRON MICROSCOPY	2.84
9JQ4	ELECTRON MICROSCOPY	2.91
9JQ5	ELECTRON MICROSCOPY	3.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P26440-F1	93.25	0.91

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 286 (proton acceptor)

Ligand- & substrate-binding residues (11): 323; 380–384; 407–408; 409–411; 165–174; 174; 198–200; 222–223; 277; 284–287; 312

Post-translational modifications (10): 58, 58, 67, 67, 78, 78, 241, 262, 262, 318

Mutagenesis-validated functional residues (4):

Position	Phenotype
286	residual isovaleryl-coa dehydrogenase activity.
286	loss of isovaleryl-coa dehydrogenase activity. does not affect isovaleryl-coa dehydrogenase activity; when associated wi
286	loss of isovaleryl-coa dehydrogenase activity.
407	does not affect isovaleryl-coa dehydrogenase activity; when associated with 286-d.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-70895	Branched-chain amino acid catabolism
R-HSA-9914355	Isovaleric acidemia
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-5668914	Diseases of metabolism
R-HSA-71291	Metabolism of amino acids and derivatives
R-HSA-9865118	Diseases of branched-chain amino acid catabolism

MSigDB gene sets: 300 (showing top): GOBP_LIPID_MODIFICATION, MODULE_93, GOBP_FATTY_ACID_CATABOLIC_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, YANG_BREAST_CANCER_ESR1_LASER_UP, PAL_PRMT5_TARGETS_UP, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, MODULE_45, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, GOBP_FATTY_ACID_BETA_OXIDATION_USING_ACYL_COA_DEHYDROGENASE, YOKOE_CANCER_TESTIS_ANTIGENS

GO Biological Process (6): L-leucine catabolic process (GO:0006552), branched-chain amino acid catabolic process (GO:0009083), fatty acid beta-oxidation using acyl-CoA dehydrogenase (GO:0033539), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631), carboxylic acid metabolic process (GO:0019752)

GO Molecular Function (8): 3-methylbutanoyl-CoA dehydrogenase activity (GO:0008470), identical protein binding (GO:0042802), flavin adenine dinucleotide binding (GO:0050660), acyl-CoA dehydrogenase activity (GO:0003995), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-CH group of donors (GO:0016627), short-chain fatty acyl-CoA dehydrogenase activity (GO:0016937)

GO Cellular Component (4): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Diseases of branched-chain amino acid catabolism	1
Disease	1
Metabolism	1
Diseases of metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
acyl-CoA dehydrogenase activity	2
mitochondrion	2
L-leucine metabolic process	1
branched-chain amino acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
amino acid catabolic process	1
branched-chain amino acid metabolic process	1
carboxylic acid catabolic process	1
fatty acid beta-oxidation	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
oxoacid metabolic process	1
short-chain fatty acyl-CoA dehydrogenase activity	1
protein binding	1
nucleotide binding	1
anion binding	1
oxidoreductase activity, acting on the CH-CH group of donors, with a flavin as acceptor	1
binding	1
catalytic activity	1
oxidoreductase activity	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

1936 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IVD	AUH	Q13825	644
IVD	BCKDHA	P12694	641
IVD	ETFDH	Q16134	617
IVD	MCCC2	Q9HCC0	594
IVD	ALDH4A1	P30038	572
IVD	PCCB	P05166	570
IVD	DBT	P11182	567
IVD	BCKDHB	P21953	561
IVD	DMGDH	Q9UI17	559
IVD	F5H5P2	F5H5P2	551
IVD	PCCA	P05165	544
IVD	HIBADH	P31937	538
IVD	MCCC1	Q96RQ3	528
IVD	ALDH6A1	Q02252	518
IVD	HMGCL	P35914	516

IntAct

51 interactions, top by confidence:

A	B	Type	Score
LYRM2	NDUFAB1	psi-mi:“MI:0914”(association)	0.730
IVD	ACTN3	psi-mi:“MI:0915”(physical association)	0.560
	IVD	psi-mi:“MI:0915”(physical association)	0.560
IVD	GPSM3	psi-mi:“MI:0915”(physical association)	0.560
KIR3DL2	METTL15	psi-mi:“MI:0914”(association)	0.530
WASHC3	WASH3P	psi-mi:“MI:0914”(association)	0.530
HMGCL	DBT	psi-mi:“MI:0914”(association)	0.530
IVD	H1-3	psi-mi:“MI:0915”(physical association)	0.400
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
PB2	SEC15L3	psi-mi:“MI:0914”(association)	0.350
IVD	ETFA	psi-mi:“MI:0914”(association)	0.350
STK11	DVL2	psi-mi:“MI:0914”(association)	0.350
IVD	ECI2	psi-mi:“MI:0914”(association)	0.350
COQ6	NDUFAB1	psi-mi:“MI:0914”(association)	0.350
IVD	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
ENG	IGKV2-28	psi-mi:“MI:0914”(association)	0.350
TEX101	NDUFA4	psi-mi:“MI:0914”(association)	0.350
STK11	HK1	psi-mi:“MI:0914”(association)	0.350
CEP135	MCRIP1	psi-mi:“MI:0914”(association)	0.350
CEP135	WWP2	psi-mi:“MI:0914”(association)	0.350
CEP135	WDR91	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
TMEM184A	NRDC	psi-mi:“MI:0914”(association)	0.350
NUDT13	ICAM1	psi-mi:“MI:0914”(association)	0.350
TRIM43	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (80): IVD (Affinity Capture-MS), IVD (Affinity Capture-MS), ETFA (Affinity Capture-Western), ETFB (Affinity Capture-Western), IVD (Affinity Capture-MS), PMPCB (Affinity Capture-MS), PMPCA (Affinity Capture-MS), ETFA (Affinity Capture-MS), IVD (Affinity Capture-MS), IVD (Affinity Capture-MS), PNMA1 (Two-hybrid), HMOX2 (Co-fractionation), PSEN1 (Co-fractionation), ECHS1 (Co-fractionation), PGD (Co-fractionation)

ESM2 similar proteins: A5A6I0, A8ALR4, A8WP91, A8XNF0, A9MQH5, B1XBG4, B4EY23, B7L4G2, B7UI85, B9U6P5, C3UVB0, C4ZPW5, F8GVD3, K4L7X3, P08503, P0A9U8, P0A9U9, P0A9V0, P11310, P12007, P15650, P26440, P28330, P41367, P45952, P45954, P51174, P70584, P79274, Q13PC1, Q22347, Q2LQN9, Q2LQP0, Q39QF4, Q39QF5, Q3SZB4, Q3SZI8, Q54RR5, Q5EAD4, Q5RBD5

Diamond homologs: A5A6I0, A8WP91, A8XNF0, B1WC61, B9U6P5, C3UVB0, D3JV03, F8GVD3, G3KIM8, H6LGM6, I6Y3V5, J7TF92, K4L7X3, O32176, O34421, O54143, P08503, P0A9U8, P0A9U9, P0A9V0, P11310, P12007, P15650, P15651, P16219, P26440, P28330, P41367, P45857, P45867, P45952, P45953, P45954, P46703, P48818, P49748, P50544, P51174, P52042, P63428

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

854 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	51
Likely pathogenic	93
Uncertain significance	207
Likely benign	356
Benign	46

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100060	NM_002225.5(IVD):c.932C>T (p.Ala311Val)	Pathogenic
1066603	NM_002225.5(IVD):c.1138+1G>A	Pathogenic
1072234	NC_000015.9:g.(?40699827)(40710472_?)del	Pathogenic
1351489	NM_002225.5(IVD):c.150del (p.Gln51fs)	Pathogenic
1393907	NM_002225.5(IVD):c.541G>T (p.Glu181Ter)	Pathogenic
1432608	NM_002225.5(IVD):c.242G>A (p.Trp81Ter)	Pathogenic
1452780	NM_002225.5(IVD):c.838_841del (p.Leu280fs)	Pathogenic
1453786	NM_002225.5(IVD):c.225del (p.Asn76fs)	Pathogenic
1459787	NC_000015.9:g.(?40698010)(40698182_?)del	Pathogenic
188720	NM_002225.5(IVD):c.457-2A>G	Pathogenic
188724	NM_002225.5(IVD):c.457-3_457-2delinsGG	Pathogenic
2190902	NM_002225.5(IVD):c.1204_1210del (p.Ile402fs)	Pathogenic
2424376	NC_000015.9:g.(?40698010)(40710472_?)del	Pathogenic
2498605	NM_002225.5(IVD):c.1083del (p.Leu362fs)	Pathogenic
2633394	NM_002225.5(IVD):c.340del (p.Glu114fs)	Pathogenic
2735812	NM_002225.5(IVD):c.275_285del (p.Ile92fs)	Pathogenic
2769189	NM_002225.5(IVD):c.235-1G>A	Pathogenic
2810468	NM_002225.5(IVD):c.259del (p.Leu87fs)	Pathogenic
2818385	NM_002225.5(IVD):c.723_724delinsTT (p.Lys242Ter)	Pathogenic
2818641	NM_002225.5(IVD):c.285del (p.Val96fs)	Pathogenic
2837791	NM_002225.5(IVD):c.144+1G>C	Pathogenic
2850099	NM_002225.5(IVD):c.1208_1230dup (p.Arg411delinsGlyLeuGlyProAlaArgTer)	Pathogenic
2863128	NM_002225.5(IVD):c.669dup (p.Ala224fs)	Pathogenic
3013988	NM_002225.5(IVD):c.985_986del (p.Met329fs)	Pathogenic
3243761	NC_000015.9:g.(?40710309)(40710462_?)del	Pathogenic
3243762	NC_000015.9:g.(?40698020)(40700209_?)del	Pathogenic
3337190	NM_002225.5(IVD):c.972del (p.Lys325fs)	Pathogenic
3562	NM_002225.5(IVD):c.125T>C (p.Leu42Pro)	Pathogenic
3565	NM_002225.5(IVD):c.145_234del (p.Leu49_Arg78del)	Pathogenic
370789	NM_002225.5(IVD):c.744dup (p.Asn249Ter)	Pathogenic

SpliceAI

2199 predictions. Top by Δscore:

Variant	Effect	Δscore
15:40405969:CAGG:C	donor_loss	1.0000
15:40405971:GGTGA:G	donor_loss	1.0000
15:40405972:G:GA	donor_loss	1.0000
15:40407632:TTA:T	acceptor_loss	1.0000
15:40407633:TAG:T	acceptor_loss	1.0000
15:40407634:A:AG	acceptor_gain	1.0000
15:40407634:A:C	acceptor_loss	1.0000
15:40407635:G:GG	acceptor_gain	1.0000
15:40407635:GCTTC:G	acceptor_gain	1.0000
15:40407722:GCGA:G	donor_gain	1.0000
15:40407724:GA:G	donor_gain	1.0000
15:40407726:G:GG	donor_gain	1.0000
15:40410609:T:A	acceptor_gain	1.0000
15:40410612:A:AG	acceptor_gain	1.0000
15:40410613:C:G	acceptor_gain	1.0000
15:40410617:A:AG	acceptor_gain	1.0000
15:40410618:C:G	acceptor_gain	1.0000
15:40410620:A:AG	acceptor_gain	1.0000
15:40410623:CACA:C	acceptor_loss	1.0000
15:40410624:ACAG:A	acceptor_loss	1.0000
15:40410627:GTTCA:G	acceptor_gain	1.0000
15:40410782:G:GT	donor_gain	1.0000
15:40410796:AGG:A	donor_loss	1.0000
15:40410797:GGTGA:G	donor_loss	1.0000
15:40411258:AGCT:A	acceptor_gain	1.0000
15:40411259:GCT:G	acceptor_gain	1.0000
15:40411259:GCTG:G	acceptor_gain	1.0000
15:40411688:GAAG:G	donor_gain	1.0000
15:40411692:G:GG	donor_gain	1.0000
15:40411692:GT:G	donor_loss	1.0000

AlphaMissense

2773 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:40411296:A:C	S168R	0.999
15:40411298:T:A	S168R	0.999
15:40411298:T:G	S168R	0.999
15:40411587:T:A	W198R	0.998
15:40411587:T:C	W198R	0.998
15:40413033:G:A	G247R	0.998
15:40413033:G:C	G247R	0.998
15:40413033:G:T	G247W	0.998
15:40413034:G:A	G247E	0.998
15:40415456:T:C	F315L	0.998
15:40415458:T:A	F315L	0.998
15:40415458:T:G	F315L	0.998
15:40418139:G:A	G386D	0.998
15:40418175:G:C	R398P	0.998
15:40418180:G:C	A400P	0.998
15:40418185:G:C	K401N	0.998
15:40418185:G:T	K401N	0.998
15:40418204:G:T	G408W	0.998
15:40418223:G:C	R414P	0.998
15:40414943:T:C	L283P	0.997
15:40414952:A:T	E286V	0.997
15:40415448:G:T	R312M	0.997
15:40415449:G:C	R312S	0.997
15:40415449:G:T	R312S	0.997
15:40416127:G:C	R340P	0.997
15:40416317:G:C	A368P	0.997
15:40416347:G:C	G378R	0.997
15:40418138:G:C	G386R	0.997
15:40418177:G:C	D399H	0.997
15:40410714:A:C	S128R	0.996

dbSNP variants (sampled 300 via entrez): RS1000020682 (15:40417023 A>T), RS1000188004 (15:40425167 T>C), RS1000283049 (15:40408949 C>A,G), RS1000463977 (15:40414705 T>C), RS1000563988 (15:40411200 G>A,T), RS1000581551 (15:40420748 A>G), RS1000694103 (15:40433123 A>G), RS1000791532 (15:40426672 T>C), RS1000913519 (15:40432850 C>T), RS1000915652 (15:40427823 T>C), RS1001116018 (15:40406881 G>T), RS1001161583 (15:40426443 C>A), RS1001253494 (15:40421401 C>T), RS1001290443 (15:40410305 C>T), RS1001329748 (15:40415948 G>C)

Disease associations

OMIM: gene MIM:607036 | disease phenotypes: MIM:243500

GenCC curated gene-disease

Disease	Classification	Inheritance
isovaleric acidemia	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
isovaleric acidemia	Definitive	AR

Mondo (2): isovaleric acidemia (MONDO:0009475), intellectual disability (MONDO:0001071)

Orphanet (2): Isovaleric acidemia (Orphanet:33), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001289	Confusion
HP:0001310	Dysmetria
HP:0001337	Tremor
HP:0001508	Failure to thrive
HP:0001735	Acute pancreatitis
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001876	Pancytopenia
HP:0001882	Decreased total leukocyte count
HP:0001942	Metabolic acidosis
HP:0001944	Dehydration
HP:0001987	Hyperammonemia
HP:0001993	Ketoacidosis
HP:0001994	Renal Fanconi syndrome
HP:0002013	Vomiting
HP:0002045	Hypothermia
HP:0002453	Abnormal globus pallidus morphology
HP:0002901	Hypocalcemia
HP:0002919	Ketonuria
HP:0003108	Hyperglycinuria
HP:0003128	Lactic acidosis

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001217_9	Metabolic traits	1.000000e-13
GCST005141_21	Cognitive ability (MTAG)	3.000000e-08
GCST005142_37	Cognitive ability	5.000000e-07
GCST005316_540	Intelligence (MTAG)	3.000000e-12
GCST007429_121	Lung function (FVC)	2.000000e-12
GCST007432_53	FEV1	3.000000e-11
GCST009758_9	Idiopathic pulmonary fibrosis	7.000000e-16
GCST010725_23	Malaria	2.000000e-06
GCST010725_38	Malaria	3.000000e-06
GCST010725_80	Malaria	7.000000e-06
GCST012020_478	Serum metabolite levels	3.000000e-19

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0004312	vital capacity
EFO:0004314	forced expiratory volume
EFO:0000768	idiopathic pulmonary fibrosis

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C538167	Acidemia, isovaleric (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression, increases methylation, affects expression, decreases expression	4
Benzo(a)pyrene	decreases methylation, affects methylation, decreases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
bisphenol A	increases expression, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, affects methylation	2
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
quinocetone	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Cadmium	increases expression, increases abundance	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Methapyrilene	increases methylation	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C9JH	SDQLCHi057-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

200 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)