HIBCH

Summary

HIBCH (3-hydroxyisobutyryl-CoA hydrolase, HGNC:4908) is a protein-coding gene on chromosome 2q32.2, encoding 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (Q6NVY1). Hydrolyzes 3-hydroxyisobutyryl-CoA (HIBYL-CoA), a saline catabolite.

This gene encodes the enzyme responsible for hydrolysis of both HIBYL-CoA and beta-hydroxypropionyl-CoA. Mutations in this gene have been associated with 3-hyroxyisobutyryl-CoA hydrolase deficiency. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 26275 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 289 total — 10 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 43
• Druggable target: yes
• MANE Select transcript: NM_014362

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4908
Approved symbol	HIBCH
Name	3-hydroxyisobutyryl-CoA hydrolase
Location	2q32.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000198130
Ensembl biotype	protein_coding
OMIM	610690
Entrez	26275

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 13 protein_coding, 5 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000359678, ENST00000392332, ENST00000392333, ENST00000399855, ENST00000409820, ENST00000409934, ENST00000410045, ENST00000414928, ENST00000416732, ENST00000485992, ENST00000486981, ENST00000489147, ENST00000489269, ENST00000495792, ENST00000870406, ENST00000870407, ENST00000870408, ENST00000870409, ENST00000870410, ENST00000955587

RefSeq mRNA: 2 — MANE Select: NM_014362 NM_014362, NM_198047

CCDS: CCDS2304, CCDS46475

Canonical transcript exons

ENST00000359678 — 14 exons

Exon	Start	End
ENSE00000964738	190294546	190294630
ENSE00000964739	190290405	190290485
ENSE00001225460	190296813	190296953
ENSE00001419164	190310754	190310796
ENSE00001597377	190244887	190244968
ENSE00001853401	190319716	190319826
ENSE00001875591	190203920	190205232
ENSE00002150091	190287586	190287638
ENSE00003502769	190252162	190252307
ENSE00003518131	190246154	190246212
ENSE00003531237	190249640	190249726
ENSE00003540127	190212956	190213075
ENSE00003623315	190261156	190261234
ENSE00003784350	190208880	190208913

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.0423 / max 227.7270, expressed in 1773 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32888	8.1370	1662
32889	5.6868	1554
32890	2.0878	1186
32887	0.0705	20
32885	0.0426	11
32886	0.0175	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nephron tubule	UBERON:0001231	98.33	gold quality
renal medulla	UBERON:0000362	98.15	gold quality
adrenal tissue	UBERON:0018303	97.04	gold quality
esophagus squamous epithelium	UBERON:0006920	96.96	gold quality
right adrenal gland cortex	UBERON:0035827	96.62	gold quality
right adrenal gland	UBERON:0001233	96.38	gold quality
jejunum	UBERON:0002115	96.15	gold quality
jejunal mucosa	UBERON:0000399	96.09	gold quality
corpus callosum	UBERON:0002336	96.05	gold quality
squamous epithelium	UBERON:0006914	96.03	gold quality
left adrenal gland	UBERON:0001234	95.95	gold quality
kidney epithelium	UBERON:0004819	95.85	gold quality
adrenal cortex	UBERON:0001235	95.81	gold quality
right lobe of liver	UBERON:0001114	95.75	gold quality
mucosa of transverse colon	UBERON:0004991	95.74	gold quality
adrenal gland	UBERON:0002369	95.73	gold quality
choroid plexus epithelium	UBERON:0003911	95.67	gold quality
kidney	UBERON:0002113	95.65	gold quality
adult mammalian kidney	UBERON:0000082	95.62	gold quality
cervix squamous epithelium	UBERON:0006922	95.61	gold quality
epithelium of esophagus	UBERON:0001976	95.48	gold quality
right uterine tube	UBERON:0001302	95.44	gold quality
left adrenal gland cortex	UBERON:0035825	95.43	gold quality
ventricular zone	UBERON:0003053	95.34	gold quality
liver	UBERON:0002107	95.27	gold quality
body of tongue	UBERON:0011876	95.20	gold quality
duodenum	UBERON:0002114	94.92	gold quality
parietal pleura	UBERON:0002400	94.88	gold quality
epithelium of nasopharynx	UBERON:0001951	94.82	gold quality
gingival epithelium	UBERON:0001949	94.68	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	2234.91
E-CURD-10	yes	149.70
E-MTAB-10290	no	52.03
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting HIBCH, 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-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-3144-3P	98.15	67.34	677
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-12116	97.94	68.91	595
HSA-MIR-5189-3P	97.52	66.33	487
HSA-MIR-5579-3P	97.00	68.81	1111
HSA-MIR-875-5P	96.74	66.48	579
HSA-MIR-193A-5P	95.70	65.33	613

Literature-anchored findings (GeneRIF, showing 8)

• Molecular analysis in both patients uncovered mutations in the HIBCH gene, including one missense mutation in a conserved part of the protein and two mutations affecting splicing. (PMID:17160907)
• findings demonstrated a novel homozygous pathogenic missense mutation c.950G <A; p.Gly317Glu in the HIBCH gene, which segregated with infantile-onset neurodegeneration within a Pakistani family; HIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome (PMID:24299452)
• Polymorphism in HIBCH is associated with HIBCH deficiency. (PMID:27132595)
• Novel (founder) mutation in HIBCH that causes a mild phenotype, allowing survival into adulthood. (PMID:27400804)
• A genetic epidemiological study in British adults and older adults shows a high heritability of the combined indicator of vitamin B12 status (cB12) and connects B12 status with utilization of mitochondrial substrates and energy metabolism. (PMID:31203192)
• The present study identified HIBCH as a critical enzyme of valine catabolism in colorectal cancer progression. (PMID:31409769)
• Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene. (PMID:32677093)
• Two genetic variants in the HIBCH and FTCDNL1 genes are associated with susceptibility to developmental dysplasia of the hips among the Han Chinese population of Southwest China. (PMID:39113043)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hibch	ENSDARG00000054867
mus_musculus	Hibch	ENSMUSG00000041426
rattus_norvegicus	Hibch	ENSRNOG00000028557
drosophila_melanogaster	Hibch	FBGN0038326
caenorhabditis_elegans		WBGENE00017301

Paralogs (13): ECHDC1 (ENSG00000093144), ECH1 (ENSG00000104823), ECHDC2 (ENSG00000121310), ECHS1 (ENSG00000127884), CDY2B (ENSG00000129873), ECHDC3 (ENSG00000134463), AUH (ENSG00000148090), CDYL (ENSG00000153046), CDYL2 (ENSG00000166446), ECI1 (ENSG00000167969), CDY1 (ENSG00000172288), CDY1B (ENSG00000172352), CDY2A (ENSG00000182415)

Protein

Protein identifiers

3-hydroxyisobutyryl-CoA hydrolase, mitochondrial — Q6NVY1 (reviewed: Q6NVY1)

Alternative names: 3-hydroxyisobutyryl-coenzyme A hydrolase

All UniProt accessions (8): A0A140VJL0, B8ZZZ0, B9A058, Q6NVY1, F8W8A6, H7BYI7, H7C126, H7C1A5

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolyzes 3-hydroxyisobutyryl-CoA (HIBYL-CoA), a saline catabolite. Has high activity toward isobutyryl-CoA. Could be an isobutyryl-CoA dehydrogenase that functions in valine catabolism. Also hydrolyzes 3-hydroxypropanoyl-CoA.

Subcellular location. Mitochondrion.

Tissue specificity. Highly expressed in liver and kidney, also detected in heart, muscle and brain (at protein level). Not detected in lung.

Disease relevance. 3-hydroxyisobutryl-CoA hydrolase deficiency (HIBCHD) [MIM:250620] An autosomal recessive inborn error of valine metabolism. It causes severely delayed psychomotor development, neurodegeneration, increased lactic acid, and brain lesions in the basal ganglia. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Amino-acid degradation; L-valine degradation.

Similarity. Belongs to the enoyl-CoA hydratase/isomerase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6NVY1-1	1	yes
Q6NVY1-2	2

RefSeq proteins (2): NP_055177, NP_932164 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029045	ClpP/crotonase-like_dom_sf	Homologous_superfamily
IPR032259	HIBYL-CoA-H	Family
IPR045004	ECH_dom	Domain

Pfam: PF16113

Enzyme classification (BRENDA):

• EC 3.1.2.4 — 3-hydroxyisobutyryl-CoA hydrolase (BRENDA: 10 organisms, 24 substrates, 17 inhibitors, 5 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3-HYDROXYPROPIONYL-COA	0.025	2
(S)-3-HYDROXY-2-METHYLPROPANOYL-COA	0.006	1
3-HYDROXY-2-METHYLPROPANOYL-COA	0.006	1
CINNAMOYL-COA	0.0029	1
3-HYDROXYISOBUTYRYL-COA	—	0

Catalyzed reactions (Rhea), 1 shown:

• 3-hydroxy-2-methylpropanoyl-CoA + H2O = 3-hydroxy-2-methylpropanoate + CoA + H(+) (RHEA:20888)

UniProt features (65 total): helix 22, modified residue 17, strand 10, sequence conflict 5, binding site 4, sequence variant 2, turn 2, transit peptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3BPT	X-RAY DIFFRACTION	1.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6NVY1-F1	93.57	0.88

Functional residue map

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

Ligand- & substrate-binding residues (4): 121; 146; 169; 177

Post-translational modifications (17): 221, 221, 234, 257, 297, 297, 301, 353, 353, 356, 360, 365, 377, 55, 55, 92, 92

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-70895	Branched-chain amino acid catabolism
R-HSA-9916722	3-hydroxyisobutyryl-CoA hydrolase deficiency

MSigDB gene sets: 236 (showing top): GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, SCHLOSSER_SERUM_RESPONSE_DN, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS, TIEN_INTESTINE_PROBIOTICS_24HR_UP, FLECHNER_BIOPSY_KIDNEY_TRANSPLANT_REJECTED_VS_OK_DN, GOBP_AMINO_ACID_CATABOLIC_PROCESS, BURTON_ADIPOGENESIS_6

GO Biological Process (2): L-valine catabolic process (GO:0006574), branched-chain amino acid catabolic process (GO:0009083)

GO Molecular Function (2): 3-hydroxyisobutyryl-CoA hydrolase activity (GO:0003860), hydrolase activity (GO:0016787)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-2 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
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
short-chain fatty acyl-CoA hydrolase activity	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2344 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HIBCH	HIBADH	P31937	687
HIBCH	ALDH6A1	Q02252	667
HIBCH	ACADSB	P45954	597
HIBCH	AKAP19	P0C876	534
HIBCH	BCKDHB	P21953	518
HIBCH	ACADVL	P49748	517
HIBCH	NEMP2	A6NFY4	507
HIBCH	ALDH2	P05091	506
HIBCH	VAT1L	Q9HCJ6	492
HIBCH	ACAD8	Q9UKU7	491
HIBCH	IVD	P26440	485
HIBCH	ADHFE1	Q8IWW8	482
HIBCH	DLD	P09622	478
HIBCH	PCCB	P05166	471
HIBCH	BCAT2	O15382	466

IntAct

37 interactions, top by confidence:

A	B	Type	Score
ETFRF1	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
SOX2	PDLIM1	psi-mi:“MI:0914”(association)	0.530
GATC	NME4	psi-mi:“MI:0914”(association)	0.530
ACAD9	PPL	psi-mi:“MI:0914”(association)	0.530
CYP1A1	SNX3	psi-mi:“MI:0914”(association)	0.530
ARRB1	SAG	psi-mi:“MI:0914”(association)	0.530
GRB2	HIBCH	psi-mi:“MI:0915”(physical association)	0.400
HIBCH	FLCN	psi-mi:“MI:0915”(physical association)	0.400
LRRK2		psi-mi:“MI:0914”(association)	0.350
H2AX	ANXA6	psi-mi:“MI:0914”(association)	0.350
GTF2E2	STX7	psi-mi:“MI:0914”(association)	0.350
HOXC5	PDLIM1	psi-mi:“MI:0914”(association)	0.350
CENPM	DNM1L	psi-mi:“MI:0914”(association)	0.350
RPL35A	SMCHD1	psi-mi:“MI:0914”(association)	0.350
NAP1L2	CEP290	psi-mi:“MI:0914”(association)	0.350
OXLD1	PRORP	psi-mi:“MI:0914”(association)	0.350
GSX1	YKT6	psi-mi:“MI:0914”(association)	0.350
USP47	LAMTOR5	psi-mi:“MI:0914”(association)	0.350
POP4	CHMP2A	psi-mi:“MI:0914”(association)	0.350
TMEM184A	NRDC	psi-mi:“MI:0914”(association)	0.350
DDX54	SYNCRIP	psi-mi:“MI:0914”(association)	0.350
SCRT2	RECQL	psi-mi:“MI:0914”(association)	0.350
HIBCH	ACADVL	psi-mi:“MI:0914”(association)	0.350
PRR19	SERPINB8	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
CIART	UQCRQ	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350
NPPB	ACOT7	psi-mi:“MI:0914”(association)	0.350

BioGRID (86): ACADVL (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), MKRN2 (Affinity Capture-MS), HIBCH (Affinity Capture-MS), ACOT9 (Co-fractionation), ALDH6A1 (Co-fractionation), CAB39 (Co-fractionation), CLIC1 (Co-fractionation), CLIC4 (Co-fractionation), CLIC5 (Co-fractionation), HIBCH (Co-fractionation), HIBCH (Co-fractionation), HIBCH (Co-fractionation), HIBCH (Co-fractionation), HIBCH (Co-fractionation)

ESM2 similar proteins: A2VDC2, A5A6K3, D4AAT7, O35952, P00937, P34949, P40939, Q01415, Q08B22, Q09669, Q1PEY5, Q1ZXF1, Q28C91, Q28FR6, Q29554, Q2HJ73, Q2TAA5, Q3KRD0, Q3TZM9, Q42942, Q55GS6, Q561R9, Q58EB4, Q5EAD2, Q5F4K8, Q5HZQ8, Q5R6J8, Q5R7Z6, Q5XF59, Q5XIE6, Q5ZJ60, Q61753, Q64428, Q68FH4, Q68FX1, Q6NMB0, Q6NVY1, Q6PI48, Q84MD8, Q8BIP0

Diamond homologs: A2VDC2, A3QFP3, A4YI89, A5WH99, A8ALR7, A9JS71, A9MYJ5, B0TL21, B1IRE0, B1LFW9, B4EY26, B4T6J5, B4TIG9, B4TWR3, B5BL54, B5F749, B5FHG4, B5R1Q9, B5RGA4, C0Q4L2, F9XMX6, J4KLY0, O07137, O07533, O34893, O53561, O74802, P07896, P0ABU0, P0ABU1, P14604, P24162, P28817, P30084, P31551, P34559, P52046, P55100, P59395, P64017

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	25
Uncertain significance	91
Likely benign	86
Benign	33

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1144	NM_014362.4(HIBCH):c.220-9T>G	Pathogenic
1146	NM_014362.4(HIBCH):c.79-3C>G	Pathogenic
1938463	NM_014362.4(HIBCH):c.469C>T (p.Arg157Ter)	Pathogenic
208532	NM_014362.4(HIBCH):c.1033G>A (p.Gly345Ser)	Pathogenic
2979318	NM_014362.4(HIBCH):c.1000C>T (p.Gln334Ter)	Pathogenic
4537294	NC_000002.11:g.(?191068645)(191184553_?)del	Pathogenic
520645	NM_014362.4(HIBCH):c.595G>T (p.Gly199Ter)	Pathogenic
689764	NM_014362.4(HIBCH):c.517+1G>A	Pathogenic
972925	NM_014362.4(HIBCH):c.835G>T (p.Glu279Ter)	Pathogenic
973483	NM_014362.4(HIBCH):c.763C>T (p.Arg255Ter)	Pathogenic
1324532	NM_014362.4(HIBCH):c.439-1G>A	Likely pathogenic
1332820	NM_014362.4(HIBCH):c.777T>A (p.Phe259Leu)	Likely pathogenic
1492266	NM_014362.4(HIBCH):c.891+1G>A	Likely pathogenic
1522611	NM_014362.4(HIBCH):c.385+2T>A	Likely pathogenic
1804879	NM_014362.4(HIBCH):c.860A>G (p.Asp287Gly)	Likely pathogenic
187864	NM_014362.4(HIBCH):c.950G>A (p.Gly317Glu)	Likely pathogenic
190268	NM_014362.4(HIBCH):c.196C>T (p.Arg66Trp)	Likely pathogenic
208531	NM_014362.4(HIBCH):c.129dup (p.Gly44fs)	Likely pathogenic
2088137	NM_014362.4(HIBCH):c.664-2A>G	Likely pathogenic
217316	NM_014362.4(HIBCH):c.1128dup (p.Lys377Ter)	Likely pathogenic
2440721	NM_014362.4(HIBCH):c.556C>T (p.Arg186Ter)	Likely pathogenic
2446035	NM_014362.4(HIBCH):c.458A>G (p.His153Arg)	Likely pathogenic
2671599	Single allele	Likely pathogenic
2690621	NM_014362.4(HIBCH):c.760_761delinsAT (p.Asp254Ile)	Likely pathogenic
3776776	NM_014362.4(HIBCH):c.12_35del (p.Glu5_Arg12del)	Likely pathogenic
3776777	NM_014362.4(HIBCH):c.536G>A (p.Gly179Asp)	Likely pathogenic
3776797	NM_014362.4(HIBCH):c.488G>A (p.Cys163Tyr)	Likely pathogenic
3891323	NM_014362.4(HIBCH):c.494_495del (p.Phe165fs)	Likely pathogenic
424194	NM_014362.4(HIBCH):c.1117AAT[1] (p.Asn374del)	Likely pathogenic
4270728	NM_014362.3(HIBCH):c.1014_1015delAG	Likely pathogenic

SpliceAI

4158 predictions. Top by Δscore:

Variant	Effect	Δscore
2:190205233:C:CC	acceptor_gain	1.0000
2:190212950:TCTTA:T	donor_loss	1.0000
2:190212951:CTTA:C	donor_loss	1.0000
2:190212952:TTA:T	donor_loss	1.0000
2:190212953:TA:T	donor_loss	1.0000
2:190212954:A:AA	donor_loss	1.0000
2:190244966:CAA:C	acceptor_gain	1.0000
2:190244969:C:CC	acceptor_gain	1.0000
2:190246208:TTAGA:T	acceptor_gain	1.0000
2:190246211:GA:G	acceptor_gain	1.0000
2:190246213:C:CC	acceptor_gain	1.0000
2:190249727:C:CC	acceptor_gain	1.0000
2:190287578:CTACT:C	donor_loss	1.0000
2:190287579:TACTT:T	donor_loss	1.0000
2:190287580:ACTTA:A	donor_loss	1.0000
2:190287581:CT:C	donor_loss	1.0000
2:190287582:TT:T	donor_loss	1.0000
2:190287583:TA:T	donor_loss	1.0000
2:190287584:A:AC	donor_gain	1.0000
2:190287584:AC:A	donor_gain	1.0000
2:190287584:ACC:A	donor_gain	1.0000
2:190287584:ACCC:A	donor_gain	1.0000
2:190287585:C:CC	donor_gain	1.0000
2:190287585:CC:C	donor_gain	1.0000
2:190287585:CCC:C	donor_gain	1.0000
2:190287585:CCCC:C	donor_gain	1.0000
2:190287585:CCCCA:C	donor_gain	1.0000
2:190287638:CCTGA:C	acceptor_loss	1.0000
2:190287639:C:CA	acceptor_loss	1.0000
2:190287639:C:CC	acceptor_gain	1.0000

AlphaMissense

2545 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:190205203:A:G	W359R	0.996
2:190205203:A:T	W359R	0.996
2:190205201:C:A	W359C	0.994
2:190205201:C:G	W359C	0.994
2:190212981:T:A	E329V	0.993
2:190252307:C:T	G173E	0.993
2:190208883:C:G	A348P	0.991
2:190261166:T:A	E169D	0.991
2:190261166:T:G	E169D	0.991
2:190287617:A:T	V136D	0.989
2:190294565:A:C	C95W	0.989
2:190252238:G:T	A196E	0.988
2:190261176:G:T	A166D	0.988
2:190205202:C:G	W359S	0.987
2:190208892:C:G	G345R	0.987
2:190261167:T:A	E169V	0.987
2:190261177:C:G	A166P	0.987
2:190294567:A:G	C95R	0.987
2:190287602:C:A	G141V	0.986
2:190208891:C:T	G345D	0.984
2:190261170:G:T	P168Q	0.984
2:190294566:C:T	C95Y	0.984
2:190212968:A:C	S333R	0.983
2:190212968:A:T	S333R	0.983
2:190212970:T:G	S333R	0.983
2:190212982:C:T	E329K	0.983
2:190213026:A:G	L314P	0.983
2:190294563:G:T	A96D	0.983
2:190252229:C:T	G199E	0.981
2:190296886:A:T	I49K	0.981

dbSNP variants (sampled 300 via entrez): RS1000032171 (2:190303934 A>C), RS1000044310 (2:190189867 G>A), RS1000047580 (2:190262801 A>G,T), RS1000061457 (2:190321437 T>C), RS1000078729 (2:190195293 C>T), RS1000089073 (2:190257643 C>G), RS1000126774 (2:190218751 G>A), RS1000138082 (2:190273510 T>C), RS1000144291 (2:190268565 G>C), RS1000155633 (2:190268256 G>A), RS1000178258 (2:190190166 A>C,G), RS1000194273 (2:190316839 A>G), RS1000199767 (2:190298131 A>C), RS1000218801 (2:190206810 G>A), RS1000229120 (2:190189963 G>A)

Disease associations

OMIM: gene MIM:610690 | disease phenotypes: MIM:250620

GenCC curated gene-disease

Disease	Classification	Inheritance
3-hydroxyisobutyryl-CoA hydrolase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Definitive	AR
3-hydroxyisobutyryl-CoA hydrolase deficiency	Definitive	AR

Mondo (2): 3-hydroxyisobutyryl-CoA hydrolase deficiency (MONDO:0009603), mitochondrial disease (MONDO:0044970)

Orphanet (2): Neurodegeneration due to 3-hydroxyisobutyryl-CoA hydrolase deficiency (Orphanet:88639), Mitochondrial disease (Orphanet:68380)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000286	Epicanthus
HP:0000486	Strabismus
HP:0000639	Nystagmus
HP:0000737	Irritability
HP:0000925	Abnormality of the vertebral column
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001274	Agenesis of corpus callosum
HP:0001298	Encephalopathy
HP:0001310	Dysmetria
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001636	Tetralogy of Fallot
HP:0001942	Metabolic acidosis
HP:0002013	Vomiting
HP:0002078	Truncal ataxia
HP:0002093	Respiratory insufficiency
HP:0002119	Ventriculomegaly
HP:0002151	Increased circulating lactate concentration
HP:0002344	Progressive neurologic deterioration
HP:0002352	Leukoencephalopathy
HP:0002360	Sleep disturbance

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003119_11	Urinary metabolites	2.000000e-20
GCST003518_96	Daytime sleep phenotypes	5.000000e-06
GCST006585_1191	Blood protein levels	3.000000e-152
GCST006866_1	Lung cancer (SNP x SNP interaction)	1.000000e-13
GCST009733_42	Urinary metabolite levels in chronic kidney disease	2.000000e-14

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005116	urinary metabolite measurement
EFO:0007828	daytime rest measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562803	Beta-Hydroxyisobutyryl CoA Deacylase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3817723 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression, increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	increases expression	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
kojic acid	decreases expression	1
tetrahydropalmatine	increases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
ochratoxin A	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylyl-coenzyme A	increases abundance	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
acryloyl-coenzyme A	increases abundance	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
bisphenol S	increases expression	1

ChEMBL screening assays

4 unique, capped per target: 2 admet, 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3821397	ADMET	Binding affinity to human recombinant HIBCH after 1 hr by Western blot analysis	Identification of Potential Off-target Toxicity Liabilities of Catechol-O-methyltransferase Inhibitors by Differential Competition Capture Compound Mass Spectrometry. — J Med Chem
CHEMBL3821398	Binding	Binding affinity to human recombinant HIBCH assessed as intensity fold change of cumulated normalized intensity of protein between capture and competition assay at 100 uM after 1 hr in presence of active Tcp-CC-13 by differential competitio	Identification of Potential Off-target Toxicity Liabilities of Catechol-O-methyltransferase Inhibitors by Differential Competition Capture Compound Mass Spectrometry. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT00786539	Not specified	COMPLETED	Mitochondria Inborn Errors of Metabolism and ANT Defects in Mitochondria Diseases
NCT00829270	Not specified	COMPLETED	Economic and Medical Evaluation of the Whole Mitochondrial DNA Screening by Surveyor and Mitochips Techniques
NCT00831948	Not specified	UNKNOWN	Identification of Large-Scale Mutations of POLG Gene by QMPSF in Patients With Mitochondrial DNA Instability.
NCT01001585	Not specified	TERMINATED	Anesthetic Effects in Mitochondrial Disease
NCT01148550	Not specified	SUSPENDED	Longitudinal Study of Mitochondrial Hepatopathies