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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
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HMGCL
3-hydroxy-3-methylglutaryl-CoA lyase
Chromosome 1 Β· 1p36.11
NCBI Gene: 3155Ensembl: ENSG00000117305.16HGNC: HGNC:5005UniProt: P35914
76PubMed Papers
21Diseases
0Drugs
103Pathogenic Variants
RESEARCH IMPACT
Variant-Rich
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
magnesium ion bindingmanganese ion bindingmetal ion bindinglipid metabolic process3-hydroxy-3-methylglutaric acidurialong chain 3-hydroxyacyl-CoA dehydrogenase deficiencygenetic disorderIntellectual disability
✦AI Summary

HMGCL (3-hydroxy-3-methylglutaryl-CoA lyase) is a mitochondrial enzyme catalyzing the final step of ketogenesis, cleaving HMG-CoA into acetyl-CoA and acetoacetate to produce ketone bodies (Ξ²-hydroxybutyrate, acetoacetate) as alternative energy sources 1. It also functions in leucine catabolism 1. The enzyme requires metal cofactors including magnesium and manganese ions for activity. Beyond canonical ketogenesis, HMGCL regulates cellular metabolism through Ξ²-hydroxybutyrate (Ξ²-HB)-mediated epigenetic modifications. HMGCL increases histone H3K9 and H3K27 acetylation, modulating transcription of genes like DPP4 and FOXM1 23. Through Ξ²-HB production, HMGCL inhibits the PI3K/AKT/mTOR signaling pathway, promoting autophagy 4. Clinically, HMGCL deficiency causes hypoketotic hypoglycemia and coma 1, and has been identified as a causative gene in contiguous gene deletion syndromes affecting multiple loci 5. In cancer contexts, HMGCL expression is often reduced, promoting tumor progression through suppressed oxidative stress and ROS generation 67. Recent evidence suggests HMGCL may serve as a tumor suppressor, with therapeutic potential through metabolic modulation 23. HMGCL is also implicated as a potential MS susceptibility gene in brain tissue 8.

Sources cited
1
HMGCL catalyzes cleavage of HMG-CoA to acetoacetic acid and acetyl-CoA in ketogenesis and leucine catabolism; HMGCL deficiency causes hypoketotic hypoglycemia and coma
PMID: 8617516
2
HMGCL increases histone H3K9 acetylation and regulates DPP4 transcription through Ξ²-OHB production; HMGCL depletion promotes HCC proliferation and metastasis
PMID: 36508088
3
HMGCL modulates H3K27ac acetylation through acetyl-CoA levels; HMGCL-mediated epigenetic changes activate FOXM1/Ξ²-catenin pathway in glioblastoma
PMID: 38069906
4
HMGCL inhibits PI3K/AKT/mTOR signaling via Ξ²-HB, promoting autophagy and suppressing osteosarcoma cell proliferation and invasion
PMID: 39985081
5
HMGCL is downregulated in nasopharyngeal carcinoma; HMGCL expression restores Ξ²-HB production, increasing ROS generation and suppressing NPC proliferation and metastasis
PMID: 28931870
6
HMGCL is part of the deregulated ketone body pathway in advanced prostate cancer associated with dioxin exposure
PMID: 37587334
7
HMGCL identified as potential causal contributor to multiple sclerosis in brain tissue through multi-omics Mendelian randomization analysis
PMID: 40280189
8
HMGCL gene can be involved in contiguous gene deletions affecting multiple loci, as documented in a case of fucosidosis with HMG-CoA lyase deficiency
PMID: 41636194
Disease Associationsβ“˜21
3-hydroxy-3-methylglutaric aciduriaOpen Targets
0.85Strong
long chain 3-hydroxyacyl-CoA dehydrogenase deficiencyOpen Targets
0.52Moderate
genetic disorderOpen Targets
0.49Moderate
Intellectual disabilityOpen Targets
0.37Weak
neurodegenerative diseaseOpen Targets
0.22Weak
hepatocellular carcinomaOpen Targets
0.09Suggestive
acute lymphoblastic leukemiaOpen Targets
0.08Suggestive
nasopharyngeal carcinomaOpen Targets
0.08Suggestive
neoplasmOpen Targets
0.08Suggestive
lung cancerOpen Targets
0.08Suggestive
osteosarcomaOpen Targets
0.07Suggestive
nonpapillary renal cell carcinomaOpen Targets
0.07Suggestive
benign prostatic hyperplasiaOpen Targets
0.05Suggestive
hyperinsulinemic hypoglycemia, familial, 4Open Targets
0.04Suggestive
coronary artery diseaseOpen Targets
0.03Suggestive
liver diseaseOpen Targets
0.02Suggestive
myeloid sarcomaOpen Targets
0.02Suggestive
atherosclerosisOpen Targets
0.02Suggestive
corneal dystrophyOpen Targets
0.02Suggestive
COVID-19Open Targets
0.02Suggestive
3-hydroxy-3-methylglutaryl-CoA lyase deficiencyUniProt
Pathogenic Variants103
NM_000191.3(HMGCL):c.109G>T (p.Glu37Ter)Pathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase|not provided|Inborn genetic diseases|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2026β†’ Residue 37
NM_000191.3(HMGCL):c.501C>A (p.Tyr167Ter)Pathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2026β†’ Residue 167
NM_000191.3(HMGCL):c.505_506del (p.Ser169fs)Pathogenic
Inborn genetic diseases|Deficiency of hydroxymethylglutaryl-CoA lyase|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2026β†’ Residue 169
NM_000191.3(HMGCL):c.876+1G>CPathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025
NM_000191.3(HMGCL):c.853del (p.Met284_Leu285insTer)Pathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase|HMGCL-related disorder|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 284
NM_000191.3(HMGCL):c.144+1G>ALikely pathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025
NM_000191.3(HMGCL):c.497+4A>GLikely pathogenic
not provided|Deficiency of hydroxymethylglutaryl-CoA lyase|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025
NM_000191.3(HMGCL):c.206_207del (p.Ser69fs)Pathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase|not provided|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 69
NM_000191.3(HMGCL):c.914_915del (p.Phe305fs)Pathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase|not provided|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 305
NM_000191.3(HMGCL):c.121C>T (p.Arg41Ter)Pathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 41
NM_000191.3(HMGCL):c.27del (p.Arg10fs)Pathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 10
NM_000191.3(HMGCL):c.286del (p.Gln96fs)Pathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 96
NM_000191.3(HMGCL):c.31C>T (p.Arg11Ter)Pathogenic
Inborn genetic diseases|Deficiency of hydroxymethylglutaryl-CoA lyase|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 11
NM_000191.3(HMGCL):c.698A>G (p.His233Arg)Pathogenic
not provided|Deficiency of hydroxymethylglutaryl-CoA lyase|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|HMGCL-related disorder
β˜…β˜…β˜†β˜†2025β†’ Residue 233
NM_000191.3(HMGCL):c.621del (p.Val208fs)Pathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 208
NM_000191.3(HMGCL):c.866del (p.Gly289fs)Pathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase
β˜…β˜…β˜†β˜†2025β†’ Residue 289
NM_000191.3(HMGCL):c.122G>A (p.Arg41Gln)Pathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase|not provided|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 41
NM_000191.3(HMGCL):c.610del (p.Asp204fs)Pathogenic
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency|Deficiency of hydroxymethylglutaryl-CoA lyase
β˜…β˜…β˜†β˜†2025β†’ Residue 204
NM_000191.3(HMGCL):c.348+1G>CLikely pathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase
β˜…β˜…β˜†β˜†2025
NM_000191.3(HMGCL):c.125A>G (p.Asp42Gly)Likely pathogenic
Deficiency of hydroxymethylglutaryl-CoA lyase|Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 42
View on ClinVar β†—
Related Genes
HMGCRProtein interaction100%MCCC2Protein interaction100%IDH3AProtein interaction100%PCCBProtein interaction100%IDH3BProtein interaction100%IDH3GProtein interaction99%
Tissue Expression6 tissues
Liver
100%
Heart
15%
Lung
11%
Brain
9%
Ovary
8%
Bone Marrow
3%
Gene Interaction Network
Click a node to explore
HMGCLHMGCRMCCC2IDH3APCCBIDH3BIDH3G
PROTEIN STRUCTURE
Preparing viewer…
PDB2CW6 Β· 2.10 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
1.03LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.72 [0.52–1.03]
RankingsWhere HMGCL stands among ~20K protein-coding genes
  • #6,249of 20,598
    Most Researched76
  • #751of 5,498
    Most Pathogenic Variants103 Β· top quartile
  • #10,221of 17,882
    Most Constrained (LOEUF)1.03
Genes detectedHMGCL
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
HMGCL-induced Ξ²-hydroxybutyrate production attenuates hepatocellular carcinoma via DPP4-mediated ferroptosis susceptibility.
PMID: 36508088
Hepatol Int Β· 2023
1.00
2
Metabolic modulation of histone acetylation mediated by HMGCL activates the FOXM1/Ξ²-catenin pathway in glioblastoma.
PMID: 38069906
Neuro Oncol Β· 2024
0.90
3
HMGCL activates autophagy in osteosarcoma through Ξ²-HB mediated inhibition of the PI3K/AKT/mTOR signaling pathway.
PMID: 39985081
J Transl Med Β· 2025
0.80
4
Persistent organic pollutants promote aggressiveness in prostate cancer.
PMID: 37587334
Oncogene Β· 2023
0.70
5
Integrated multi-omics insight into the molecular networks of oxidative stress in triggering multiple sclerosis.
PMID: 40280189
Neurobiol Dis Β· 2025
0.60