HMGCLL1
protein-coding3-hydroxymethyl-3-methylglutaryl-CoA lyase like 1
Gene summary
Enables hydroxymethylglutaryl-CoA lyase activity. Involved in ketone body biosynthetic process. Located in several cellular components, including cytosol; endoplasmic reticulum; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~144.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HMGCLL1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001042406.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 0 | |||||
| missense | 55 | 1 | 56 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 57 | 1 | 0 | 58 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001035865.1 | 9 | MANE Select | |
| Ensembl | ENSP00000274901.4 | 9 | MANE Select | |
| RefSeq | NP_001274670.1 | 8 | Standard | |
| RefSeq | NP_001274675.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Butanoate metabolism - Homo sapiens (human)
- Peroxisome - Homo sapiens (human)
- Synthesis and degradation of ketone bodies - Homo sapiens (human)
- Valine, leucine and isoleucine degradation - Homo sapiens (human)
- ketogenesis
Biological Process
- leucine catabolic process
- lipid metabolic process
- ketone body biosynthetic process
Molecular Function
- hydroxymethylglutaryl-CoA lyase activity
- metal ion binding
Cellular Component
- endoplasmic reticulum
- endoplasmic reticulum membrane
- cytosol
- membrane
- perinuclear region of cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000398661
- Coding exons
- 10
- Length
- 144846
- Individuals with no LoFs
- 124635
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 159
- Defined
- 124794
- p
- 0.000637
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.486 | 218 | 199 | 1.10 | 0.00000951 | 2397 |
| Missense (PolyPhen) | 92 | 84.258 | 1.0919 | 1058 | ||
| Synonymous | 0.318 | 69 | 72.4 | 0.952 | 0.00000385 | 736 |
| Loss of Function | 1.34 | 13 | 19.4 | 0.671 | 9.83e-7 | 233 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00086 | 0.00084 | rare |
| Latino/Admixed American | 0.0023 | 0.0023 | notable |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.0010 | 0.00095 | notable |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00023 | 0.00022 | rare |
| South Asian | 0.00073 | 0.00072 | rare |
| Other | 0.00050 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Non-mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase that catalyzes a cation-dependent cleavage of (S)-3-hydroxy- 3-methylglutaryl-CoA into acetyl-CoA and acetoacetate, a key step in ketogenesis, the products of which support energy production in nonhepatic animal tissues. {ECO:0000269|PubMed:22847177, ECO:0000269|PubMed:22865860}.;
Recessive Scores
- pRec
- 0.165
Intolerance Scores
- LoFtool
- 0.327
- RVIS EVS
- 0.11
- RVIS percentile EVS
- 61.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.126
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |