GeneBe

HMGCS1

protein-coding

3-hydroxy-3-methylglutaryl-CoA synthase 1

Gene summary

Enables hydroxymethylglutaryl-CoA synthase activity and protein homodimerization activity. Predicted to be involved in acetyl-CoA metabolic process and farnesyl diphosphate biosynthetic process, mevalonate pathway. Located in cytosol; nucleoplasm; and plasma membrane. [provided by Alliance of Genome Resources, Jun 2026]

Previous symbols:
  • HMGCS

MANE transcript

NM_001098272.3

Inheritance

AR

ClinVar variants

P:8U:30B:2

Top phenotype

rigid spine syndrome

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr5:43,287,470-43,313,512

External References & Databases

Ensembl (ENSG00000112972)NCBI Gene (3157)OMIM (142940)HGNC:5007GenCCUniProt (Q01581)AlphaFoldClinVar (HMGCS1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~26.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

rigid spine syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019951

Submitter: PanelApp Australia

rigid spine syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019951

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HMGCS1 variants in ClinVar

4 Conditions Cataloged
not specifiedTotal: 27
Congenital myopathy 28 with rigid spineTotal: 7
Rigid spine syndromeTotal: 7
not providedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001098272.3. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
 1
missense
4
clinvar
2
clinvar
25
clinvar
2
clinvar
 33
nonsense
0
start loss
1
clinvar
 1
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
1
clinvar
3
clinvar
 4
Total53302040

Highest pathogenic variant AF is 0.0000041091107

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001098272.3RefSeqNP_001091742.19MANE Select
ENST00000325110.11EnsemblENSP00000322706.69MANE Select
NM_001324219.2RefSeqNP_001311148.19Standard
NM_001324220.2RefSeqNP_001311149.19Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
hmgcs1Danio rerio

Structure: oligodendrocyte

Quality: mislocalised dorsally

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Mevalonate pathway
  • Butanoate metabolism - Homo sapiens (human)
  • Synthesis and degradation of ketone bodies - Homo sapiens (human)
  • Terpenoid backbone biosynthesis - Homo sapiens (human)
  • Valine, leucine and isoleucine degradation - Homo sapiens (human)

Biological Process

  • liver development
  • acetyl-CoA metabolic process
  • lipid metabolic process
  • cholesterol biosynthetic process
  • brain development

Molecular Function

  • hydroxymethylglutaryl-CoA synthase activity
  • drug binding
  • isomerase activity
  • protein homodimerization activity
  • organic acid binding

Cellular Component

  • cytoplasm
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000325110
Coding exons
9
Length
24118
Individuals with no LoFs
125720
Homozygous LoFs
0
Heterozygous LoFs
4
Defined
125724
p
0.0000159
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.041352770.4870.00001363387
Missense (PolyPhen)25109.880.227531309
Synonymous2.276896.30.7060.000004571011
Loss of Function4.24122.90.04360.00000106311

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000180.000018rare
South Asian00.0absent
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: This enzyme condenses acetyl-CoA with acetoacetyl-CoA to form HMG-CoA, which is the substrate for HMG-CoA reductase.;

Recessive Scores

pRec
0.402

Intolerance Scores

LoFtool
0.133
RVIS EVS
-0.41
RVIS percentile EVS
26.23

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.928

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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