3-hydroxy-3-methylglutaryl-CoA synthase deficiency: genes and variants
3-hydroxy-3-methylglutaryl-CoA synthase deficiency is linked to 1 analyzed protein (HMGCS2). 19 DNA variants are known to cause it; 96 more are uncertain, and 1 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
HMGCS2: Hydroxymethylglutaryl-CoA synthase, mitochondrial
It catalyzes the rate-limiting mitochondrial step of ketone-body synthesis, allowing the liver to convert fatty-acid-derived acetyl-CoA into ketones during fasting. Biallelic deficiency causes impaired ketogenesis with fasting hypoglycemia and potentially severe metabolic decompensation.
19 disease-causing and 96 uncertain variants in HMGCS2 are linked to 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.
Known disease-causing variants in 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| HMGCS2 R501P | 501 | Disease-causing (★★) | |
| HMGCS2 G388R | 388 | Disease-causing (★★) | |
| HMGCS2 R501Q | 501 | Disease-causing (★★) | |
| HMGCS2 G212R | 212 | Disease-causing (★★) | |
| HMGCS2 R500H | 500 | Disease-causing (★★) | |
| HMGCS2 F174L | 174 | Disease-causing (★★) | |
| HMGCS2 V54M | 54 | Disease-causing (★★) | |
| HMGCS2 F364I | 364 | Disease-causing (★★) | |
| HMGCS2 D240V | 240 | Disease-causing (★) | |
| HMGCS2 G219E | 219 | Disease-causing (★) | |
| HMGCS2 G55D | 55 | Disease-causing (★) | |
| HMGCS2 E74K | 74 | Disease-causing (★) | |
| HMGCS2 A171V | 171 | Disease-causing (★) | |
| HMGCS2 D240A | 240 | Disease-causing (★) | |
| HMGCS2 V253A | 253 | Disease-causing (★) | |
| HMGCS2 T302I | 302 | Disease-causing (★) | |
| HMGCS2 D136G | 136 | Disease-causing (★) | |
| HMGCS2 V141D | 141 | Disease-causing (★) | |
| HMGCS2 Y167C | 167 | Disease-causing |
Uncertain variants in 3-hydroxy-3-methylglutaryl-CoA synthase deficiency that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| HMGCS2 R500C | 500 | Conflicting reports (★) | +6: 3 other pathogenic changes within 3 positions; R500H at the same position is pathogenic; REVEL 0.818 |
Frequently asked questions
Which genes are linked to 3-hydroxy-3-methylglutaryl-CoA synthase deficiency?
In CATVariant, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency is linked to 1 analyzed protein: HMGCS2 (Hydroxymethylglutaryl-CoA synthase, mitochondrial).
How many genetic variants are linked to 3-hydroxy-3-methylglutaryl-CoA synthase deficiency?
130 variants: 19 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 96 are of uncertain significance or have conflicting reports.
Which uncertain variants in 3-hydroxy-3-methylglutaryl-CoA synthase deficiency look disease-causing?
1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example HMGCS2 R500C. These are leads for expert review, not diagnoses.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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