HMGCS2

Summary

HMGCS2 (3-hydroxy-3-methylglutaryl-CoA synthase 2, HGNC:5008) is a protein-coding gene on chromosome 1p12, encoding Hydroxymethylglutaryl-CoA synthase, mitochondrial (P54868). Catalyzes the first irreversible step in ketogenesis, condensing acetyl-CoA to acetoacetyl-CoA to form HMG-CoA, which is converted by HMG-CoA reductase (HMGCR) into mevalonate.

The protein encoded by this gene belongs to the HMG-CoA synthase family. It is a mitochondrial enzyme that catalyzes the first reaction of ketogenesis, a metabolic pathway that provides lipid-derived energy for various organs during times of carbohydrate deprivation, such as fasting. Mutations in this gene are associated with HMG-CoA synthase deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3158 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (Definitive, ClinGen)
• GWAS associations: 4
• Clinical variants (ClinVar): 342 total — 28 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 25
• MANE Select transcript: NM_005518

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5008
Approved symbol	HMGCS2
Name	3-hydroxy-3-methylglutaryl-CoA synthase 2
Location	1p12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000134240
Ensembl biotype	protein_coding
OMIM	600234
Entrez	3158

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 20 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000369406, ENST00000472375, ENST00000476640, ENST00000544913, ENST00000886228, ENST00000886229, ENST00000886230, ENST00000886231, ENST00000886232, ENST00000886233, ENST00000886234, ENST00000886235, ENST00000886236, ENST00000886237, ENST00000886238, ENST00000886239, ENST00000886240, ENST00000886241, ENST00000886242, ENST00000886243, ENST00000886244, ENST00000886245

RefSeq mRNA: 2 — MANE Select: NM_005518 NM_001166107, NM_005518

CCDS: CCDS53353, CCDS905

Canonical transcript exons

ENST00000369406 — 10 exons

Exon	Start	End
ENSE00000913363	119759118	119759282
ENSE00000913366	119753280	119753386
ENSE00000913367	119752549	119752674
ENSE00000913368	119750797	119750908
ENSE00001449966	119748002	119748841
ENSE00002311092	119768741	119768905
ENSE00003466859	119759864	119759989
ENSE00003564495	119764172	119764626
ENSE00003592048	119755427	119755597
ENSE00003653165	119757273	119757438

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 99.63.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 4.1740 / max 998.2976, expressed in 165 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14085	4.1385	163
14086	0.0355	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.63	gold quality
mucosa of transverse colon	UBERON:0004991	99.44	gold quality
liver	UBERON:0002107	99.40	gold quality
jejunal mucosa	UBERON:0000399	99.26	gold quality
colonic mucosa	UBERON:0000317	98.97	gold quality
rectum	UBERON:0001052	98.95	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.91	gold quality
duodenum	UBERON:0002114	97.15	gold quality
renal medulla	UBERON:0000362	93.28	gold quality
adult mammalian kidney	UBERON:0000082	93.12	gold quality
transverse colon	UBERON:0001157	91.00	gold quality
diaphragm	UBERON:0001103	89.66	gold quality
apex of heart	UBERON:0002098	88.92	gold quality
mucosa of urinary bladder	UBERON:0001259	88.89	gold quality
adult organism	UBERON:0007023	88.57	gold quality
right testis	UBERON:0004534	88.44	gold quality
ileal mucosa	UBERON:0000331	88.31	gold quality
kidney	UBERON:0002113	87.87	gold quality
left testis	UBERON:0004533	87.86	gold quality
nasal cavity epithelium	UBERON:0005384	86.85	gold quality
jejunum	UBERON:0002115	86.60	gold quality
testis	UBERON:0000473	85.90	gold quality
body of stomach	UBERON:0001161	85.59	gold quality
stomach	UBERON:0000945	85.37	gold quality
colonic epithelium	UBERON:0000397	85.13	gold quality
nephron tubule	UBERON:0001231	84.68	gold quality
cardia of stomach	UBERON:0001162	84.67	gold quality
urinary bladder	UBERON:0001255	84.30	gold quality
minor salivary gland	UBERON:0001830	84.00	gold quality
pigmented layer of retina	UBERON:0001782	83.59	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-9	yes	53.90
E-GEOD-125970	yes	51.81
E-MTAB-10553	yes	38.03
E-HCAD-10	yes	18.68
E-MTAB-5061	no	3.12
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF6, CNBP, CREB1, FOXA2, FOXO3, HMGA1, HNF4A, NCOR2, NR1I2, NR2F1, PPARA, RXRA, SP1, SREBF2, TBP, YY1

miRNA regulators (miRDB)

36 targeting HMGCS2, 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-6873-3P	100.00	71.42	2626
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-12113	99.32	67.54	1072
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-302F	98.44	69.02	1776
HSA-MIR-7114-3P	98.42	66.53	569
HSA-MIR-624-3P	98.37	67.06	1067
HSA-MIR-4773	98.35	67.30	1710

Literature-anchored findings (GeneRIF, showing 32)

• Ketogenesis is an undesirable metabolic characteristic of the proliferating cell, which is down-regulated through c-Myc-mediated repression of the key metabolic gene HMGCS2. (PMID:16940161)
• The authors report high-resolution crystal structures of the human cytosolic (hHMGCS1) and mitochondrial (hHMGCS2) isoforms in binary product complexes. (PMID:20346956)
• Human HMGCS2 regulates mitochondrial fatty acid oxidation and FGF21 expression (PMID:21502324)
• An alternative transcript of HMGCS2 carrying a deletion of exon 4, and two alternative transcripts of HMGCL with deletions of exons 5 and 6, and exons 5, 6 and 7, respectively, were detected. (PMID:21952825)
• In Fe-S cluster-deficient muscles, results show a dramatic up-regulation of the ketogenic enzyme HMGCS2 and the secreted protein FGF21 (fibroblast growth factor 21). (PMID:23943793)
• FABP7 and HMGCS2 may have roles in apocrine differentiation categorizing apocrine carcinoma of the breast (PMID:25389781)
• High expression of either HSD17B2 or HMGCS2 predicted poor susceptibility of rectal cancer to preoperative chemoradiotherapy. (PMID:25929810)
• this studies demonstrate that HMGCS2 functions as a transcriptional factor that binds to peroxisome proliferator-activated receptor alpha (PPARalpha), resulting in Src expression and activation in a metabolically independent manner (PMID:27816970)
• HMGCS2 shares with ketone bodies common features in autophagic clearance of APP, suggesting that ketone bodies play an important role in HMGCS2 regulation of the autophagy. (PMID:28320515)
• Our data also suggested that apart from heart, the expression of HMGCS2 was also different in kidney and spleen between control and STZ treated mice. In conclusion, The HMGCS2 molecule may potentially be involved in T1D induced cardiac dysfunction. (PMID:28676675)
• miR-107-mediated decrease of HMGCS2 indicates poor outcomes and promotes cell migration in hepatocellular carcinoma (PMID:28867541)
• several nutrients as well as specific nutritional related hormonal conditions are able to affect significantly HMGCS2 gene expression. (PMID:28888048)
• HMGCS2 intronic single-nucleotide polymorphism (rs9943291) was associated with thiazide-like diuretic/chlorthalidone-induced glucose change in hypertensive patients. (PMID:29523524)
• Canonical pathway analysis, using Ingenuity Pathway Analysis software, revealed that the only genes in the “superpathway of cholesterol biosynthesis” were Idi1 (upregulated) and Hmgcs2 (downregulated). The Idi1 and Hmgcs2 genes have regulatory roles in atrial lipotoxic myopathy associated with atrial enlargement (PMID:30567295)
• that HMGCS2 may be capable of predicting the risk of biochemical recurrence in prostate cancer patients after radical prostatectomy (PMID:31176575)
• HMGCS2 expression is significantly reduced in colorectal cancer compared with healthy control, which is inversely correlated with microvessel density in colorectal cancer by immunohistochemistry analysis. What is more, knockdown HMGCS2 expression in HT-29 cells significantly contributed endothelial cell tube formation (PMID:31355161)
• The results identified HMGCS2 as a downstream target of Wnt/beta-catenin/PPARgamma signaling in intestinal epithelial cells. And, Wnt/beta-catenin/PPARgamma signaling regulates intestinal cell differentiation, at least in part, through regulation of ketogenesis. (PMID:31546785)
• we screened 46,XY DSD patients with gonadal dysgenesis and identified two unrelated patients with a deletion and a deleterious missense variant in HMGCS2 respectively. However, both variants were heterozygous, suggesting that HMGCS2 might not be the causative gene (PMID:31910233)
• Expanding the clinical spectrum of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency with Turkish cases harboring novel HMGCS2 gene mutations and literature review. (PMID:32259399)
• Expanding phenotypic and mutational spectra of mitochondrial HMG-CoA synthase deficiency. (PMID:33045405)
• Fructose drives mitochondrial metabolic reprogramming in podocytes via Hmgcs2-stimulated fatty acid degradation. (PMID:34238920)
• HMGCS2 in metabolic pathways was associated with overall survival in hepatocellular carcinoma: A LASSO-derived study. (PMID:34260294)
• SLC38A4 functions as a tumour suppressor in hepatocellular carcinoma through modulating Wnt/beta-catenin/MYC/HMGCS2 axis. (PMID:34274945)
• Epigenetic inactivation of hydroxymethylglutaryl CoA synthase reduces ketogenesis and facilitates tumor cell motility in clear cell renal carcinoma. (PMID:34624592)
• PXR Suppresses PPARalpha-Dependent HMGCS2 Gene Transcription by Inhibiting the Interaction between PPARalpha and PGC1alpha. (PMID:34944058)
• Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis. (PMID:35421611)
• LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease. (PMID:36629048)
• HMGCS2 serves as a potential biomarker for inhibition of renal clear cell carcinoma growth. (PMID:37670031)
• Downregulation of HMGCS2 mediated AECIIs lipid metabolic alteration promotes pulmonary fibrosis by activating fibroblasts. (PMID:38658970)
• BET inhibition decreases HMGCS2 and sensitizes resistant pancreatic tumors to gemcitabine. (PMID:38704133)
• A novel lncRNA LOC101928222 promotes colorectal cancer angiogenesis by stabilizing HMGCS2 mRNA and increasing cholesterol synthesis. (PMID:38965575)
• ADORA3 activation promotes goblet cell differentiation via enhancing HMGCS2-mediated ketogenesis in ulcerative colitis. (PMID:39098229)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hmgcs2	ENSMUSG00000027875
rattus_norvegicus	Hmgcs2	ENSRNOG00000019120
drosophila_melanogaster	Hmgs	FBGN0010611
caenorhabditis_elegans		WBGENE00017769

Paralogs (1): HMGCS1 (ENSG00000112972)

Protein

Protein identifiers

Hydroxymethylglutaryl-CoA synthase, mitochondrial — P54868 (reviewed: P54868)

Alternative names: 3-hydroxy-3-methylglutaryl coenzyme A synthase

All UniProt accessions (2): A0A140VJL2, P54868

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the first irreversible step in ketogenesis, condensing acetyl-CoA to acetoacetyl-CoA to form HMG-CoA, which is converted by HMG-CoA reductase (HMGCR) into mevalonate.

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion.

Tissue specificity. Expression in liver is 200-fold higher than in any other tissue. Low expression in colon, kidney, testis, and pancreas. Very low expression in heart and skeletal muscle. Not detected in brain. Highest expression detected in heart and skeletal muscle.

Post-translational modifications. Succinylated. Desuccinylated by SIRT5. Succinylation, at least at Lys-83 and Lys-310, inhibits the enzymatic activity.

Disease relevance. 3-hydroxy-3-methylglutaryl-CoA synthase-2 deficiency (HMGCS2D) [MIM:605911] A metabolic disorder characterized by severe hypoketotic hypoglycemia, encephalopathy, and hepatomegaly. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 2/3.

Similarity. Belongs to the thiolase-like superfamily. HMG-CoA synthase family.

Isoforms (3)

UniProt ID	Names	Canonical?
P54868-1	1	yes
P54868-2	2
P54868-3	3, HMGCS2delta4

RefSeq proteins (2): NP_001159579, NP_005509* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000590	HMG_CoA_synt_AS	Active_site
IPR010122	HMG_CoA_synthase_euk	Family
IPR013528	HMG_CoA_synth_N	Domain
IPR013746	HMG_CoA_synt_C_dom	Domain
IPR016039	Thiolase-like	Homologous_superfamily

Pfam: PF01154, PF08540

Enzyme classification (BRENDA):

• EC 2.3.3.10 — hydroxymethylglutaryl-CoA synthase (BRENDA: 66 organisms, 77 substrates, 73 inhibitors, 102 Km, 11 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-COA	0.0015–1.561	77
ACETOACETYL-COA	0.0001–0.115	22
S-(3-OXOBUTYL)-COA	0.019–0.116	3

Catalyzed reactions (Rhea), 1 shown:

• acetoacetyl-CoA + acetyl-CoA + H2O = (3S)-3-hydroxy-3-methylglutaryl-CoA + CoA + H(+) (RHEA:10188)

UniProt features (112 total): modified residue 28, helix 26, sequence variant 20, strand 17, binding site 10, active site 3, turn 2, splice variant 2, sequence conflict 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2WYA	X-RAY DIFFRACTION	1.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54868-F1	92.00	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.

Catalytic / active sites (3): 132 (proton donor/acceptor); 166 (acyl-thioester intermediate); 301 (proton donor/acceptor)

Ligand- & substrate-binding residues (10): 258; 301; 310; 380; 414; 80; 81; 166; 204; 208

Post-translational modifications (28): 52, 83, 83, 221, 243, 256, 256, 306, 310, 310, 333, 342, 342, 350, 350, 354, 354, 358, 358, 433 …

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-77111	Synthesis of Ketone Bodies
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 310 (showing top): MODULE_172, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_CELLULAR_RESPONSE_TO_LIPID, GNF2_GSTM1, GOBP_RESPONSE_TO_CORTICOSTEROID, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GNF2_HPN, SMID_BREAST_CANCER_RELAPSE_IN_LUNG_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (41): kidney development (GO:0001822), liver development (GO:0001889), acetyl-CoA metabolic process (GO:0006084), cholesterol biosynthetic process (GO:0006695), midgut development (GO:0007494), response to nutrient (GO:0007584), response to temperature stimulus (GO:0009266), response to xenobiotic stimulus (GO:0009410), response to metal ion (GO:0010038), farnesyl diphosphate biosynthetic process, mevalonate pathway (GO:0010142), lung development (GO:0030324), cellular response to insulin stimulus (GO:0032869), multicellular organismal response to stress (GO:0033555), response to testosterone (GO:0033574), response to glucagon (GO:0033762), response to triglyceride (GO:0034014), response to monosaccharide (GO:0034284), response to prostaglandin F (GO:0034696), response to starvation (GO:0042594), response to ethanol (GO:0045471), ketone body biosynthetic process (GO:0046951), response to cAMP (GO:0051591), response to growth hormone (GO:0060416), adipose tissue development (GO:0060612), response to linoleic acid (GO:0070543), cellular response to lipopolysaccharide (GO:0071222), cellular response to amino acid stimulus (GO:0071230), cellular response to glucocorticoid stimulus (GO:0071385), cellular response to fatty acid (GO:0071398), lipid metabolic process (GO:0006629), steroid biosynthetic process (GO:0006694), steroid metabolic process (GO:0008202), cholesterol metabolic process (GO:0008203), isoprenoid biosynthetic process (GO:0008299), response to bacterium (GO:0009617), sterol biosynthetic process (GO:0016126), response to insulin (GO:0032868), cellular response to hormone stimulus (GO:0032870), response to peptide hormone (GO:0043434), response to glucocorticoid (GO:0051384)

GO Molecular Function (4): hydroxymethylglutaryl-CoA synthase activity (GO:0004421), identical protein binding (GO:0042802), transferase activity (GO:0016740), acyltransferase activity (GO:0016746)

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

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Regulation of lipid metabolism by PPARalpha	1
Ketone body metabolism	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to chemical	3
animal organ development	2
response to nutrient levels	2
response to stress	2
response to lipid	2
renal system development	1
gland development	1
hepaticobiliary system development	1
acyl-CoA metabolic process	1
cholesterol metabolic process	1
sterol biosynthetic process	1
secondary alcohol biosynthetic process	1
digestive tract development	1
response to abiotic stimulus	1
phospholipid biosynthetic process	1
terpenoid biosynthetic process	1
farnesyl diphosphate metabolic process	1
isoprenoid biosynthetic process via mevalonate	1
respiratory tube development	1
respiratory system development	1
response to insulin	1
cellular response to peptide hormone stimulus	1
multicellular organismal process	1
response to ketone	1
response to peptide hormone	1
response to oxygen-containing compound	1
response to carbohydrate	1
response to prostaglandin	1
response to alcohol	1
acyltransferase activity, acyl groups converted into alkyl on transfer	1
protein binding	1
catalytic activity	1
transferase activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2502 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HMGCS2	HMGCR	P04035	938
HMGCS2	FDPS	P14324	929
HMGCS2	FDFT1	P37268	901
HMGCS2	COASY	Q13057	899
HMGCS2	ACAT1	P24752	853
HMGCS2	SREBF2	Q12772	833
HMGCS2	SREBF1	P36956	803
HMGCS2	ACAA2	P42765	795
HMGCS2	HMGCL	P35914	788
HMGCS2	PPARA	Q07869	785
HMGCS2	DHCR7	Q9UBM7	747
HMGCS2	SQLE	Q14534	743
HMGCS2	GGPS1	O95749	742
HMGCS2	MVD	P53602	742
HMGCS2	BDH1	Q02338	741

IntAct

9 interactions, top by confidence:

A	B	Type	Score
YWHAZ	HSPB1	psi-mi:“MI:0914”(association)	0.680
HMGCS2	MYH9	psi-mi:“MI:0915”(physical association)	0.400
PDE4DIP	A2ML1	psi-mi:“MI:0914”(association)	0.350
NFATC1	OBSL1	psi-mi:“MI:0914”(association)	0.350
TEX101	NDUFA4	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
SSR3	HMGCS2	psi-mi:“MI:0914”(association)	0.350

BioGRID (15): HMGCS2 (Two-hybrid), HMGCS2 (Affinity Capture-MS), HMGCS2 (Affinity Capture-MS), HMGCS2 (Biochemical Activity), HMGCS2 (Affinity Capture-MS), HMGCS2 (Affinity Capture-MS), HMGCS2 (Proximity Label-MS), HMGCS2 (Affinity Capture-MS), HMGCS2 (Affinity Capture-MS), HMGCS2 (Affinity Capture-MS), HMGCS2 (Affinity Capture-MS), HMGCS2 (Affinity Capture-MS), HMGCS2 (Cross-Linking-MS (XL-MS)), HMGCS2 (Affinity Capture-MS), APP (Reconstituted Complex)

ESM2 similar proteins: A0A1D8PTW6, A0A6S5ZZ88, A3PFB5, A7Z5J9, A8G7D1, F9X3D9, I1RY35, K7PL94, O02734, P07259, P07756, P13704, P17425, P20967, P22791, P23129, P23228, P31327, P40830, P43099, P54839, P54868, P54869, P54870, P54871, P54872, P54873, P54874, P54961, Q01581, Q06879, Q2KIE6, Q49XM5, Q4L6C4, Q4P3F1, Q4UKI8, Q4WBQ3, Q4WXT8, Q54JE4, Q54X49

Diamond homologs: A0A1D8PTW6, A0A6S5ZZ88, F9X3D9, I1RY35, K7PL94, O02734, P13704, P17425, P22791, P23228, P54839, P54868, P54869, P54870, P54871, P54872, P54873, P54874, P54961, Q01581, Q2KIE6, Q4P3F1, Q4WBQ3, Q4WXT8, Q5R7Z9, Q86HL5, Q8JZK9, V5XYR2, C5A401, O58410, D4GWR6, O30256, Q2NHU7, A0A5Q0QN66, A1RSQ5, A3MV40, Q9FD71, Q8ZVP4, B1Y953, C6A2L5

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
SIRT5	“up-regulates activity”	HMGCS2	“post translational modification”
HMGCS2	“down-regulates quantity”	acetyl-CoA	“chemical modification”
HMGCS2	“down-regulates quantity”	acetoacetyl-CoA	“chemical modification”
HMGCS2	“up-regulates quantity”	(3S)-3-hydroxy-3-methylglutaryl-CoA(5-)	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	28
Likely pathogenic	20
Uncertain significance	137
Likely benign	99
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1120051	NM_005518.4(HMGCS2):c.72dup (p.Pro25fs)	Pathogenic
1184725	NM_005518.4(HMGCS2):c.851-2A>C	Pathogenic
1327460	NM_005518.4(HMGCS2):c.39dup (p.Leu14fs)	Pathogenic
1327461	NM_005518.4(HMGCS2):c.717T>G (p.Tyr239Ter)	Pathogenic
1327465	NM_005518.4(HMGCS2):c.1394del (p.Asn465fs)	Pathogenic
1327467	NM_005518.4(HMGCS2):c.1017-2A>G	Pathogenic
1327469	NM_005518.4(HMGCS2):c.788del (p.Leu263fs)	Pathogenic
1424635	NM_005518.4(HMGCS2):c.1030G>T (p.Glu344Ter)	Pathogenic
1453176	NM_005518.4(HMGCS2):c.1016+1G>A	Pathogenic
1458530	NC_000001.10:g.(?120311344)(120311467_?)del	Pathogenic
2080601	NM_005518.4(HMGCS2):c.682C>T (p.Arg228Ter)	Pathogenic
2149225	NM_005518.4(HMGCS2):c.1354C>T (p.Arg452Ter)	Pathogenic
2230120	NM_005518.4(HMGCS2):c.67dup (p.Leu23fs)	Pathogenic
280473	NM_005518.4(HMGCS2):c.862C>T (p.Arg288Ter)	Pathogenic
2964858	NM_005518.4(HMGCS2):c.1229dup (p.Ser411fs)	Pathogenic
3693126	NM_005518.4(HMGCS2):c.634G>T (p.Gly212Ter)	Pathogenic
3730215	NM_005518.4(HMGCS2):c.810C>G (p.Tyr270Ter)	Pathogenic
449457	NM_005518.4(HMGCS2):c.1162G>A (p.Gly388Arg)	Pathogenic
4706223	NM_005518.4(HMGCS2):c.536G>A (p.Trp179Ter)	Pathogenic
4742331	NM_005518.4(HMGCS2):c.850+1G>A	Pathogenic
488532	NM_005518.4(HMGCS2):c.1017-2del	Pathogenic
488533	NM_005518.4(HMGCS2):c.772del (p.Ser258fs)	Pathogenic
644135	NM_005518.4(HMGCS2):c.850+2T>C	Pathogenic
827683	NM_005518.4(HMGCS2):c.1480C>T (p.Arg494Ter)	Pathogenic
832206	NC_000001.11:g.(?119768721)(119768864_?)del	Pathogenic
859738	NM_005518.4(HMGCS2):c.559+1G>A	Pathogenic
9258	NM_005518.4(HMGCS2):c.1270C>T (p.Arg424Ter)	Pathogenic
9262	NM_005518.4(HMGCS2):c.500A>G (p.Tyr167Cys)	Pathogenic
1175190	NM_005518.4(HMGCS2):c.1347_1351del (p.Ala450fs)	Likely pathogenic
1175191	NM_005518.4(HMGCS2):c.1201G>T (p.Glu401Ter)	Likely pathogenic

SpliceAI

1412 predictions. Top by Δscore:

Variant	Effect	Δscore
1:119752543:TCTTA:T	donor_loss	1.0000
1:119752544:CTTA:C	donor_loss	1.0000
1:119752546:TA:T	donor_loss	1.0000
1:119752547:A:AC	donor_gain	1.0000
1:119752547:A:T	donor_loss	1.0000
1:119752547:AC:A	donor_gain	1.0000
1:119752548:C:CC	donor_gain	1.0000
1:119752548:C:CG	donor_loss	1.0000
1:119752548:CC:C	donor_gain	1.0000
1:119752671:GAGC:G	acceptor_gain	1.0000
1:119752672:AGC:A	acceptor_gain	1.0000
1:119752675:C:CC	acceptor_gain	1.0000
1:119753275:CTCA:C	donor_loss	1.0000
1:119753276:TCA:T	donor_loss	1.0000
1:119753277:CA:C	donor_loss	1.0000
1:119753279:C:CT	donor_loss	1.0000
1:119753383:GTGG:G	acceptor_gain	1.0000
1:119753384:TGG:T	acceptor_gain	1.0000
1:119753387:C:CC	acceptor_gain	1.0000
1:119755422:CTCA:C	donor_gain	1.0000
1:119755425:A:AC	donor_gain	1.0000
1:119755426:C:CG	donor_gain	1.0000
1:119755426:CT:C	donor_gain	1.0000
1:119755426:CTGGG:C	donor_gain	1.0000
1:119755594:CCCC:C	acceptor_gain	1.0000
1:119755595:CCC:C	acceptor_gain	1.0000
1:119755595:CCCC:C	acceptor_gain	1.0000
1:119755596:CCC:C	acceptor_gain	1.0000
1:119759115:TA:T	donor_loss	1.0000
1:119759116:A:AG	donor_loss	1.0000

AlphaMissense

3292 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:119759245:G:C	F241L	0.999
1:119759245:G:T	F241L	0.999
1:119759247:A:G	F241L	0.999
1:119764314:T:A	K139N	0.998
1:119764314:T:G	K139N	0.998
1:119757388:G:C	H301D	0.997
1:119759250:C:G	D240H	0.997
1:119753317:A:C	S419R	0.996
1:119753317:A:T	S419R	0.996
1:119753319:T:G	S419R	0.996
1:119755474:G:C	N380K	0.996
1:119755474:G:T	N380K	0.996
1:119755478:C:T	G379E	0.996
1:119755479:C:A	G379W	0.996
1:119759239:T:A	K243N	0.996
1:119759239:T:G	K243N	0.996
1:119759249:T:A	D240V	0.996
1:119759905:G:T	A215D	0.996
1:119759962:T:A	D196V	0.996
1:119759971:A:T	V193D	0.996
1:119759249:T:C	D240G	0.995
1:119764297:A:T	L145H	0.995
1:119764306:T:A	K142I	0.995
1:119764336:T:A	E132V	0.995
1:119755478:C:A	G379V	0.994
1:119759249:T:G	D240A	0.994
1:119759956:G:T	A198D	0.994
1:119764233:G:C	C166W	0.994
1:119764256:C:G	G159R	0.994
1:119764315:T:A	K139I	0.994

dbSNP variants (sampled 300 via entrez): RS1000110541 (1:119760750 T>C), RS1000438330 (1:119761108 A>G), RS1000851484 (1:119755039 C>T), RS1000903043 (1:119752911 A>G), RS1001293749 (1:119765124 T>C), RS1001340516 (1:119766698 C>T), RS1001534919 (1:119748084 G>A,T), RS1001637282 (1:119749222 A>G), RS1001857580 (1:119758760 A>G), RS1002288349 (1:119760372 C>T), RS1002352310 (1:119747648 G>A), RS1002369335 (1:119747876 C>A,G,T), RS1002412524 (1:119764863 T>C), RS1002502519 (1:119751958 T>A), RS1002548815 (1:119759273 C>A,T)

Disease associations

OMIM: gene MIM:600234 | disease phenotypes: MIM:605911, MIM:601815

GenCC curated gene-disease

Disease	Classification	Inheritance
3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Definitive	AR

Mondo (2): 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (MONDO:0011614), PHGDH deficiency (MONDO:0011152)

Orphanet (2): 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (Orphanet:35701), 3-phosphoglycerate dehydrogenase deficiency, infantile/juvenile form (Orphanet:79351)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001259	Coma
HP:0001298	Encephalopathy
HP:0001325	Hypoglycemic coma
HP:0001397	Hepatic steatosis
HP:0001939	Abnormality of metabolism/homeostasis
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002148	Hypophosphatemia
HP:0002240	Hepatomegaly
HP:0002570	Steatorrhea
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0002919	Ketonuria
HP:0003215	Dicarboxylic aciduria
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0011463	Childhood onset
HP:0025435	Increased circulating lactate dehydrogenase concentration
HP:0030781	Increased circulating free fatty acid level
HP:0031956	Elevated circulating aspartate aminotransferase concentration
HP:0031964	Elevated circulating alanine aminotransferase concentration
HP:0040155	Elevated urinary 3-hydroxybutyric acid

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005577_4	Change in glucose in response to thiazide diuretic treatment in hypertension	4.000000e-08
GCST009391_723	Metabolite levels	7.000000e-09
GCST012251_10	Macular telangiectasia type 2	1.000000e-20
GCST012252_1	Macular telangiectasia type 2	8.000000e-22

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004468	glucose measurement
EFO:0009774	serine measurement
EFO:1002009	macular telangiectasia type 2

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C567784	3-Hydroxy-3-Methylglutaryl-CoA Synthase 2 Deficiency (supp.)
C566618	Phosphoglycerate Dehydrogenase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs9943291	Toxicity	3	chlorothiazide;hydrochlorothiazide	Hyperglycemia;Hypertension

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs9943291	HMGCS2	3	1.62	1	chlorothiazide;hydrochlorothiazide

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Lanosterol biosynthesis pathway

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
perfluorooctanoic acid	affects cotreatment, increases expression, affects expression	6
Valproic Acid	affects expression, decreases expression, affects cotreatment, increases expression	6
Benzo(a)pyrene	affects methylation, affects cotreatment, decreases expression, increases methylation	4
perfluorooctane sulfonic acid	decreases expression, affects cotreatment, increases expression, affects expression	3
perfluoro-n-nonanoic acid	increases expression, affects cotreatment, affects expression, decreases expression	3
GW 7647	increases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression	3
pirinixic acid	affects binding, increases activity, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
perfluorohexanesulfonic acid	increases expression, affects cotreatment, affects expression	2
Acetaminophen	affects cotreatment, decreases expression	2
Chenodeoxycholic Acid	affects cotreatment, decreases expression	2
Nickel	decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases methylation, affects expression, decreases expression	2
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	increases expression	1
perfluorodecanesulfonic acid	increases expression	1
testosterone enanthate	affects cotreatment, decreases expression	1
methyleugenol	decreases expression	1
fenofibric acid	affects binding, increases expression	1
benzo(b)fluoranthene	affects cotreatment, decreases expression	1
ascorbate-2-phosphate	affects binding, affects cotreatment, increases expression	1
sodium arsenite	decreases expression	1
benz(a)anthracene	affects cotreatment, decreases expression	1
chrysene	affects cotreatment, decreases expression	1
perfluorodecanoic acid	decreases expression	1
ciglitazone	affects binding, increases expression	1
tetrachlorodian	increases expression	1
diethyl malate	increases expression	1
cetrorelix	decreases expression, affects cotreatment	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1N5	Abcam K-562 HMGCS2 KO	Cancer cell line	Female
CVCL_D2JQ	Abcam Raji HMGCS2 KO	Cancer cell line	Male
CVCL_UQ71	Abcam Jurkat HMGCS2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening