HMGCLL1

Summary

HMGCLL1 (3-hydroxy-3-methylglutaryl-CoA lyase like 1, HGNC:21359) is a protein-coding gene on chromosome 6p12.1, encoding 3-hydroxy-3-methylglutaryl-CoA lyase, cytoplasmic (Q8TB92). Non-mitochondrial 3-hydroxy-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.

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.

Source: NCBI Gene 54511 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 66 total
• MANE Select transcript: NM_001042406

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21359
Approved symbol	HMGCLL1
Name	3-hydroxy-3-methylglutaryl-CoA lyase like 1
Location	6p12.1
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP434G1411, bA418P12.1, er-cHL
Ensembl gene	ENSG00000146151
Ensembl biotype	protein_coding
OMIM	619050
Entrez	54511

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000274901, ENST00000308161, ENST00000370850, ENST00000370852, ENST00000398661, ENST00000428842, ENST00000507223, ENST00000508459, ENST00000515546, ENST00000893699, ENST00000957848, ENST00000957849

RefSeq mRNA: 5 — MANE Select: NM_001042406 NM_001042406, NM_001287741, NM_001287746, NM_001287753, NM_019036

CCDS: CCDS43474, CCDS43475, CCDS75472, CCDS75473

Canonical transcript exons

ENST00000274901 — 9 exons

Exon	Start	End
ENSE00001417482	55578948	55579192
ENSE00002085698	55434373	55435763
ENSE00003467043	55499236	55499299
ENSE00003538649	55495419	55495607
ENSE00003621104	55514048	55514196
ENSE00003641605	55439434	55439559
ENSE00003648670	55541729	55541836
ENSE00003659511	55542060	55542140
ENSE00003660768	55516508	55516603

Expression profiles

Bgee: expression breadth ubiquitous, 188 present calls, max score 90.11.

FANTOM5 (CAGE): breadth broad, TPM avg 2.1453 / max 63.0627, expressed in 387 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74041	1.3779	326
74043	0.4885	249
74042	0.2789	204

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	90.11	gold quality
islet of Langerhans	UBERON:0000006	89.70	gold quality
calcaneal tendon	UBERON:0003701	83.46	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.32	gold quality
prefrontal cortex	UBERON:0000451	82.51	gold quality
Brodmann (1909) area 9	UBERON:0013540	81.54	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.53	gold quality
Brodmann (1909) area 46	UBERON:0006483	81.23	gold quality
superior frontal gyrus	UBERON:0002661	81.20	gold quality
secondary oocyte	CL:0000655	81.18	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.79	gold quality
hypothalamus	UBERON:0001898	80.70	gold quality
frontal cortex	UBERON:0001870	80.55	gold quality
neocortex	UBERON:0001950	80.35	gold quality
spinal cord	UBERON:0002240	80.24	gold quality
nucleus accumbens	UBERON:0001882	80.15	gold quality
cerebral cortex	UBERON:0000956	79.78	gold quality
anterior cingulate cortex	UBERON:0009835	79.73	gold quality
Brodmann (1909) area 23	UBERON:0013554	79.02	gold quality
endothelial cell	CL:0000115	78.85	silver quality
postcentral gyrus	UBERON:0002581	78.62	gold quality
forebrain	UBERON:0001890	78.31	gold quality
entorhinal cortex	UBERON:0002728	78.14	gold quality
brain	UBERON:0000955	77.99	gold quality
right frontal lobe	UBERON:0002810	77.52	gold quality
parietal lobe	UBERON:0001872	77.32	gold quality
cerebellar cortex	UBERON:0002129	77.27	gold quality
cerebellar hemisphere	UBERON:0002245	77.25	gold quality
cerebellum	UBERON:0002037	76.94	gold quality
substantia nigra	UBERON:0002038	76.70	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	6.07
E-ANND-3	yes	4.21

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

84 targeting HMGCLL1, 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-340-5P	100.00	72.50	4437
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917

Literature-anchored findings (GeneRIF, showing 2)

• there are nine mature transcripts for the novel gene HMGCLL1 (PMID:22847177)
• analysis of HMGCLL1 as an extramitochondrial human 3-hydroxy-3-methylglutaryl-CoA lyase and comparison with MHGCL (PMID:22865860)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hmgcll1	ENSDARG00000088740
mus_musculus	Hmgcll1	ENSMUSG00000007908
rattus_norvegicus	Hmgcll1	ENSRNOG00000011193
drosophila_melanogaster	Hmgcl	FBGN0031877
caenorhabditis_elegans	Y71G12B.10	WBGENE00022150

Paralogs (1): HMGCL (ENSG00000117305)

Protein

Protein identifiers

3-hydroxy-3-methylglutaryl-CoA lyase, cytoplasmic — Q8TB92 (reviewed: Q8TB92)

Alternative names: 3-hydroxy-3-methylglutaryl-CoA lyase-like protein 1, Endoplasmic reticulum 3-hydroxy-3-methylglutaryl-CoA lyase

All UniProt accessions (5): Q8TB92, B7Z212, B7Z4D4, D6RHJ2, G5E9S9

UniProt curated annotations — full annotation on UniProt →

Function. Non-mitochondrial 3-hydroxy-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.

Subcellular location. Cytoplasm. Cytosol. Endoplasmic reticulum membrane.

Pathway. Metabolic intermediate metabolism; (S)-3-hydroxy-3-methylglutaryl-CoA degradation; acetoacetate from (S)-3-hydroxy-3-methylglutaryl-CoA: step 1/1.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the HMG-CoA lyase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8TB92-1	1	yes
Q8TB92-2	2
Q8TB92-4	3
Q8TB92-5	4

RefSeq proteins (5): NP_001035865, NP_001274670, NP_001274675, NP_001274682, NP_061909 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000891	PYR_CT	Domain
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR043594	HMGL	Family

Pfam: PF00682

Catalyzed reactions (Rhea), 1 shown:

• (3S)-3-hydroxy-3-methylglutaryl-CoA = acetoacetate + acetyl-CoA (RHEA:24404)

UniProt features (19 total): binding site 5, splice variant 4, mutagenesis site 4, initiator methionine 1, chain 1, sequence conflict 1, domain 1, active site 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TB92-F1	84.83	0.74

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 (1): 311

Ligand- & substrate-binding residues (5): 86; 87; 278; 280; 320

Post-translational modifications (1): 2

Mutagenesis-validated functional residues (4):

Position	Phenotype
2	abolishes myristoylation and induces a subcellular location change.
86	abolishes catalytic activity.
237	abolishes catalytic activity.
278	abolishes catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-77111	Synthesis of Ketone Bodies

MSigDB gene sets: 86 (showing top): GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOZGIT_ESR1_TARGETS_DN, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, chr6p12, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS, ACTTTAT_MIR1425P, GOBP_AMINO_ACID_CATABOLIC_PROCESS, GOBP_FATTY_ACID_DERIVATIVE_BIOSYNTHETIC_PROCESS, GOBP_FATTY_ACID_DERIVATIVE_METABOLIC_PROCESS, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK

GO Biological Process (3): L-leucine catabolic process (GO:0006552), ketone body biosynthetic process (GO:0046951), lipid metabolic process (GO:0006629)

GO Molecular Function (5): hydroxymethylglutaryl-CoA lyase activity (GO:0004419), metal ion binding (GO:0046872), catalytic activity (GO:0003824), lyase activity (GO:0016829), oxo-acid-lyase activity (GO:0016833)

GO Cellular Component (6): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), membrane (GO:0016020), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Ketone body metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
L-leucine metabolic process	1
branched-chain amino acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
small molecule biosynthetic process	1
fatty acid derivative biosynthetic process	1
primary metabolic process	1
oxo-acid-lyase activity	1
cation binding	1
molecular_function	1
catalytic activity	1
carbon-carbon lyase activity	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1974 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HMGCLL1	OXCT2	Q9BYC2	581
HMGCLL1	HMGCS2	P54868	559
HMGCLL1	AUH	Q13825	559
HMGCLL1	HMGCS1	Q01581	545
HMGCLL1	OXCT1	P55809	539
HMGCLL1	A0A1W2PS29	A0A1W2PS29	492
HMGCLL1	A0A1W2PPQ1	A0A1W2PPQ1	481
HMGCLL1	ACAT1	P24752	464
HMGCLL1	AGXT	P21549	442
HMGCLL1	CS	O75390	440
HMGCLL1	GPI	P06744	429
HMGCLL1	MCEE	Q96PE7	425
HMGCLL1	BDH1	Q02338	420
HMGCLL1	WDFY4	Q6ZS81	419
HMGCLL1	HAO2	Q9NYQ3	418

IntAct

4 interactions, top by confidence:

A	B	Type	Score
HMGCLL1	LSP1	psi-mi:“MI:0914”(association)	0.350
HMGCLL1	ADAMTS4	psi-mi:“MI:0914”(association)	0.350
HMGCL	PDHX	psi-mi:“MI:0914”(association)	0.350

BioGRID (21): HMGCL (Affinity Capture-MS), VPS13C (Affinity Capture-MS), HMGCLL1 (Co-fractionation), HMGCLL1 (Co-fractionation), HMGCLL1 (Co-fractionation), HMGCLL1 (Co-fractionation), HMGCLL1 (Co-fractionation), HMGCLL1 (Co-fractionation), VPS13C (Affinity Capture-MS), HMGCL (Affinity Capture-MS), LSP1 (Affinity Capture-MS), HBA2 (Affinity Capture-MS), TF (Affinity Capture-MS), HPX (Affinity Capture-MS), ADAMTS4 (Affinity Capture-MS)

ESM2 similar proteins: A1ABR4, A1JPN1, A1JPN5, A2BIR6, A4W9L0, A7MTM7, A8AHC4, A8GDR8, B1LLL0, B4ETL8, B7LM75, B7LQ59, B7MAU4, B7MVL2, B7NNT5, B7USB4, O43252, O54820, O88428, O95340, P17812, P49915, P70698, Q09580, Q0P4K0, Q0TH97, Q1RB62, Q2M197, Q32LQ3, Q3THK7, Q4V7C6, Q4V7F3, Q569M2, Q5R5P3, Q5RA96, Q5XHA8, Q60967, Q6DJC2, Q6PEB4, Q758R9

Diamond homologs: A3NML2, A3P825, A5UWE6, A7NLU2, A8WG57, A9WGE2, D4A5C3, O34873, O81027, P13703, P35914, P35915, P38060, P97519, Q0PHX9, Q29448, Q2T7S9, Q3ACM0, Q3JK55, Q5R9E1, Q63JB1, Q8HXZ6, Q8JZS7, Q8TB92, Q9I2A0, A0PR18, A7IDU6, A8GG86, B1VRH5, B2HGH1, B8ESV2, Q5NXN2, Q6D796, Q99PZ1, Q9X9Q0, A1AWA1, A5CWZ3, P54610, Q2RHL3, Q47884

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	56
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2076 predictions. Top by Δscore:

Variant	Effect	Δscore
6:55499234:A:AC	donor_gain	1.0000
6:55499235:C:CC	donor_gain	1.0000
6:55499235:CTT:C	donor_gain	1.0000
6:55514046:AC:A	donor_gain	1.0000
6:55514047:CC:C	donor_gain	1.0000
6:55514090:T:TA	donor_gain	1.0000
6:55514111:T:A	donor_gain	1.0000
6:55541724:CATA:C	donor_loss	1.0000
6:55541725:ATACC:A	donor_loss	1.0000
6:55541726:TACCT:T	donor_loss	1.0000
6:55541728:C:CG	donor_loss	1.0000
6:55551794:G:GA	donor_gain	1.0000
6:55435788:A:T	acceptor_gain	0.9900
6:55439432:A:AC	donor_gain	0.9900
6:55439433:C:CC	donor_gain	0.9900
6:55514043:AGT:A	donor_loss	0.9900
6:55514044:GTA:G	donor_loss	0.9900
6:55514045:T:G	donor_loss	0.9900
6:55514046:A:AA	donor_loss	0.9900
6:55514047:CCCT:C	donor_gain	0.9900
6:55514047:CCCTC:C	donor_loss	0.9900
6:55514107:A:AC	donor_gain	0.9900
6:55514108:C:CC	donor_gain	0.9900
6:55514108:CTTT:C	donor_gain	0.9900
6:55514193:CAAC:C	acceptor_gain	0.9900
6:55514194:AACC:A	acceptor_loss	0.9900
6:55514195:ACCT:A	acceptor_loss	0.9900
6:55514196:CCT:C	acceptor_loss	0.9900
6:55514197:C:A	acceptor_loss	0.9900
6:55514197:C:CC	acceptor_gain	0.9900

AlphaMissense

2222 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:55495559:C:G	D249H	0.998
6:55541756:G:C	S120R	0.998
6:55541756:G:T	S120R	0.998
6:55541758:T:G	S120R	0.998
6:55542079:T:A	D87V	0.998
6:55439514:A:G	C311R	0.997
6:55495466:G:C	H280D	0.997
6:55495472:G:C	H278D	0.997
6:55495558:T:A	D249V	0.997
6:55495558:T:G	D249A	0.997
6:55541793:A:G	L108P	0.997
6:55541813:T:A	K101N	0.997
6:55541813:T:G	K101N	0.997
6:55542079:T:G	D87A	0.997
6:55542080:C:G	D87H	0.997
6:55439485:A:C	N320K	0.996
6:55439485:A:T	N320K	0.996
6:55495464:A:C	H280Q	0.996
6:55495464:A:T	H280Q	0.996
6:55495549:C:T	G252E	0.996
6:55499277:A:G	C219R	0.996
6:55514143:A:C	F179L	0.996
6:55514143:A:T	F179L	0.996
6:55514145:A:G	F179L	0.996
6:55542073:A:G	L89S	0.996
6:55542078:A:C	D87E	0.996
6:55542078:A:T	D87E	0.996
6:55542082:C:A	R86M	0.996
6:55435693:G:A	S361F	0.995
6:55495469:A:G	C279R	0.995

dbSNP variants (sampled 300 via entrez): RS1000007559 (6:55445632 C>G), RS1000012671 (6:55455132 T>C,G), RS1000012846 (6:55635075 A>G), RS1000047578 (6:55481982 T>A), RS1000051216 (6:55615113 A>C,T), RS1000060063 (6:55561907 T>G), RS1000101355 (6:55630218 T>C), RS1000102474 (6:55532327 A>G), RS1000108620 (6:55677057 GC>G), RS1000109762 (6:55574528 T>C,G), RS1000109894 (6:55559656 A>G), RS1000143391 (6:55653967 A>G), RS1000151349 (6:55614800 C>A,T), RS1000156908 (6:55667734 A>G,T), RS1000159874 (6:55583914 G>A)

Disease associations

OMIM: gene MIM:619050 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001762_697	Obesity-related traits	3.000000e-07
GCST002934_12	Zinc levels	4.000000e-06
GCST006288_548	Heel bone mineral density	3.000000e-07
GCST006979_288	Heel bone mineral density	1.000000e-19
GCST007565_162	Morning person	8.000000e-16
GCST008058_219	Estimated glomerular filtration rate	2.000000e-12
GCST008473_43	Visceral fat	9.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005116	urinary metabolite measurement
EFO:0009270	heel bone mineral density
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
entinostat	decreases expression, increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Valproic Acid	decreases expression, increases expression	2
methylmercuric chloride	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
nutlin 3	increases expression, affects cotreatment	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Catechin	affects cotreatment, increases expression	1
Copper	affects cotreatment, decreases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Folic Acid	decreases expression	1
Silicon Dioxide	decreases expression	1
Triclosan	increases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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