HMGCS1

Summary

HMGCS1 (3-hydroxy-3-methylglutaryl-CoA synthase 1, HGNC:5007) is a protein-coding gene on chromosome 5p12, encoding Hydroxymethylglutaryl-CoA synthase, cytoplasmic (Q01581). Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form HMG-CoA, which is converted by HMG-CoA reductase (HMGCR) into mevalonate, a precursor for cholesterol synthesis. It is a common-essential gene (DepMap: required in 97.8% of cancer cell lines).

Enables protein homodimerization activity. Predicted to be involved in acetyl-CoA metabolic process and farnesyl diphosphate biosynthetic process, mevalonate pathway. Predicted to be located in cytosol.

Source: NCBI Gene 3157 — RefSeq curated summary.

At a glance

• Gene–disease (curated): rigid spine syndrome (Strong, GenCC)
• Clinical variants (ClinVar): 45 total — 7 pathogenic
• Phenotypes (HPO): 17
• Cancer dependency (DepMap): dependent in 97.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_001098272

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5007
Approved symbol	HMGCS1
Name	3-hydroxy-3-methylglutaryl-CoA synthase 1
Location	5p12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000112972
Ensembl biotype	protein_coding
OMIM	142940
Entrez	3157

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 4 retained_intron

ENST00000325110, ENST00000433297, ENST00000507004, ENST00000507293, ENST00000508319, ENST00000511774, ENST00000514610, ENST00000715988

RefSeq mRNA: 9 — MANE Select: NM_001098272 NM_001098272, NM_001324219, NM_001324220, NM_001324222, NM_001324223, NM_001324224, NM_001330663, NM_001364188, NM_002130

CCDS: CCDS34154

Canonical transcript exons

ENST00000325110 — 11 exons

Exon	Start	End
ENSE00000742603	43292474	43292637
ENSE00000742605	43292848	43292973
ENSE00000742607	43294056	43294162
ENSE00000742609	43294691	43294861
ENSE00000821231	43297002	43297166
ENSE00000971122	43298009	43298134
ENSE00001175150	43295752	43295917
ENSE00001383321	43313356	43313412
ENSE00003848530	43287470	43291220
ENSE00004028527	43307766	43307824
ENSE00004028528	43298518	43298975

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 99.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 91.0435 / max 1537.2073, expressed in 1816 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
61558	82.4914	1805
61559	3.2027	1253
61560	1.9569	998
61549	1.8643	789
61553	0.4690	232
61551	0.3992	187
61550	0.3584	171
61552	0.2062	87
61557	0.0955	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	99.63	gold quality
ventricular zone	UBERON:0003053	99.43	gold quality
ganglionic eminence	UBERON:0004023	99.25	gold quality
cortical plate	UBERON:0005343	98.82	gold quality
embryo	UBERON:0000922	98.10	gold quality
esophagus mucosa	UBERON:0002469	97.64	gold quality
mammalian vulva	UBERON:0000997	97.51	gold quality
skin of abdomen	UBERON:0001416	97.01	gold quality
upper leg skin	UBERON:0004262	96.92	gold quality
skin of leg	UBERON:0001511	95.99	gold quality
islet of Langerhans	UBERON:0000006	95.89	gold quality
zone of skin	UBERON:0000014	95.88	gold quality
amniotic fluid	UBERON:0000173	95.70	gold quality
prefrontal cortex	UBERON:0000451	95.69	gold quality
vagina	UBERON:0000996	95.67	gold quality
right lobe of liver	UBERON:0001114	95.61	gold quality
rectum	UBERON:0001052	95.60	gold quality
pons	UBERON:0000988	95.41	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.35	gold quality
gingival epithelium	UBERON:0001949	95.11	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.02	gold quality
duodenum	UBERON:0002114	94.74	gold quality
superior vestibular nucleus	UBERON:0007227	94.74	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.63	gold quality
spinal cord	UBERON:0002240	94.49	gold quality
right frontal lobe	UBERON:0002810	94.49	gold quality
lower esophagus mucosa	UBERON:0035834	94.42	gold quality
gingiva	UBERON:0001828	94.35	gold quality
dorsal root ganglion	UBERON:0000044	94.32	gold quality
pharyngeal mucosa	UBERON:0000355	94.29	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	3255.97
E-MTAB-6819	yes	2223.94
E-MTAB-8495	yes	401.93
E-MTAB-8142	yes	124.47
E-HCAD-5	yes	34.76
E-GEOD-84465	yes	23.75
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CCDC3, CREBBP, HDAC1, HNF4A, NFYA, PPARA, SREBF1, SREBF2, YY1

miRNA regulators (miRDB)

193 targeting HMGCS1, 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-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
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-5193	100.00	67.26	1744
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-545-3P	99.95	70.74	2783

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 19)

• ACBP is a transcriptional regulator of the HMGCS1 and HMGCR genes encoding rate-limiting enzymes of cholesterol synthesis pathway. (PMID:19088433)
• The authors report high-resolution crystal structures of the human cytosolic (hHMGCS1) and mitochondrial (hHMGCS2) isoforms in binary product complexes. (PMID:20346956)
• Data suggest that HMGCS1 (HMG-CoA synthase 1) signals through ketogenesis/acetoacetate to promote cell proliferation and BRAF(V600E)-dependent MEK1 activation in BRAF(V600E)-positive melanoma and colon cancer cells; HMGCS1 co-localizes with HMGCL (HMG-CoA lyase) and BRAF(V600E) in cytosol of melanoma and colon cancer cells. (BRAF = proto-oncogene protein B-raf) (PMID:28468827)
• Study showed that 5’isomiRNA of miR-140-3p (miR-140-3p-1) was preferentially expressed during the entire spectrum of preneoplastic progression in the MCF10A-derived triple negative breast cancer model. miR-140-3p-1 and its novel direct gene targets, HMGCR and HMGCS1, key enzymes in the cholesterol biosynthesis pathway, were deregulated in the normal-to-preneoplastic transition. (PMID:30537987)
• A new genetic locus for antipsychotic-induced weight gain: A genome-wide study of first-episode psychosis patients using amisulpride (from the OPTiMiSE cohort). (PMID:32126890)
• The mevalonate precursor enzyme HMGCS1 is a novel marker and key mediator of cancer stem cell enrichment in luminal and basal models of breast cancer. (PMID:32692762)
• Umbilical cord plasma-derived exosomes from preeclamptic women induce vascular dysfunction by targeting HMGCS1 in endothelial cells. (PMID:33120050)
• HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis. (PMID:33601148)
• TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination. (PMID:34347016)
• Interaction of Gal-7 with HMGCS1 In Vitro May Facilitate Cholesterol Deposition in Cultured Keratinocytes. (PMID:34454908)
• circHMGCS1-016 reshapes immune environment by sponging miR-1236-3p to regulate CD73 and GAL-8 expression in intrahepatic cholangiocarcinoma. (PMID:34526098)
• Pan-cancer analysis reveals the oncogenic role of 3-hydroxy-3-methylglutaryl-CoA synthase 1. (PMID:34549901)
• Compartmentalized activities of HMGCS1 control cervical cancer radiosensitivity. (PMID:36328117)
• Antidiabetic drug metformin suppresses tumorigenesis through inhibition of mevalonate pathway enzyme HMGCS1. (PMID:36356901)
• P4HA1 activates HMGCS1 to promote nasopharyngeal carcinoma ferroptosis resistance and progression. (PMID:36702290)
• VIMAS1 promotes proliferation and drives enzalutamide resistance in prostate cancer via IGF2BP2mediated HMGCS1 mRNA stabilization. (PMID:36734275)
• CSN6-SPOP-HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation. (PMID:38308184)
• Decreased HMGCS1 inhibits proliferation and inflammatory response of keratinocytes and ameliorates imiquimod-induced psoriasis via the STAT3/IL-23 axis. (PMID:38608446)
• Circular RNA HMGCS1 sponges MIR4521 to aggravate type 2 diabetes-induced vascular endothelial dysfunction. (PMID:39235443)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hmgcs1	ENSDARG00000103025
mus_musculus	Hmgcs1	ENSMUSG00000093930
rattus_norvegicus	Hmgcs1	ENSRNOG00000016552
drosophila_melanogaster	Hmgs	FBGN0010611
caenorhabditis_elegans		WBGENE00017769

Paralogs (1): HMGCS2 (ENSG00000134240)

Protein

Protein identifiers

Hydroxymethylglutaryl-CoA synthase, cytoplasmic — Q01581 (reviewed: Q01581)

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

All UniProt accessions (2): D6RIW1, Q01581

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form HMG-CoA, which is converted by HMG-CoA reductase (HMGCR) into mevalonate, a precursor for cholesterol synthesis.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

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.

RefSeq proteins (9): NP_001091742, NP_001311148, NP_001311149, NP_001311151, NP_001311152, NP_001311153, NP_001317592, NP_001351117, NP_002121 (=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 (79 total): helix 26, strand 17, binding site 15, modified residue 6, sequence conflict 6, active site 3, turn 3, chain 1, region of interest 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2P8U	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q01581-F1	91.79	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): 95 (proton donor/acceptor); 129 (acyl-thioester intermediate); 264 (proton donor/acceptor)

Ligand- & substrate-binding residues (15): 167; 171; 221; 221; 264; 269; 273; 273; 343; 377; 43; 44–46 …

Post-translational modifications (6): 4, 46, 273, 476, 495, 516

Mutagenesis-validated functional residues (1):

Position	Phenotype
129	loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-2426168	Activation of gene expression by SREBF (SREBP)
R-HSA-9969896	Lanosterol biosynthesis
R-HSA-191273	Cholesterol biosynthesis

MSigDB gene sets: 387 (showing top): MODULE_172, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, PID_HNF3B_PATHWAY, ATACCTC_MIR202, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ACETYL_COA_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, CHANG_IMMORTALIZED_BY_HPV31_DN, KRASNOSELSKAYA_ILF3_TARGETS_DN

GO Biological Process (9): acetyl-CoA metabolic process (GO:0006084), lipid metabolic process (GO:0006629), cholesterol biosynthetic process (GO:0006695), farnesyl diphosphate biosynthetic process, mevalonate pathway (GO:0010142), steroid biosynthetic process (GO:0006694), steroid metabolic process (GO:0008202), cholesterol metabolic process (GO:0008203), isoprenoid biosynthetic process (GO:0008299), sterol biosynthetic process (GO:0016126)

GO Molecular Function (5): hydroxymethylglutaryl-CoA synthase activity (GO:0004421), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Regulation of lipid metabolism by PPARalpha	1
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1
Cholesterol biosynthesis	1
Metabolism of steroids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid biosynthetic process	2
sterol metabolic process	2
cellular anatomical structure	2
acyl-CoA metabolic process	1
primary metabolic process	1
cholesterol metabolic process	1
sterol biosynthetic process	1
secondary alcohol biosynthetic process	1
phospholipid biosynthetic process	1
terpenoid biosynthetic process	1
farnesyl diphosphate metabolic process	1
isoprenoid biosynthetic process via mevalonate	1
steroid metabolic process	1
lipid metabolic process	1
secondary alcohol metabolic process	1
isoprenoid metabolic process	1
steroid biosynthetic process	1
acyltransferase activity, acyl groups converted into alkyl on transfer	1
identical protein binding	1
protein dimerization activity	1
binding	1
catalytic activity	1
transferase activity	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

2482 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HMGCS1	HMGCR	P04035	975
HMGCS1	FDPS	P14324	973
HMGCS1	FDFT1	P37268	945
HMGCS1	SREBF2	Q12772	904
HMGCS1	SQLE	Q14534	889
HMGCS1	DHCR7	Q9UBM7	880
HMGCS1	CYP51A1	Q16850	872
HMGCS1	SREBF1	P36956	855
HMGCS1	COASY	Q13057	851
HMGCS1	ACAT1	P24752	845
HMGCS1	MVK	Q03426	841
HMGCS1	DHCR24	Q15392	831
HMGCS1	IDI1	Q13907	828
HMGCS1	NSDHL	Q15738	822
HMGCS1	HSD17B7	P56937	813

IntAct

76 interactions, top by confidence:

A	B	Type	Score
SLC22A5	HMGCS1	psi-mi:“MI:0915”(physical association)	0.560
OR5F1	UBA6	psi-mi:“MI:0914”(association)	0.530
FSD1	UBFD1	psi-mi:“MI:0914”(association)	0.530
CDK5R1	DENR	psi-mi:“MI:0914”(association)	0.530
OR10H3	HMGCS1	psi-mi:“MI:0914”(association)	0.530
SLC22A5	CLGN	psi-mi:“MI:0914”(association)	0.530
SERPINB5	ALDH2	psi-mi:“MI:0914”(association)	0.530
PPP1R14C	HMGCS1	psi-mi:“MI:0915”(physical association)	0.400
KSR1	FBLL1	psi-mi:“MI:0914”(association)	0.350
KSR1	DDX39A	psi-mi:“MI:0914”(association)	0.350
KSR1		psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
SERPINB5	RAP1BL	psi-mi:“MI:0914”(association)	0.350
CDK15	A2ML1	psi-mi:“MI:0914”(association)	0.350
SDC1	ARVCF	psi-mi:“MI:0914”(association)	0.350
FGB	NME2	psi-mi:“MI:0914”(association)	0.350
NFYA	NME2P1	psi-mi:“MI:0914”(association)	0.350
MBD5	NME2P1	psi-mi:“MI:0914”(association)	0.350
	SYNGR1	psi-mi:“MI:0914”(association)	0.350
ZDHHC5	HACD3	psi-mi:“MI:0914”(association)	0.350
G3BP1	AGPS	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (157): HMGCS1 (Affinity Capture-MS), HMGCS1 (Affinity Capture-MS), HMGCS1 (Affinity Capture-MS), HMGCS1 (Affinity Capture-MS), HMGCS1 (Affinity Capture-MS), HMGCS1 (Affinity Capture-MS), HMGCS1 (Affinity Capture-MS), ATP6V1E1 (Co-fractionation), HMGCS1 (Co-fractionation), IMPDH1 (Co-fractionation), MVD (Co-fractionation), NEDD8 (Co-fractionation), NMD3 (Co-fractionation), RAD23B (Co-fractionation), SCP2 (Co-fractionation)

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, A0A5Q0QN66, A1RSQ5, A3MV40, Q9FD71, D4GWR6, Q8ZVP4, B1Y953, C6A2L5, Q51798

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
P4HA1	“up-regulates quantity by expression”	HMGCS1	“transcriptional regulation”
HMGCS1	down-regulates	Ferroptosis

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	0
Uncertain significance	24
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
2580362	NM_001098272.3(HMGCS1):c.1339T>C (p.Ser447Pro)	Pathogenic
2580363	NM_001098272.3(HMGCS1):c.86A>T (p.Gln29Leu)	Pathogenic
2580364	NM_001098272.3(HMGCS1):c.344_345del (p.Ser115fs)	Pathogenic
2580365	NM_001098272.3(HMGCS1):c.1289G>A (p.Arg430Lys)	Pathogenic
2580366	NM_001098272.3(HMGCS1):c.890G>T (p.Gly297Val)	Pathogenic
4533190	NM_001098272.2:c.1289G>A	Pathogenic
4533192	NM_001098272.2:c.1289G>A	Pathogenic

SpliceAI

1421 predictions. Top by Δscore:

Variant	Effect	Δscore
5:43291219:TG:T	acceptor_gain	1.0000
5:43296997:CTTA:C	donor_loss	1.0000
5:43296998:TTA:T	donor_loss	1.0000
5:43296999:TAC:T	donor_loss	1.0000
5:43297000:A:AC	donor_gain	1.0000
5:43297000:ACCT:A	donor_loss	1.0000
5:43297001:C:CC	donor_gain	1.0000
5:43297001:CCTTT:C	donor_gain	1.0000
5:43297164:GCCC:G	acceptor_loss	1.0000
5:43297166:CC:C	acceptor_loss	1.0000
5:43297166:CCTAT:C	acceptor_gain	1.0000
5:43297167:C:CA	acceptor_loss	1.0000
5:43297167:C:CC	acceptor_gain	1.0000
5:43297168:T:A	acceptor_loss	1.0000
5:43298003:ACTT:A	donor_loss	1.0000
5:43298004:CTTA:C	donor_loss	1.0000
5:43298005:TTA:T	donor_loss	1.0000
5:43298006:TAC:T	donor_loss	1.0000
5:43298007:A:AT	donor_loss	1.0000
5:43298008:C:G	donor_loss	1.0000
5:43298008:CCT:C	donor_gain	1.0000
5:43298130:CCGTC:C	acceptor_gain	1.0000
5:43298131:CGTCC:C	acceptor_gain	1.0000
5:43298134:CCT:C	acceptor_loss	1.0000
5:43298135:CTGAA:C	acceptor_loss	1.0000
5:43298136:T:G	acceptor_loss	1.0000
5:43298513:CATA:C	donor_loss	1.0000
5:43298514:ATACC:A	donor_loss	1.0000
5:43298515:TA:T	donor_loss	1.0000
5:43298516:ACCAT:A	donor_gain	1.0000

AlphaMissense

3399 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:43297129:A:C	F204L	1.000
5:43297129:A:T	F204L	1.000
5:43297131:A:G	F204L	1.000
5:43298700:C:G	R89P	1.000
5:43292555:T:A	R464S	0.999
5:43292555:T:G	R464S	0.999
5:43294734:A:G	Y345H	0.999
5:43294738:A:C	N343K	0.999
5:43294738:A:T	N343K	0.999
5:43297123:C:A	K206N	0.999
5:43297123:C:G	K206N	0.999
5:43297125:T:C	K206E	0.999
5:43298050:G:T	A178D	0.999
5:43298107:T:A	D159V	0.999
5:43298116:A:T	V156D	0.999
5:43298131:C:G	R151P	0.999
5:43298579:G:C	C129W	0.999
5:43298602:C:G	G122R	0.999
5:43298602:C:T	G122R	0.999
5:43298660:C:A	K102N	0.999
5:43298660:C:G	K102N	0.999
5:43298682:T:A	E95V	0.999
5:43298697:A:G	L90P	0.999
5:43292556:C:G	R464T	0.998
5:43294106:C:T	G378D	0.998
5:43294742:C:A	G342V	0.998
5:43294742:C:T	G342E	0.998
5:43297045:G:C	C232W	0.998
5:43297130:A:C	F204C	0.998
5:43297130:A:G	F204S	0.998

dbSNP variants (sampled 300 via entrez): RS1000301603 (5:43287805 T>G), RS1000586255 (5:43303138 T>C), RS1000606372 (5:43290639 A>G), RS1000729894 (5:43306155 A>G), RS1000771758 (5:43310513 T>C), RS1000814770 (5:43295357 T>C), RS1000914355 (5:43312379 A>T), RS1000927854 (5:43305828 T>A), RS1000953099 (5:43299163 C>A,T), RS1001140301 (5:43310765 T>C,G), RS1001427398 (5:43294923 G>T), RS1001448634 (5:43307364 T>C,G), RS1001457649 (5:43313814 G>A), RS1001594570 (5:43302522 G>A,C), RS1001628569 (5:43295321 G>A)

Disease associations

OMIM: gene MIM:142940 | disease phenotypes: MIM:621433

GenCC curated gene-disease

Disease	Classification	Inheritance
rigid spine syndrome	Strong	Autosomal recessive

Mondo (2): rigid spine syndrome (MONDO:0019951), congenital myopathy 28 with rigid spine (MONDO:0980756)

Orphanet (1): Rigid spine syndrome (Orphanet:97244)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000508	Ptosis
HP:0001283	Bulbar palsy
HP:0002460	Distal muscle weakness
HP:0002650	Scoliosis
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003306	Spinal rigidity
HP:0003691	Scapular winging
HP:0003701	Proximal muscle weakness
HP:0003805	Rimmed vacuoles
HP:0011463	Childhood onset
HP:0012548	Fatty replacement of skeletal muscle
HP:0012664	Reduced left ventricular ejection fraction
HP:0030319	Weakness of facial musculature
HP:0032341	Reduced forced vital capacity
HP:0100614	Myositis

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535683	Rigid spine syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Lanosterol biosynthesis pathway

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
hymeglusin	Inhibitor	7.0	pIC50
(S)-3-hydroxy-3-methylglutaryl-CoA	Feedback inhibition	5.9	pKi

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects cotreatment, decreases expression, increases expression	10
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression, increases methylation	7
sodium arsenite	increases abundance, increases expression, affects cotreatment, decreases expression	6
fatostatin	decreases expression, increases reaction, increases response to substance	6
bisphenol A	increases expression, affects expression, decreases expression	5
Tretinoin	affects cotreatment, decreases expression, increases expression	4
Cyclosporine	decreases expression, increases expression	4
Aflatoxin B1	affects expression, decreases expression, decreases methylation	4
perfluorooctane sulfonic acid	decreases expression	3
Resveratrol	affects cotreatment, increases expression, decreases reaction	3
Tetrachlorodibenzodioxin	decreases expression	3
Particulate Matter	affects cotreatment, decreases expression, increases abundance, increases expression	3
benzo(b)fluoranthene	affects cotreatment, decreases expression	2
perfluorooctanoic acid	increases expression	2
cupric chloride	decreases expression	2
perfluorodecanoic acid	affects reaction, increases expression, affects cotreatment	2
mercuric bromide	decreases expression, affects cotreatment	2
epigallocatechin gallate	increases expression, affects cotreatment, decreases expression	2
avobenzone	increases expression	2
entinostat	decreases expression, affects cotreatment	2
bisphenol S	increases expression, affects cotreatment, decreases methylation	2
bisphenol AF	increases expression	2
Sunitinib	increases expression	2
Troglitazone	increases activity, increases expression, decreases expression, affects binding	2
Acetaminophen	decreases expression	2
Caffeine	decreases reaction, increases expression, decreases phosphorylation	2
Clozapine	increases expression	2
Dexamethasone	affects cotreatment, increases expression, decreases expression	2
Fluoxetine	increases expression	2
Haloperidol	increases expression	2

Clinical trials (associated diseases)

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