GGPS1

Summary

GGPS1 (geranylgeranyl diphosphate synthase 1, HGNC:4249) is a protein-coding gene on chromosome 1q42.3, encoding Geranylgeranyl pyrophosphate synthase (O95749). Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins. It is a common-essential gene (DepMap: required in 96.7% of cancer cell lines).

This gene is a member of the prenyltransferase family and encodes a protein with geranylgeranyl diphosphate (GGPP) synthase activity. The enzyme catalyzes the synthesis of GGPP from farnesyl diphosphate and isopentenyl diphosphate. GGPP is an important molecule responsible for the C20-prenylation of proteins and for the regulation of a nuclear hormone receptor. Alternate transcriptional splice variants, both protein-coding and non-protein-coding, have been found for this gene.

Source: NCBI Gene 9453 — RefSeq curated summary.

At a glance

• Gene–disease (curated): muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 49 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 96.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_004837

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4249
Approved symbol	GGPS1
Name	geranylgeranyl diphosphate synthase 1
Location	1q42.3
Locus type	gene with protein product
Status	Approved
Aliases	GGPPS1
Ensembl gene	ENSG00000152904
Ensembl biotype	protein_coding
OMIM	606982
Entrez	9453

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 21 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000282841, ENST00000358966, ENST00000391855, ENST00000471812, ENST00000482013, ENST00000488594, ENST00000489692, ENST00000497327, ENST00000855443, ENST00000855444, ENST00000855445, ENST00000855446, ENST00000855447, ENST00000918187, ENST00000918188, ENST00000918189, ENST00000918190, ENST00000918191, ENST00000918192, ENST00000918193, ENST00000918194, ENST00000918195, ENST00000944251

RefSeq mRNA: 5 — MANE Select: NM_004837 NM_001037277, NM_001037278, NM_001371477, NM_001371478, NM_004837

CCDS: CCDS1604

Canonical transcript exons

ENST00000282841 — 4 exons

Exon	Start	End
ENSE00001887351	235342011	235344532
ENSE00001938009	235328570	235328778
ENSE00002320687	235335242	235335334
ENSE00003488034	235341708	235341778

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 95.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.2109 / max 177.2784, expressed in 1733 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9182	22.7264	1798
9183	6.2166	1672
9185	1.2828	804
9179	0.3815	101
9178	0.2137	87
9180	0.0963	30
9181	0.0138	3
202009	0.0061	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	95.74	gold quality
male germ cell	CL:0000015	95.11	gold quality
cortical plate	UBERON:0005343	94.10	gold quality
ganglionic eminence	UBERON:0004023	93.77	gold quality
islet of Langerhans	UBERON:0000006	93.28	gold quality
upper leg skin	UBERON:0004262	92.82	gold quality
gluteal muscle	UBERON:0002000	92.45	gold quality
cranial nerve II	UBERON:0000941	92.31	gold quality
colonic epithelium	UBERON:0000397	92.23	gold quality
embryo	UBERON:0000922	92.01	gold quality
gingival epithelium	UBERON:0001949	91.97	gold quality
left testis	UBERON:0004533	91.96	gold quality
testis	UBERON:0000473	91.89	gold quality
right testis	UBERON:0004534	91.87	gold quality
ventricular zone	UBERON:0003053	91.84	gold quality
triceps brachii	UBERON:0001509	91.82	gold quality
calcaneal tendon	UBERON:0003701	91.77	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.73	gold quality
adrenal tissue	UBERON:0018303	91.54	gold quality
parotid gland	UBERON:0001831	91.47	gold quality
heart right ventricle	UBERON:0002080	91.36	gold quality
cauda epididymis	UBERON:0004360	91.33	gold quality
gingiva	UBERON:0001828	91.28	gold quality
cartilage tissue	UBERON:0002418	91.17	gold quality
palpebral conjunctiva	UBERON:0001812	91.11	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.99	gold quality
nasal cavity mucosa	UBERON:0001826	90.63	gold quality
corpus epididymis	UBERON:0004359	90.61	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.61	gold quality
eye	UBERON:0000970	90.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-88	yes	22.61
E-ANND-3	yes	9.03

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 96.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 18)

• crystal structure; it reveals that three dimers join together to form a propeller-bladed hexameric molecule with a mass of approximately 200 kDa (PMID:16698791)
• Farnesyltranstransferase mutations are associated with lonafarnib resistance (PMID:17536018)
• results indicate that the active form of GGPS in the solution is an octamer rather than hexamer or dimer (PMID:17646172)
• Study suggested that GGPS1 -8188A ins/del polymorphism may confer susceptibility to femoral neck BMD response to bisphosphonate therapy in Korean women. (PMID:20191015)
• these results reveal a new EGR-1/GGPPS/MAPK signaling pathway that controls cigarette smoke-induced pulmonary inflammation. (PMID:21224049)
• the Egr-1/GGPPS/Erk1/2 pathway is responsible for insulin resistance during hyperinsulinism (PMID:21321112)
• Egr-1 most likely does not induce the constitutive activation of Erk1/2 through its target gene GGPS1. (PMID:23478574)
• GGPPS1 may play a critical role during the development of HCC from cirrhosis and is of clinical significance for predicting biological character of HCC. (PMID:24716791)
• results may support a model in which accumulation of susceptibility variants (including some in relevant genes, notably GGPS1) may lead to a possible genetic component of predisposition to atypical femoral fractures. (PMID:28467865)
• Overexpression of GGPPS correlates with poor prognosis of lung adenocarcinoma and contributes to metastasis through regulating epithelial-mesenchymal transition. (PMID:29377583)
• the impact of the mutated GGPPS and the relevance of the downstream effects in bone cells make it a strong candidate for Atypical femoral fractures susceptibility. (PMID:30184270)
• Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM). (PMID:32399598)
• GGPS1 Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome. (PMID:32403198)
• The Genetics of Atypical Femur Fractures-a Systematic Review. (PMID:33587247)
• Knockout of GGPPS1 restrains rab37-mediated autophagy in response to ventilator-induced lung injury. (PMID:35334098)
• GGPS1-associated muscular dystrophy with and without hearing loss. (PMID:35869884)
• Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target. (PMID:36650113)
• Evidence for a non-membrane bound isoform of geranylgeranyl diphosphate synthase 1 in rat. (PMID:8419360)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ggps1	ENSDARG00000023627
mus_musculus	Ggps1	ENSMUSG00000021302
rattus_norvegicus	Ggps1	ENSRNOG00000016767
drosophila_melanogaster	qm	FBGN0019662

Paralogs (2): PDSS1 (ENSG00000148459), PDSS2 (ENSG00000164494)

Protein

Protein identifiers

Geranylgeranyl pyrophosphate synthase — O95749 (reviewed: O95749)

Alternative names: (2E,6E)-farnesyl diphosphate synthase, Dimethylallyltranstransferase, Farnesyl diphosphate synthase, Farnesyltranstransferase, Geranylgeranyl diphosphate synthase, Geranyltranstransferase

All UniProt accessions (3): O95749, C9J6G3, C9J7M1

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins.

Subunit / interactions. Homohexamer; trimer of homodimers.

Subcellular location. Cytoplasm. Perinuclear region. Myofibril. Sarcomere. Z line.

Tissue specificity. Abundantly expressed in testis. Found in other tissues to a lower extent. Expressed in dermal fibroblast and skeletal muscle.

Disease relevance. Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome (MDHLO) [MIM:619518] An autosomal recessive disorder characterized by early-onset progressive muscle weakness, sensorineural hearing loss, and primary amenorrhea due to ovarian insufficiency. Some patients become wheelchair-bound by the second decade, whereas others have a milder phenotype and maintain independent ambulation into adulthood. Most patients have respiratory insufficiency. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Subject to product inhibition by geranylgeranyl diphosphate.

Cofactor. Binds 3 Mg(2+) ions.

Pathway. Isoprenoid biosynthesis; farnesyl diphosphate biosynthesis; farnesyl diphosphate from geranyl diphosphate and isopentenyl diphosphate: step 1/1. Isoprenoid biosynthesis; geranyl diphosphate biosynthesis; geranyl diphosphate from dimethylallyl diphosphate and isopentenyl diphosphate: step 1/1. Isoprenoid biosynthesis; geranylgeranyl diphosphate biosynthesis; geranylgeranyl diphosphate from farnesyl diphosphate and isopentenyl diphosphate: step 1/1.

Similarity. Belongs to the FPP/GGPP synthase family.

Isoforms (2)

UniProt ID	Names	Canonical?
O95749-1	1	yes
O95749-2	2

RefSeq proteins (5): NP_001032354, NP_001032355, NP_001358406, NP_001358407, NP_004828* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000092	Polyprenyl_synt	Family
IPR008949	Isoprenoid_synthase_dom_sf	Homologous_superfamily
IPR033749	Polyprenyl_synt_CS	Conserved_site

Pfam: PF00348

Enzyme classification (BRENDA):

• EC 2.5.1.29 — geranylgeranyl diphosphate synthase (BRENDA: 82 organisms, 119 substrates, 146 inhibitors, 193 Km, 59 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ISOPENTENYL DIPHOSPHATE	0.0003–0.267	75
DIMETHYLALLYL DIPHOSPHATE	0.0009–0.39	30
(2E,6E)-FARNESYL DIPHOSPHATE	0.0006–0.275	22
FARNESYL DIPHOSPHATE	0.0005–0.121	17
GERANYL DIPHOSPHATE	0.0007–0.022	17
TRANS,TRANS-FARNESYL DIPHOSPHATE	0.0004–0.055	15
(E,E)-FARNESYL DIPHOSPHATE	0.0014–0.0044	10
MG2+	0.0034–0.035	2
(E)-GERANYL DIPHOSPHATE	0.0272	1

Catalyzed reactions (Rhea), 3 shown:

• isopentenyl diphosphate + (2E,6E)-farnesyl diphosphate = (2E,6E,10E)-geranylgeranyl diphosphate + diphosphate (RHEA:17653)
• isopentenyl diphosphate + (2E)-geranyl diphosphate = (2E,6E)-farnesyl diphosphate + diphosphate (RHEA:19361)
• isopentenyl diphosphate + dimethylallyl diphosphate = (2E)-geranyl diphosphate + diphosphate (RHEA:22408)

UniProt features (42 total): helix 16, binding site 14, sequence variant 5, strand 2, chain 1, modified residue 1, splice variant 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
9CSL	X-RAY DIFFRACTION	2.1
6R4V	X-RAY DIFFRACTION	2.2
9HJS	X-RAY DIFFRACTION	2.51
9HJZ	X-RAY DIFFRACTION	2.54
2Q80	X-RAY DIFFRACTION	2.7
6C56	X-RAY DIFFRACTION	2.8
6G31	X-RAY DIFFRACTION	3
6G32	X-RAY DIFFRACTION	3.28
6C57	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95749-F1	94.52	0.89

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (14): 25; 151; 152; 185; 202; 212; 28; 57; 64; 64; 68; 68 …

Post-translational modifications (1): 1

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

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

MSigDB gene sets: 241 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, BLALOCK_ALZHEIMERS_DISEASE_UP, KEGG_TERPENOID_BACKBONE_BIOSYNTHESIS, ATF3_Q6, GOBP_LIPID_METABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS, CREB_Q3, WHN_B, MARTINEZ_RESPONSE_TO_TRABECTEDIN_DN, GOBP_ISOPRENOID_BIOSYNTHETIC_PROCESS, ACEVEDO_LIVER_CANCER_UP, REACTOME_CHOLESTEROL_BIOSYNTHESIS

GO Biological Process (6): isoprenoid metabolic process (GO:0006720), isoprenoid biosynthetic process (GO:0008299), geranyl diphosphate biosynthetic process (GO:0033384), geranylgeranyl diphosphate biosynthetic process (GO:0033386), trans, trans-farnesyl diphosphate biosynthetic process (GO:0045337), lipid metabolic process (GO:0006629)

GO Molecular Function (9): dimethylallyltranstransferase activity (GO:0004161), geranylgeranyl diphosphate synthase activity (GO:0004311), (2E,6E)-farnesyl diphosphate synthase activity (GO:0004337), identical protein binding (GO:0042802), metal ion binding (GO:0046872), prenyltransferase activity (GO:0004659), protein binding (GO:0005515), transferase activity (GO:0016740), prenyl diphosphate synthase activity (GO:0120531)

GO Cellular Component (5): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), Z disc (GO:0030018), perinuclear region of cytoplasm (GO:0048471)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
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
cellular anatomical structure	5
phospholipid biosynthetic process	3
terpenoid biosynthetic process	3
prenyl diphosphate synthase activity	3
cytoplasm	2
lipid metabolic process	1
isoprenoid metabolic process	1
lipid biosynthetic process	1
geranyl diphosphate metabolic process	1
geranylgeranyl diphosphate metabolic process	1
farnesyl diphosphate metabolic process	1
dimethylallyl diphosphate metabolic process	1
primary metabolic process	1
protein binding	1
cation binding	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
binding	1
catalytic activity	1
prenyltransferase activity	1
nuclear lumen	1
intracellular anatomical structure	1
I band	1

Protein interactions and networks

STRING

2334 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GGPS1	RSAD2	Q8WXG1	953
GGPS1	FDPS	P14324	943
GGPS1	FDFT1	P37268	873
GGPS1	HMGCR	P04035	860
GGPS1	MVK	Q03426	853
GGPS1	MVD	P53602	847
GGPS1	HMGCS1	Q01581	806
GGPS1	IDI1	Q13907	805
GGPS1	IDI2	Q9BXS1	802
GGPS1	SQLE	Q14534	776
GGPS1	HMGA1	P10910	773
GGPS1	PMVK	Q15126	771
GGPS1	HMGCS2	P54868	742
GGPS1	ACAT1	P24752	733
GGPS1	ACAT2	Q9BWD1	701

IntAct

84 interactions, top by confidence:

A	B	Type	Score
GGPS1	GGPS1	psi-mi:“MI:0915”(physical association)	0.740
RNASE3	GGPS1	psi-mi:“MI:0914”(association)	0.640
TULP3	GGPS1	psi-mi:“MI:0914”(association)	0.640
GGPS1	ATOX1	psi-mi:“MI:0915”(physical association)	0.560
ATOX1	GGPS1	psi-mi:“MI:0915”(physical association)	0.560
SDCBP	GGPS1	psi-mi:“MI:0915”(physical association)	0.560
ODAPH	TCAF2	psi-mi:“MI:0914”(association)	0.530
GGPS1	CCDC85C	psi-mi:“MI:0914”(association)	0.530
ZBTB42	MID1	psi-mi:“MI:0914”(association)	0.530
ZNF669	LRP4	psi-mi:“MI:0914”(association)	0.530
TADA2B	SUPT3H	psi-mi:“MI:0914”(association)	0.530
ZNF517	GGPS1	psi-mi:“MI:0914”(association)	0.530
SPATA24	GGPS1	psi-mi:“MI:0914”(association)	0.530
FOXD4	PDHX	psi-mi:“MI:0914”(association)	0.530
AVPI1	UNC119B	psi-mi:“MI:0914”(association)	0.530
ADCYAP1	GGPS1	psi-mi:“MI:0914”(association)	0.530
ZBTB42	GGPS1	psi-mi:“MI:0914”(association)	0.530
NDEL1	OFD1	psi-mi:“MI:0914”(association)	0.530

BioGRID (101): GGPS1 (Two-hybrid), GGPS1 (Two-hybrid), FAM120A (Affinity Capture-MS), ZNF696 (Affinity Capture-MS), IQGAP1 (Affinity Capture-MS), CCDC85C (Affinity Capture-MS), HOXA5 (Affinity Capture-MS), SLTM (Affinity Capture-MS), TUSC1 (Affinity Capture-MS), GGPS1 (Affinity Capture-MS), GGPS1 (Affinity Capture-RNA), RPS14 (Co-fractionation), SNRPE (Co-fractionation), TUSC1 (Affinity Capture-MS), GGPS1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D8PH78, A0A1V0QSA8, A0A1V0QSH7, A0A7D0AGU9, A0A7J6HWR9, A0A858E6N7, A0A858E7G0, B4YA15, E9F5E9, F9WZD2, H1VQB1, O14230, O24241, O24242, O64905, O95749, O97463, P05369, P07735, P08524, P08836, P0C565, P49349, P49350, P49351, P49352, P49353, P56966, P9WEQ2, P9WEW8, P9WEX3, P9WEX9, Q09152, Q27556, Q27567, Q43315, Q4JHN6, Q4WEB8, Q54BK1, Q672V6

Diamond homologs: A0A0E3D8L3, A0A0E3D8M9, A0A0E3D8N1, A0A0E3D8P4, A0A0P0ZD79, A0A0P0ZEM1, A0A0U5G0B1, A0A140JWS2, A0A140JWT3, A0A169T193, A0A1B4XBK0, A0A1L7VFX3, A0A1L9UKS1, A0A1L9WQI2, A0A1U8QLG8, A0A1V0QSA8, A0A1V1FVQ6, A0A1Y1C7Q5, A0A2I6PJ05, A0A2L0VXR5, A0A2Z6AQX6, A0A2Z6AQX7, A0A2Z6FZ31, A0A348DU52, A0A348FUE1, A0A3Q9FFM1, A0A3S5XFG0, A0A6S6QJ62, A0A7D0AGU9, A0A858E4Y6, A0A858E4Y8, A0A858E6N7, A0A858E7G0, A0A858E7J4, A0A858E899, A0A858EAD5, A0A8D5M3Y5, A0A8H4CUY8, A0A8K1AY78, A1C8C3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	33
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1232301	NM_004837.4(GGPS1):c.781C>G (p.Arg261Gly)	Pathogenic
1232302	NM_004837.4(GGPS1):c.776A>G (p.Tyr259Cys)	Pathogenic
1232305	NM_004837.4(GGPS1):c.854T>G (p.Val285Gly)	Pathogenic
57387	GRCh38/hg38 1q42.13-44(chr1:230106271-243677283)x1	Pathogenic
3233259	NM_004837.4(GGPS1):c.770T>G (p.Phe257Cys)	Likely pathogenic

SpliceAI

540 predictions. Top by Δscore:

Variant	Effect	Δscore
1:235327571:C:G	donor_gain	0.9900
1:235335241:GATTA:G	acceptor_gain	0.9900
1:235341700:A:G	acceptor_gain	0.9900
1:235341702:TTGCA:T	acceptor_loss	0.9900
1:235341703:TGCA:T	acceptor_loss	0.9900
1:235341704:GCA:G	acceptor_loss	0.9900
1:235341705:C:CG	acceptor_loss	0.9900
1:235341706:A:AG	acceptor_gain	0.9900
1:235341706:A:AT	acceptor_loss	0.9900
1:235341707:G:A	acceptor_loss	0.9900
1:235341707:G:GG	acceptor_gain	0.9900
1:235341774:TACAG:T	donor_loss	0.9900
1:235341775:ACAGG:A	donor_loss	0.9900
1:235341776:CAGGT:C	donor_loss	0.9900
1:235341777:AG:A	donor_loss	0.9900
1:235341779:GTATT:G	donor_loss	0.9900
1:235341780:T:C	donor_loss	0.9900
1:235342007:TTA:T	acceptor_loss	0.9900
1:235342008:TA:T	acceptor_loss	0.9900
1:235342009:A:AG	acceptor_gain	0.9900
1:235342009:AGATT:A	acceptor_loss	0.9900
1:235342010:G:GG	acceptor_gain	0.9900
1:235342010:GATT:G	acceptor_gain	0.9900
1:235335240:A:AG	acceptor_gain	0.9800
1:235335241:G:GG	acceptor_gain	0.9800
1:235335241:GATT:G	acceptor_gain	0.9800
1:235335330:ACCAG:A	donor_loss	0.9800
1:235335331:CCAG:C	donor_loss	0.9800
1:235335332:CAGGT:C	donor_loss	0.9800
1:235335333:AG:A	donor_loss	0.9800

AlphaMissense

1982 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:235342060:A:T	D64V	1.000
1:235342047:A:C	S60R	0.999
1:235342049:T:A	S60R	0.999
1:235342049:T:G	S60R	0.999
1:235342059:G:C	D64H	0.999
1:235342060:A:C	D64A	0.999
1:235342061:T:A	D64E	0.999
1:235342061:T:G	D64E	0.999
1:235342062:G:C	D65H	0.999
1:235342063:A:C	D65A	0.999
1:235342063:A:T	D65V	0.999
1:235342071:G:C	D68H	0.999
1:235342072:A:C	D68A	0.999
1:235342072:A:T	D68V	0.999
1:235342073:C:A	D68E	0.999
1:235342073:C:G	D68E	0.999
1:235342321:A:T	K151I	0.999
1:235342419:T:C	F184L	0.999
1:235342421:C:A	F184L	0.999
1:235342421:C:G	F184L	0.999
1:235342435:A:C	D189A	0.999
1:235342435:A:T	D189V	0.999
1:235342601:A:C	K244N	0.999
1:235342601:A:T	K244N	0.999
1:235342038:C:G	H57D	0.998
1:235342051:T:C	L61S	0.998
1:235342062:G:T	D65Y	0.998
1:235342063:A:G	D65G	0.998
1:235342064:T:A	D65E	0.998
1:235342064:T:G	D65E	0.998

dbSNP variants (sampled 300 via entrez): RS1000029341 (1:235327792 C>A,G), RS1000185772 (1:235336246 C>G), RS1000211747 (1:235329709 T>G), RS1000299929 (1:235337597 TAAA>T), RS1000555238 (1:235327514 C>T), RS1000637354 (1:235338681 G>A), RS1000777808 (1:235341952 A>C), RS1000794755 (1:235332508 A>G), RS1000857363 (1:235331176 G>A,T), RS1000912968 (1:235332813 T>G), RS1001092873 (1:235330049 C>T), RS1001261833 (1:235342899 G>A,T), RS1001574960 (1:235330538 T>A), RS1001924226 (1:235339544 G>A,C), RS1002074111 (1:235325784 G>A)

Disease associations

OMIM: gene MIM:606982 | disease phenotypes: MIM:619518, MIM:160565

GenCC curated gene-disease

Disease	Classification	Inheritance
muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome	Strong	Autosomal recessive

Mondo (6): muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome (MONDO:0859189), tubular aggregate myopathy (MONDO:0008051), neuromuscular disease (MONDO:0019056), premature menopause (MONDO:0001119), myopathy (MONDO:0005336), sensorineural hearing loss disorder (MONDO:0020678)

Orphanet (2): Tubular aggregate myopathy (Orphanet:2593), Neuromuscular disease (Orphanet:68381)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0001270	Motor delay
HP:0001508	Failure to thrive
HP:0001558	Decreased fetal movement
HP:0001612	Weak cry
HP:0002033	Poor suck
HP:0002093	Respiratory insufficiency
HP:0002505	Loss of ambulation
HP:0002650	Scoliosis
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003323	Progressive muscle weakness
HP:0003577	Congenital onset
HP:0003687	Centrally nucleated skeletal muscle fibers
HP:0003805	Rimmed vacuoles
HP:0004322	Short stature
HP:0008209	Premature ovarian insufficiency
HP:0008222	Female infertility
HP:0025717	Skeletal muscle autophagosome accumulation
HP:0032341	Reduced forced vital capacity
HP:0033686	Mitochondrial hypertrophy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005212_7	Asthma	3.000000e-06

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D009468	Neuromuscular Diseases	C10.668

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4769 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 52,506 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL319144	MINODRONIC ACID	4	2,895
CHEMBL4303669	ZOLEDRONIC ACID	4	523
CHEMBL997	IBANDRONIC ACID	4	48,864
CHEMBL561057	SQ109	2	224

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 (20 total), top 20:

Ligand	Action	Affinity	Parameter
BPH-608	Inhibition	7.22	pKi
BPH-675	Inhibition	7.15	pKi
BPH-742	Inhibition	7.0	pIC50
(2E, 6E)-farnesylbisphosphonate	Inhibition	7.0	pIC50
BPH-629	Inhibition	6.96	pKi
BPH-676	Inhibition	6.96	pKi
3-azageranylgeranyl diphosphate	Inhibition	6.85	pIC50
compound 14 [PMID: 18800762]	Inhibition	6.55	pIC50
BPH-715	Inhibition	6.55	pIC50
compound 12 [PMID: 12014956]	Inhibition	6.51	pIC50
compound 16 [PMID: 18800762]	Inhibition	6.46	pIC50
compound 19 [PMID: 18800762]	Inhibition	6.23	pIC50
BPH-628	Inhibition	6.14	pIC50
BPH-252	Inhibition	6.14	pIC50
digeranyl bisphosphonate	Inhibition	6.0	pIC50
compound 11 [PMID: 18800762]	Inhibition	5.6	pIC50
geranylgeranyl diphosphate	Feedback inhibition	4.6	pKi
compound 47 [PMID: 18800762]	Inhibition	4.56	pIC50
compound 51 [PMID: 18800762]	Inhibition	4.1	pIC50
minodronic acid	Inhibition	4.0	pIC50

Binding affinities (BindingDB)

57 measured of 59 human assays (63 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
[1-hydroxy-2-(1H-imidazol-1-yl)-1-phosphonoethyl]phosphonic acid	IC50	4 nM
hydrogen [2-(dodecyldimethylphosphanylium)-1-phosphonoethyl]phosphonate	IC50	100 nM
3-(decyloxy)-5-(2-hydrogen phosphonato-2-phosphonoethyl)-1-methylpyridin-1-ium	IC50	280 nM
Bisphpshonate-715	IC50	280 nM
{2-[dodecyl(methyl)amino]-1-phosphonoethyl}phosphonic acid	IC50	350 nM
3-decyl-1-(2-hydrogen phosphonato-2-phosphonoethyl)pyridin-1-ium	IC50	400 nM
3-bromo-5-(decyloxy)-1-(2-hydrogen phosphonato-2-phosphonoethyl)pyridin-1-ium	IC50	510 nM
{2-[3-(decyloxy)phenyl]-1-hydroxy-1-phosphonoethyl}phosphonic acid	IC50	590 nM
1-(2-hydrogen phosphonato-2-phosphonoethyl)-4-octylpyridin-1-ium	IC50	660 nM
(1-hydroxy-1-phosphonononyl)phosphonic acid	IC50	710 nM
3-(decyloxy)-5-(3,5-difluorophenyl)-1-(2-hydrogen phosphonato-2-phosphonoethyl)pyridin-1-ium	IC50	760 nM
hydrogen {2-[dimethyl(octyl)phosphanylium]-1-phosphonoethyl}phosphonate	IC50	890 nM
(1-hydroxy-1-phosphonodecyl)phosphonic acid	IC50	890 nM
[(6E,11E)-2,6,12,16-tetramethyl-9-phosphonoheptadeca-2,6,11,15-tetraen-9-yl]phosphonic acid	IC50	980 nM
3-[(3,7-dimethyloctyl)oxy]-1-(2-hydrogen phosphonato-2-phosphonoethyl)pyridin-1-ium	IC50	1150 nM
hydrogen {2-[dodecyl(methyl)sulfanylium]-1-phosphonoethyl}phosphonate	IC50	1230 nM
3-(decylamino)-1-(2-hydrogen phosphonato-2-phosphonoethyl)pyridin-1-ium	IC50	1260 nM
1-(2-hydrogen phosphonato-2-hydroxy-2-phosphonoethyl)-3-octylpyridin-1-ium	IC50	1380 nM
hydrogen {2-[methyl(tetradecyl)sulfanylium]-1-phosphonoethyl}phosphonate	IC50	1480 nM
1-(2-hydrogen phosphonato-2-phosphonoethyl)-3-(oct-1-yn-1-yl)pyridin-1-ium	IC50	1740 nM
[(6E,11E)-9-phosphonoheptadeca-6,11-dien-9-yl]phosphonic acid	IC50	1860 nM
3-(heptyloxy)-5-(2-hydrogen phosphonato-2-phosphonoethyl)-1-methylpyridin-1-ium	IC50	2140 nM
{1-[3-(decyloxy)phenyl]-2-phosphonodecan-2-yl}phosphonic acid	IC50	2340 nM
(9-phosphonoheptadecan-9-yl)phosphonic acid	IC50	2510 nM
1-(2-hydrogen phosphonato-2-phosphonoethyl)-3-(octane-1-sulfonamido)pyridin-1-ium	IC50	2510 nM
3-(3-butoxyphenyl)-1-(2-hydrogen phosphonato-2-phosphonoethyl)pyridin-1-ium	IC50	2510 nM
(1-hydroxy-1-phosphonododecyl)phosphonic acid	IC50	2690 nM
3-(dodecyloxy)-1-(2-hydrogen phosphonato-2-phosphonoethyl)pyridin-1-ium	IC50	3020 nM
hydrogen {2-[methyl(octyl)sulfanylium]-1-phosphonoethyl}phosphonate	IC50	3240 nM
{1-hydroxy-2-[3-(3-phenylphenyl)phenoxy]-1-phosphonoethyl}phosphonic acid	IC50	4070 nM
{1-hydroxy-3-[methyl(4-phenylbutyl)amino]-1-phosphonopropyl}phosphonic acid	IC50	4170 nM
{2-[5-(decyloxy)pyridin-3-yl]-1-phosphonoethyl}phosphonic acid	IC50	4570 nM
{2-[5-(dodecyloxy)pyridin-3-yl]-1-phosphonoethyl}phosphonic acid	IC50	5010 nM
3-hexyl-1-(2-hydrogen phosphonato-2-phosphonoethyl)pyridin-1-ium	IC50	6310 nM
hydrogen {2-[methyl(pentyl)sulfanylium]-1-phosphonoethyl}phosphonate	IC50	8710 nM
3-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-1-(2-hydrogen phosphonato-2-phosphonoethyl)pyridin-1-ium	IC50	8910 nM
1-(2-hydrogen phosphonato-2-phosphonoethyl)-3-phenylpyridin-1-ium	IC50	10000 nM
1-(2-hydrogen phosphonato-2-hydroxy-2-phosphonoethyl)-3-(3-phenylphenyl)pyridin-1-ium	IC50	11200 nM
(1-hydroxy-1-phosphonoheptyl)phosphonic acid	IC50	11200 nM
1-(2-hydrogen phosphonato-2-hydroxy-2-phosphonoethyl)-3-phenylpyridin-1-ium	IC50	14100 nM
CHEMBL4550442	IC50	23200 nM
[1,3-bis(2,4-dichlorophenyl)-2-phosphonopropan-2-yl]phosphonic acid	IC50	27500 nM
1-(2-hydrogen phosphonato-2-phosphonoethyl)-3-methylpyridin-1-ium	IC50	53700 nM
hydrogen [2-(dimethylsulfanylium)-1-hydroxy-1-phosphonoethyl]phosphonate	IC50	66100 nM
hydrogen {2-[methyl(propyl)sulfanylium]-1-phosphonoethyl}phosphonate	IC50	66100 nM
(2-carbamimidamido-1-hydroxy-1-phosphonoethyl)phosphonic acid	IC50	74100 nM
{1-hydroxy-3-[methyl(pentyl)amino]-1-phosphonopropyl}phosphonic acid	IC50	79400 nM
hydrogen {2-[(10-carboxydecyl)(methyl)sulfanylium]-1-phosphonoethyl}phosphonate	IC50	79400 nM
3-[3-(2-ethoxyethoxy)propyl]-1-(2-hydrogen phosphonato-2-phosphonoethyl)pyridin-1-ium	IC50	93300 nM
3-bromo-1-(2-hydrogen phosphonato-2-phosphonoethyl)pyridin-1-ium	IC50	107000 nM

ChEMBL bioactivities

282 potent at pChembl≥5 of 360 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.10	IC50	8	nM	CHEMBL5395051
7.92	IC50	12	nM	CHEMBL5397309
7.92	IC50	12	nM	CHEMBL5412066
7.89	IC50	13	nM	CHEMBL5429622
7.82	IC50	15	nM	CHEMBL5087030
7.77	IC50	17	nM	CHEMBL5088349
7.75	IC50	18	nM	CHEMBL5094672
7.75	IC50	18	nM	CHEMBL5397879
7.72	IC50	19	nM	CHEMBL4455060
7.70	Ki	20	nM	CHEMBL262616
7.70	IC50	20	nM	CHEMBL5082193
7.70	IC50	20	nM	CHEMBL5402998
7.68	IC50	21	nM	CHEMBL5077349
7.68	IC50	21	nM	CHEMBL5077117
7.64	IC50	23	nM	CHEMBL5083916
7.64	IC50	23	nM	CHEMBL5085126
7.64	IC50	23	nM	CHEMBL5075557
7.64	IC50	23	nM	CHEMBL5089506
7.62	IC50	24	nM	CHEMBL5080782
7.60	IC50	25	nM	CHEMBL4472025
7.60	IC50	25	nM	CHEMBL5436148
7.57	IC50	27	nM	CHEMBL4577077
7.54	IC50	29	nM	CHEMBL5088555
7.54	IC50	29	nM	CHEMBL5434884
7.52	IC50	30	nM	CHEMBL5430391
7.52	IC50	30	nM	CHEMBL5426733
7.51	IC50	31	nM	CHEMBL5075029
7.51	IC50	31	nM	CHEMBL5432841
7.47	IC50	34	nM	CHEMBL5080121
7.44	IC50	36	nM	CHEMBL5092247
7.43	IC50	37	nM	CHEMBL4471037
7.43	IC50	37	nM	CHEMBL2347859
7.42	IC50	38	nM	CHEMBL5082291
7.41	IC50	39	nM	CHEMBL4455060
7.41	IC50	39	nM	CHEMBL5081807
7.41	IC50	39	nM	CHEMBL5432576
7.40	IC50	40	nM	CHEMBL5439593
7.39	IC50	41	nM	CHEMBL4465832
7.39	IC50	41	nM	CHEMBL5094424
7.39	IC50	41	nM	CHEMBL5425444
7.39	IC50	41	nM	CHEMBL5425171
7.38	IC50	42	nM	CHEMBL4472025
7.35	IC50	45	nM	CHEMBL3775876
7.35	IC50	45	nM	CHEMBL5082037
7.32	IC50	48	nM	CHEMBL5411257
7.31	IC50	49	nM	CHEMBL4465832
7.31	IC50	49.4	nM	CHEMBL5592797
7.30	IC50	50	nM	CHEMBL4465832
7.28	IC50	52	nM	CHEMBL5088273
7.28	IC50	52.1	nM	CHEMBL5591404

PubChem BioAssay actives

289 with measured affinity, of 833 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[phosphono-[[6-[3-[[4-(trifluoromethyl)phenyl]carbamoyl]phenyl]-1H-pyrazolo[5,4-d]pyrimidin-4-yl]amino]methyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0080	uM
[[[1-methyl-6-[3-[[4-(trifluoromethyl)phenyl]carbamoyl]phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0120	uM
[phosphono-[[2-[3-[[4-(trifluoromethyl)phenyl]carbamoyl]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]methyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0120	uM
[[[9-methyl-2-[3-[[4-(trifluoromethyl)phenyl]carbamoyl]phenyl]purin-6-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0130	uM
[[[2-[3-[(3-bromo-4-methylphenyl)carbamoyl]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0150	uM
[[[2-[3-[[(2S)-2-(3-fluoro-4-methoxyphenyl)-2-propan-2-yloxyacetyl]amino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0170	uM
[phosphono-[[2-[3-[[4-(trifluoromethyl)benzoyl]amino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]methyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0180	uM
[[[2-[3-[(4-fluorophenyl)carbamoyl]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0180	uM
[[[2-(3-benzamidophenyl)thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0190	uM
[1-hydroxy-2-[3-(4-phenylphenyl)phenyl]-1-phosphonoethyl]phosphonic acid	326142: Binding affinity to human GGPPS	ki	0.0200	uM
[[[2-[3-[[(2R)-2-(3-fluoro-4-methoxyphenyl)-2-propan-2-yloxyacetyl]amino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0200	uM
[phosphono-[[1-propan-2-yl-6-[3-[[4-(trifluoromethyl)phenyl]carbamoyl]phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]amino]methyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0200	uM
[[[2-[3-[[(2S)-2-phenyl-2-propan-2-yloxyacetyl]amino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0210	uM
[[[2-[3-[(3-fluoro-4-methylbenzoyl)amino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0210	uM
[[[2-[3-[(2-phenylacetyl)amino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0230	uM
[[[2-[3-[(3-fluoro-4-methoxyphenyl)sulfamoyl]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0230	uM
[[[2-[3-[(3-fluoro-4-methylphenyl)sulfonylamino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0230	uM
[[[2-[3-[[(2R)-2-phenyl-2-propan-2-yloxyacetyl]amino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0230	uM
[[[2-[3-[(3-fluoro-4-methoxyphenyl)sulfonylamino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0240	uM
[[[2-[3-[(4-fluorobenzoyl)amino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0250	uM
[[[6-[3-[(3-fluoro-4-methoxyphenyl)carbamoyl]phenyl]-1H-pyrazolo[5,4-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0250	uM
[[[2-[3-[(3-fluoro-4-methoxyphenyl)carbamoyl]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0270	uM
[[[2-[3-[(3-fluoro-4-methoxybenzoyl)amino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0290	uM
[[[1-ethyl-6-[3-[(4-fluorophenyl)carbamoyl]phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0290	uM
[[[1-ethyl-6-[3-[[4-(trifluoromethyl)phenyl]carbamoyl]phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0300	uM
[[[6-[3-[(4-fluorophenyl)carbamoyl]phenyl]-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0300	uM
[[[2-[3-[(3-fluoro-4-methylphenyl)carbamoyl]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0310	uM
[[[6-[3-[(4-fluorophenyl)carbamoyl]phenyl]-1-methylpyrazolo[3,4-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0310	uM
[[[2-[3-[(3-fluoro-4-methoxyphenyl)carbamoylamino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0340	uM
[[[2-[3-[(3-bromo-4-methoxybenzoyl)amino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0360	uM
[[[2-[3-[(4-methylbenzoyl)amino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1584450: Inhibition of human N-terminal His6-tagged GGPPS Y246D mutant expressed in Escherichia coli BL21(DE3) using [14C]-IPP and FPP as substrates after 10 mins by scintillation counting	ic50	0.0370	uM
[[(2-phenylthieno[2,3-d]pyrimidin-4-yl)amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0370	uM
[[[2-[3-[[(2S)-2-methoxy-2-phenylacetyl]amino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0380	uM
[[[2-[3-[[(2R)-2-methoxy-2-phenylacetyl]amino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0390	uM
[[[6-[3-[(4-fluorophenyl)carbamoyl]phenyl]-1H-pyrazolo[5,4-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0390	uM
[[[1-ethyl-6-[3-[(3-fluoro-4-methoxyphenyl)carbamoyl]phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0400	uM
[[[2-[3-[(4-fluorophenyl)carbamoylamino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0410	uM
[[[2-[3-(phenylcarbamoyl)phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0410	uM
[[[2-[3-[(4-fluorophenyl)carbamoyl]phenyl]-9-methylpurin-6-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0410	uM
[[[6-[3-[(3-fluoro-4-methoxyphenyl)carbamoyl]phenyl]-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0410	uM
[2-[1-(4,8-dimethylnona-3,7-dienyl)triazol-4-yl]-1-phosphonoethyl]phosphonic acid	1920838: Inhibition of GGPP synthase (unknown origin)	ic50	0.0450	uM
tetrasodium;[2-[1-[(3E)-4,8-dimethylnona-3,7-dienyl]triazol-4-yl]-1-phosphonatoethyl]-dioxido-oxo-lambda5-phosphane	1282453: Inhibition of recombinant GGDPS (unknown origin) assessed as radiolabeled GGPP formation preincubated for 10 mins followed by addition of 10 uM FPP substrate and [14C]IPP for 30 mins by liquid scintillation counter analysis	ic50	0.0450	uM
[[[6-[3-[(3-fluoro-4-methoxyphenyl)carbamoyl]phenyl]-1-methylpyrazolo[3,4-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0480	uM
[1-amino-2-[1-[(3Z)-4,8-dimethylnona-3,7-dienyl]triazol-4-yl]-1-phosphonoethyl]phosphonic acid	2115534: Inhibition of GGDPS (unknown origin) using uRAP1a as substrate in RPMI-8226 cells assessed as disruption of geranylgeranylation by measuring unmodified Rap1a incubated for 48 hrs by immunoblot analysis	ic50	0.0494	uM
[phosphono-[[2-[3-[[5-(trifluoromethyl)pyridine-2-carbonyl]amino]phenyl]thieno[2,3-d]pyrimidin-4-yl]amino]methyl]phosphonic acid	1825549: Inhibition of recombinant human N- terminal His-tagged /TEV cleavage site fused GGPPS (1 to 300 residues) expressed in Escherichia coli BL21 (DE3) using FPP and IPP as substrates preincubated for 10 mins followed by substrate addition measured after 6 mins by by beckman coulter counting method	ic50	0.0520	uM
[1-amino-2-[1-[(3E)-4,8-dimethylnona-3,7-dienyl]triazol-4-yl]-1-phosphonoethyl]phosphonic acid	2115534: Inhibition of GGDPS (unknown origin) using uRAP1a as substrate in RPMI-8226 cells assessed as disruption of geranylgeranylation by measuring unmodified Rap1a incubated for 48 hrs by immunoblot analysis	ic50	0.0521	uM
[[[6-[3-[(3-fluoro-4-methoxyphenyl)carbamoyl]phenyl]-2-methylpyrazolo[3,4-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0560	uM
[[[2-[3-[(3-fluoro-4-methoxyphenyl)carbamoyl]phenyl]-9-methylpurin-6-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0580	uM
[1-hydroxy-2-[3-(3-phenylphenyl)phenyl]-1-phosphonoethyl]phosphonic acid	326142: Binding affinity to human GGPPS	ki	0.0600	uM
[[[2-ethyl-6-[3-[(3-fluoro-4-methoxyphenyl)carbamoyl]phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]amino]-phosphonomethyl]phosphonic acid	2022788: Inhibition of N-terminal His6 tagged human GGPPS expressed in Escherichia coli BL21(DE3) cells in presence of FPP and [14C]IPP by scintillation counting analysis	ic50	0.0670	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Valproic Acid	affects expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
dicrotophos	decreases expression	1
geranylgeranyl pyrophosphate	decreases activity	1
methylmercuric chloride	decreases expression	1
butyraldehyde	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
GW 4064	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
digeranyl bisphosphonate	decreases activity	1
jinfukang	decreases expression	1
Zoledronic Acid	decreases activity	1
Acetamides	decreases activity	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	increases expression	1
Cadmium	increases abundance, increases expression	1
Hydrogen Peroxide	decreases expression, affects cotreatment	1
Selenium	decreases expression	1
Theophylline	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Vitamin E	decreases expression	1
Isotretinoin	decreases expression	1
Cyclosporine	decreases expression	1
Sodium Selenite	increases expression	1
Cadmium Chloride	increases abundance, increases expression	1
Oleic Acid	affects cotreatment, decreases expression	1

ChEMBL screening assays

129 unique, capped per target: 128 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1028089	Binding	Inhibition of human recombinant geranylgeranyl diphosphate synthase	Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation. — J Med Chem
CHEMBL4817806	ADMET	Inhibition of recombinant human N-terminal His6-tagged GGPPS assessed as reduction in pyrophosphate release using GPP as substrate upto 200 uM incubated for 30 mins followed by substrate addition by PPiLight detection reagent based luminesc	Nonbisphosphonate inhibitors of Plasmodium falciparum FPPS/GGPPS. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00331656	PHASE4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00994552	PHASE4	UNKNOWN	Comparison of Pressure Support and Pressure Control Ventilation in Chronic Respiratory Failure
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00942227	PHASE3	COMPLETED	The Value of Traction in Treatment of Lumbar Radiculopathy
NCT00979108	PHASE3	COMPLETED	The Value of Traction in the Treatment of Cervical Radiculopathy
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02436096	PHASE3	COMPLETED	A Study to Evaluate eFFIcacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With fibRoMyalgia
NCT02829814	PHASE3	TERMINATED	Repeat of: A Study to Evaluate Efficacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With Fibromyalgia
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT01074359	PHASE2	TERMINATED	Safety and Efficacy Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation
NCT01371149	PHASE2	COMPLETED	Patient -Ventilator Interaction in Chronic Respiratory Failure
NCT02022072	PHASE2	TERMINATED	Evaluation of Vital Capacity
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03406780	PHASE2	COMPLETED	A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT06339580	PHASE2	RECRUITING	Assessment of Volume-targeted Ventilation in Patients With Neuromuscular Disease
NCT07071935	PHASE2	NOT_YET_RECRUITING	A Clinical Trial of Early Ventilation in Amyotrophic Lateral Sclerosis (EVENT ALS)
NCT07287189	PHASE2	RECRUITING	Phase 2 Study of SAT-3247 in Pediatric Ambulatory Patients
NCT00252252	PHASE1	COMPLETED	AutoVPAP Versus VPAP; Assessment of Sleep and Ventilation
NCT01560741	PHASE1	UNKNOWN	Telemedicine and Ventilator Titration in Chronic Respiratory Patients Initiating Non-invasive Ventilation
NCT01621984	PHASE1	COMPLETED	Therapeutic Riding and Neuromuscular Disease
NCT01758510	PHASE1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT03440034	PHASE1	COMPLETED	Study of Pioglitazone in Sporadic Inclusion Body Myositis
NCT05730842	PHASE1	COMPLETED	Absorption, Metabolism, Excretion and Absolute Bioavailability of EDG-5506 in Healthy Volunteers
NCT03272802	PHASE2/PHASE3	UNKNOWN	Treatment Effect of Edaravone in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00860951	PHASE1/PHASE2	COMPLETED	P300 Brain Computer Interface Keyboard to Operate Assistive Technology
NCT02362425	PHASE1/PHASE2	COMPLETED	Antioxidant Therapy in RYR1-Related Congenital Myopathy
NCT00001201	Not specified	COMPLETED	Evaluation of Neuromuscular Disease
NCT00002044	Not specified	COMPLETED	A Pilot Study To Evaluate the Effect of Retrovir (Zidovudine: AZT) in the Treatment of Human Immunodeficiency Virus (HIV) Associated Dementia and Neuromuscular Diseases
NCT00004553	Not specified	COMPLETED	Electromyography to Diagnose Neuromuscular Disorders
NCT00015470	Not specified	COMPLETED	Diagnostic Evaluation of Patients With Neuromuscular Disease
NCT00017745	Not specified	COMPLETED	Phenotype/Genotype Correlations in Neuromuscular Disorders
NCT00695591	Not specified	COMPLETED	Home Sleep Testing in Neuromuscular Disease Patients