MVD

Summary

MVD (mevalonate diphosphate decarboxylase, HGNC:7529) is a protein-coding gene on chromosome 16q24.2, encoding Diphosphomevalonate decarboxylase (P53602). Catalyzes the ATP dependent decarboxylation of (R)-5-diphosphomevalonate to form isopentenyl diphosphate (IPP). It is a selective cancer dependency (DepMap: 71.8% of cell lines).

The enzyme mevalonate pyrophosphate decarboxylase catalyzes the conversion of mevalonate pyrophosphate into isopentenyl pyrophosphate in one of the early steps in cholesterol biosynthesis. It decarboxylates and dehydrates its substrate while hydrolyzing ATP.

Source: NCBI Gene 4597 — RefSeq curated summary.

At a glance

• Gene–disease (curated): porokeratosis 7, multiple types (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 123 total — 6 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 6
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 71.8% of screened cell lines
• MANE Select transcript: NM_002461

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7529
Approved symbol	MVD
Name	mevalonate diphosphate decarboxylase
Location	16q24.2
Locus type	gene with protein product
Status	Approved
Aliases	MPD
Ensembl gene	ENSG00000167508
Ensembl biotype	protein_coding
OMIM	603236
Entrez	4597

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 8 protein_coding, 7 retained_intron, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000301012, ENST00000561895, ENST00000562651, ENST00000562741, ENST00000562981, ENST00000563170, ENST00000563463, ENST00000563785, ENST00000565149, ENST00000565610, ENST00000565720, ENST00000565842, ENST00000566636, ENST00000567064, ENST00000568133, ENST00000568709, ENST00000569177, ENST00000899621, ENST00000899622, ENST00000930046, ENST00000960172, ENST00000960173, ENST00000960174

RefSeq mRNA: 1 — MANE Select: NM_002461 NM_002461

CCDS: CCDS10968

Canonical transcript exons

ENST00000301012 — 10 exons

Exon	Start	End
ENSE00002604252	88663011	88663091
ENSE00003492446	88655656	88655730
ENSE00003526097	88653300	88653408
ENSE00003534175	88651940	88652605
ENSE00003557268	88657436	88657582
ENSE00003571463	88658650	88658720
ENSE00003635951	88654692	88654807
ENSE00003656812	88656105	88656304
ENSE00003675254	88657915	88658029
ENSE00003687996	88655199	88655417

Expression profiles

Bgee: expression breadth ubiquitous, 189 present calls, max score 98.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.7971 / max 1479.3508, expressed in 1813 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158559	37.3915	1812
158558	3.2912	1235
158557	0.1143	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.19	gold quality
cerebellar hemisphere	UBERON:0002245	97.76	gold quality
cerebellar cortex	UBERON:0002129	97.51	gold quality
cortical plate	UBERON:0005343	97.50	gold quality
lower esophagus mucosa	UBERON:0035834	97.08	gold quality
right frontal lobe	UBERON:0002810	96.99	gold quality
ganglionic eminence	UBERON:0004023	96.40	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.27	gold quality
upper lobe of left lung	UBERON:0008952	95.93	gold quality
granulocyte	CL:0000094	95.90	gold quality
skin of abdomen	UBERON:0001416	95.86	gold quality
mucosa of transverse colon	UBERON:0004991	95.76	gold quality
esophagus mucosa	UBERON:0002469	95.57	gold quality
ventricular zone	UBERON:0003053	95.35	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.10	gold quality
right lung	UBERON:0002167	95.07	gold quality
left testis	UBERON:0004533	95.05	gold quality
right testis	UBERON:0004534	94.91	gold quality
skin of leg	UBERON:0001511	94.90	gold quality
cingulate cortex	UBERON:0003027	94.78	gold quality
anterior cingulate cortex	UBERON:0009835	94.69	gold quality
right lobe of thyroid gland	UBERON:0001119	94.60	gold quality
cerebellum	UBERON:0002037	94.43	gold quality
adenohypophysis	UBERON:0002196	94.39	gold quality
right lobe of liver	UBERON:0001114	94.23	gold quality
transverse colon	UBERON:0001157	94.22	gold quality
adrenal tissue	UBERON:0018303	94.13	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.12	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.05	gold quality
body of stomach	UBERON:0001161	93.93	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	650.59
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting MVD, 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-6721-5P	99.93	68.92	2981
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-5008-5P	98.42	65.87	1019

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 71.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• functional importance of R161 and N17 in the binding and orientation of mevalonate diphosphate (PMID:18823933)
• Patients with disseminated superficial actinic porokeratosis (DSAP) and linear porokeratosis (LP) exhibit monoallelic germline mutations in genes encoding mevalonate pathway enzymes, such as MVD or MVK (PMID:31207227)
• Recurrent MVD mutation in European patients with disseminated porokeratosis. (PMID:32767669)
• ADAMTS1, MPDZ, MVD, and SEZ6: candidate genes for autosomal recessive nonsyndromic hearing impairment. (PMID:34135477)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mvda	ENSDARG00000099336
mus_musculus	Mvd	ENSMUSG00000006517
rattus_norvegicus	Mvd	ENSRNOG00000013376
drosophila_melanogaster	Mvd	FBGN0030683
caenorhabditis_elegans		WBGENE00012984

Protein

Protein identifiers

Diphosphomevalonate decarboxylase — P53602 (reviewed: P53602)

Alternative names: Mevalonate (diphospho)decarboxylase, Mevalonate pyrophosphate decarboxylase

All UniProt accessions (5): P53602, H3BP35, H3BQ47, H3BRZ1, H3BVC4

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the ATP dependent decarboxylation of (R)-5-diphosphomevalonate to form isopentenyl diphosphate (IPP). Functions in the mevalonate (MVA) pathway leading to isopentenyl diphosphate (IPP), a key precursor for the biosynthesis of isoprenoids and sterol synthesis.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in heart, skeletal muscle, lung, liver, brain, pancreas, kidney and placenta.

Disease relevance. Porokeratosis 7, multiple types (POROK7) [MIM:614714] A form of porokeratosis, a disorder of faulty keratinization characterized by one or more atrophic patches surrounded by a distinctive hyperkeratotic ridgelike border called the cornoid lamella. The keratotic lesions can progress to overt cutaneous neoplasms, typically squamous cell carcinomas. Multiple clinical variants of porokeratosis are recognized, including porokeratosis of Mibelli, linear porokeratosis, disseminated superficial actinic porokeratosis, palmoplantar porokeratosis, and punctate porokeratosis. Different clinical presentations can be observed among members of the same family. Individuals expressing more than one variant have also been reported. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Steroid biosynthesis; cholesterol biosynthesis.

Similarity. Belongs to the diphosphomevalonate decarboxylase family.

RefSeq proteins (1): NP_002452* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005935	Mev_decarb	Family
IPR014721	Ribsml_uS5_D2-typ_fold_subgr	Homologous_superfamily
IPR020568	Ribosomal_Su5_D2-typ_SF	Homologous_superfamily
IPR029765	Mev_diP_decarb	Family
IPR036554	GHMP_kinase_C_sf	Homologous_superfamily
IPR041431	Mvd1_C	Domain
IPR053859	MVD-like_N	Domain

Pfam: PF18376, PF22700

Enzyme classification (BRENDA):

• EC 4.1.1.33 — diphosphomevalonate decarboxylase (BRENDA: 29 organisms, 51 substrates, 55 inhibitors, 86 Km, 35 kcat entries)

Substrate kinetics (BRENDA)

16 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0005–7.7	37
5-DIPHOSPHOMEVALONATE	0.01–12.5	24
(R)-5-DIPHOSPHOMEVALONATE	0.0093–4.4	11
(R,S)-5-DIPHOSPHOMEVALONATE	0.005–0.0091	2
(3R)-3-CYCLOPROPYL-3-HYDROXY-5-[[HYDROXY(PHOSPHO	0.001	1
(3R)-3-ETHYL-3-HYDROXY-5-[[HYDROXY(PHOSPHONOOXY)	0.0015	1
(3R)-3-HYDROXY-3-(2-[[HYDROXY(PHOSPHONOOXY)PHOSP	0.016	1
(3R)-3-HYDROXY-3-(2-[[HYDROXY(PHOSPHONOOXY)PHOSP	0.029	1
(3R)-3-HYDROXY-3-(2-[[HYDROXY(PHOSPHONOOXY)PHOSP	0.0063	1
(3R)-3-HYDROXY-3-(2-[[HYDROXY(PHOSPHONOOXY)PHOSP	0.0028	1
(3R)-3-HYDROXY-3-(2-[[HYDROXY(PHOSPHONOOXY)PHOSP	0.0017	1
(3R)-3-HYDROXY-3-(2-[[HYDROXY(PHOSPHONOOXY)PHOSP	0.0029	1
CTP	0.47	1
DIPHOSPHOMEVALONATE	0.0012	1
GTP	0.3	1

Catalyzed reactions (Rhea), 1 shown:

• (R)-5-diphosphomevalonate + ATP = isopentenyl diphosphate + ADP + phosphate + CO2 (RHEA:23732)

UniProt features (58 total): strand 19, helix 14, sequence variant 11, turn 5, binding site 4, modified residue 2, initiator methionine 1, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3D4J	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P53602-F1	92.52	0.83

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 (4): 23–26; 78; 156–161; 212

Post-translational modifications (2): 2, 96

Mutagenesis-validated functional residues (1):

Position	Phenotype
17	15-fold inflation in km for mevalonate diphosphate.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-2426168	Activation of gene expression by SREBF (SREBP)
R-HSA-446199	Synthesis of dolichyl-phosphate
R-HSA-9969896	Lanosterol biosynthesis
R-HSA-191273	Cholesterol biosynthesis
R-HSA-1430728	Metabolism
R-HSA-1655829	Regulation of cholesterol biosynthesis by SREBP (SREBF)
R-HSA-392499	Metabolism of proteins
R-HSA-446193	Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-446219	Synthesis of substrates in N-glycan biosythesis
R-HSA-556833	Metabolism of lipids
R-HSA-597592	Post-translational protein modification
R-HSA-8957322	Metabolism of steroids

MSigDB gene sets: 228 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, JI_RESPONSE_TO_FSH_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ACETYL_COA_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, CHANG_IMMORTALIZED_BY_HPV31_DN, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, NIKOLSKY_BREAST_CANCER_16Q24_AMPLICON, GERY_CEBP_TARGETS, AMIT_EGF_RESPONSE_120_HELA

GO Biological Process (9): cholesterol biosynthetic process (GO:0006695), positive regulation of cell population proliferation (GO:0008284), isoprenoid biosynthetic process (GO:0008299), isopentenyl diphosphate biosynthetic process, mevalonate pathway (GO:0019287), lipid metabolic process (GO:0006629), steroid biosynthetic process (GO:0006694), steroid metabolic process (GO:0008202), cholesterol metabolic process (GO:0008203), sterol biosynthetic process (GO:0016126)

GO Molecular Function (7): diphosphomevalonate decarboxylase activity (GO:0004163), ATP binding (GO:0005524), Hsp70 protein binding (GO:0030544), protein homodimerization activity (GO:0042803), nucleotide binding (GO:0000166), lyase activity (GO:0016829), carboxy-lyase activity (GO:0016831)

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

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Metabolism of steroids	2
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1
Synthesis of substrates in N-glycan biosythesis	1
Cholesterol biosynthesis	1
Asparagine N-linked glycosylation	1
Post-translational protein modification	1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1
Metabolism	1
Metabolism of proteins	1
Metabolism of lipids	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
cholesterol metabolic process	1
sterol biosynthetic process	1
secondary alcohol biosynthetic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
isoprenoid metabolic process	1
acetyl-CoA metabolic process	1
isopentenyl diphosphate biosynthetic process	1
primary metabolic process	1
steroid metabolic process	1
lipid metabolic process	1
secondary alcohol metabolic process	1
steroid biosynthetic process	1
carboxy-lyase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
heat shock protein binding	1
protein-folding chaperone binding	1
identical protein binding	1
protein dimerization activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
carbon-carbon lyase activity	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1110 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MVD	MVK	Q03426	913
MVD	PMVK	Q15126	912
MVD	FDPS	P14324	857
MVD	GGPS1	O95749	847
MVD	IDI1	Q13907	843
MVD	HMGCR	P04035	841
MVD	SQLE	Q14534	816
MVD	FDFT1	P37268	811
MVD	HMGCS1	Q01581	810
MVD	IDI2	Q9BXS1	804
MVD	ACAT1	P24752	797
MVD	ACAT2	Q9BWD1	782
MVD	LSS	P48449	763
MVD	HMGCS2	P54868	742
MVD	NSDHL	Q15738	717

IntAct

16 interactions, top by confidence:

A	B	Type	Score
CTBP2	ZNF217	psi-mi:“MI:0914”(association)	0.690
LRIF1	SMCHD1	psi-mi:“MI:0914”(association)	0.680
Smc3	RAD21	psi-mi:“MI:0914”(association)	0.600
atp6v0d_human	ATP6AP2	psi-mi:“MI:0914”(association)	0.530
CDK1	CHEK1	psi-mi:“MI:0914”(association)	0.350
Med22	MED7	psi-mi:“MI:0914”(association)	0.350
SETD1B	WBP4	psi-mi:“MI:0914”(association)	0.350
ATP6V0D1		psi-mi:“MI:0914”(association)	0.350
MVD	FASN	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
NPPB	ACOT7	psi-mi:“MI:0914”(association)	0.350
SNRNP27	BPNT1	psi-mi:“MI:0914”(association)	0.350
GNB5	MVD	psi-mi:“MI:0915”(physical association)	0.000
MVD	EEF1G	psi-mi:“MI:0915”(physical association)	0.000
EIF4EBP1	MVD	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (63): MVD (Co-fractionation), MVD (Co-fractionation), MVD (Affinity Capture-MS), MVD (Affinity Capture-MS), MVD (Affinity Capture-MS), MVD (Affinity Capture-MS), MVD (Affinity Capture-MS), MVD (Affinity Capture-MS), MVD (Affinity Capture-MS), MVD (Affinity Capture-RNA), MVD (Affinity Capture-MS), MVD (Affinity Capture-MS), HSPA9 (Two-hybrid), HSPA9 (Affinity Capture-Western), BTAF1 (Affinity Capture-Western)

ESM2 similar proteins: A0A1D8PC43, A0A1D8PLH0, A5H2P4, A5H2Q8, B0B9G5, B0BB44, B1VB82, C4R4R8, C5DVG6, C5FY68, C5M1X2, D0EAP4, F4JCU3, F8QQQ7, G9BIY1, I1S130, O13963, O23722, O43056, P04385, P07277, P09608, P13045, P17423, P24521, P32377, P38095, P53070, P53602, Q0P570, Q2UFN0, Q3KMW4, Q4WFT3, Q4WNV9, Q54KE6, Q54YQ9, Q5B1L4, Q5U403, Q62967, Q6BLS3

Diamond homologs: A0A1D8PC43, D0EAP4, F4JCU3, F8QQQ7, G9BIY1, I1S130, O13963, O23722, P32377, P53602, Q0P570, Q4WNV9, Q54YQ9, Q5U403, Q62967, Q6BY07, Q751D8, Q97UL5, Q99JF5

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
AKT1	“up-regulates activity”	MVD	phosphorylation
MVD	“up-regulates activity”	RAC1	lipidation
MVD	“up-regulates quantity by stabilization”	KRAS
MVD	“up-regulates quantity by stabilization”	HRAS
MVD	“up-regulates quantity by stabilization”	NRAS
HSPA9	“down-regulates activity”	MVD	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	3
Uncertain significance	90
Likely benign	8
Benign	4

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1301637	NM_002461.3(MVD):c.141+1del	Pathogenic
1323302	NM_002461.3(MVD):c.1013+1G>T	Pathogenic
253039	NM_002461.3(MVD):c.746T>C (p.Phe249Ser)	Pathogenic
253040	NM_002461.3(MVD):c.875A>G (p.Asn292Ser)	Pathogenic
267479	Single allele	Pathogenic
3243328	NC_000016.9:g.(?87921735)(89484776_?)del	Pathogenic
1344672	NM_002461.3(MVD):c.811_815del (p.Phe271fs)	Likely pathogenic
3350259	NM_002461.3(MVD):c.71-2A>C	Likely pathogenic
3779982	NM_002461.3(MVD):c.1014-1G>T	Likely pathogenic

SpliceAI

2152 predictions. Top by Δscore:

Variant	Effect	Δscore
16:88653294:CCTCA:C	donor_loss	1.0000
16:88653295:CTCAC:C	donor_loss	1.0000
16:88653296:TCA:T	donor_loss	1.0000
16:88653298:A:C	donor_loss	1.0000
16:88653299:C:CA	donor_loss	1.0000
16:88653408:CCT:C	acceptor_loss	1.0000
16:88653409:C:CG	acceptor_loss	1.0000
16:88653410:T:C	acceptor_loss	1.0000
16:88654690:A:AC	donor_gain	1.0000
16:88654691:C:CC	donor_gain	1.0000
16:88654691:CGTGT:C	donor_gain	1.0000
16:88655418:C:CC	acceptor_gain	1.0000
16:88655729:ACCT:A	acceptor_loss	1.0000
16:88655730:CCTG:C	acceptor_loss	1.0000
16:88657578:GCGGA:G	acceptor_gain	1.0000
16:88657579:CGGA:C	acceptor_gain	1.0000
16:88657579:CGGAC:C	acceptor_gain	1.0000
16:88657580:GGA:G	acceptor_gain	1.0000
16:88657580:GGAC:G	acceptor_loss	1.0000
16:88657582:ACTG:A	acceptor_loss	1.0000
16:88657583:C:CC	acceptor_gain	1.0000
16:88657583:C:CG	acceptor_loss	1.0000
16:88657913:A:AC	donor_gain	1.0000
16:88657913:ACTCT:A	donor_gain	1.0000
16:88657914:C:CA	donor_gain	1.0000
16:88657914:CT:C	donor_gain	1.0000
16:88657914:CTCT:C	donor_gain	1.0000
16:88657914:CTCTC:C	donor_gain	1.0000
16:88657917:T:A	donor_gain	1.0000
16:88657953:T:TA	donor_gain	1.0000

AlphaMissense

2576 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:88658671:G:C	S40R	0.997
16:88658671:G:T	S40R	0.997
16:88658673:T:G	S40R	0.997
16:88663030:G:C	N17K	0.995
16:88663030:G:T	N17K	0.995
16:88656200:A:G	W170R	0.992
16:88656200:A:T	W170R	0.992
16:88656222:G:C	S162R	0.992
16:88656222:G:T	S162R	0.992
16:88656224:T:G	S162R	0.992
16:88657440:G:C	C133W	0.992
16:88655316:G:C	S260R	0.991
16:88655316:G:T	S260R	0.991
16:88655318:T:G	S260R	0.991
16:88656234:G:C	S158R	0.991
16:88656234:G:T	S158R	0.991
16:88656236:T:G	S158R	0.991
16:88655680:A:C	S218R	0.990
16:88655680:A:T	S218R	0.990
16:88655682:T:G	S218R	0.990
16:88663014:A:G	Y23H	0.990
16:88658672:C:A	S40I	0.989
16:88655668:G:C	S222R	0.987
16:88655668:G:T	S222R	0.987
16:88655670:T:G	S222R	0.987
16:88663015:C:A	K22N	0.987
16:88663015:C:G	K22N	0.987
16:88657441:C:T	C133Y	0.986
16:88663025:G:T	A19E	0.986
16:88658672:C:T	S40N	0.984

dbSNP variants (sampled 300 via entrez): RS1000078836 (16:88660005 G>A,C), RS1000224441 (16:88655799 C>T), RS1000510917 (16:88652000 A>C,G), RS1000667256 (16:88652372 A>T), RS1000922064 (16:88663296 G>A,T), RS1001123026 (16:88660045 C>T), RS1001254094 (16:88653181 C>G), RS1001260161 (16:88660283 G>T), RS1001406216 (16:88655965 C>G,T), RS1001429506 (16:88652603 C>T), RS1001464758 (16:88658494 G>A), RS1001520966 (16:88652743 T>C), RS1001706757 (16:88653021 G>A), RS1002125501 (16:88659005 G>A), RS1002180607 (16:88660922 C>T)

Disease associations

OMIM: gene MIM:603236 | disease phenotypes: MIM:614714, MIM:148050

GenCC curated gene-disease

Disease	Classification	Inheritance
porokeratosis 7, multiple types	Strong	Autosomal dominant
nonsyndromic genetic hearing loss	Strong	Autosomal dominant
disseminated superficial actinic porokeratosis	Supportive	Autosomal dominant

Mondo (6): porokeratosis 7, multiple types (MONDO:0013868), linear porokeratosis (MONDO:0023246), 16q24.3 microdeletion syndrome (MONDO:0016838), KBG syndrome (MONDO:0007846), disseminated superficial actinic porokeratosis (MONDO:0019212), nonsyndromic genetic hearing loss (MONDO:0019497)

Orphanet (2): 16q24.3 microdeletion syndrome (Orphanet:261250), KBG syndrome (Orphanet:2332)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000989	Pruritus
HP:0000992	Cutaneous photosensitivity
HP:0001036	Parakeratosis
HP:0002860	Squamous cell carcinoma
HP:0200044	Porokeratosis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003479_9	Hair color	1.000000e-07
GCST006947_20	Feeling fed-up	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009588	feeling “fed-up” measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C537015	KBG syndrome (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4340 (SINGLE PROTEIN)

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 (13 total), top 13:

Ligand	Action	Affinity	Parameter
diphosphoglycolyl proline	Competitive	8.64	pKi
6-fluoromevalonate pyrophosphate	Competitive	7.43	pKi
6-fluoromevalonate 5-diphosphate	Competitive	7.21	pKi
analog 3 [Vlattas et al., 1996]	Competitive	6.12	pKi
P’-geranyl 3,5,8-trihydroxy-3-methyloctanate 8-diphosphate	Competitive	5.7	pIC50
P’-geranyl 3,5,7-trihydroxy-3-methylheptanate 7-diphosphate	Competitive	5.59	pIC50
2-fluoromevalonate 5-diphosphate	Irreversible inhibition	5.52	pKi
P’-geranyl 2-fluoromevalonate 5-diphosphate	Competitive	5.38	pKi
geranyl diphosphate	Feedback inhibition	5.3	pIC50
P’-geranyl 3,5,9-trihydroxy-3-methylnonanate 9-diphosphate	Competitive	5.19	pKi
2,2-difluoromevalonate 5-diphosphate	Competitive	5.12	pIC50
compound 18 [PMID: 17888661]	Competitive	4.1	pIC50
compound 19 [PMID: 17888661]	Competitive	3.92	pIC50

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.05	IC50	9	nM	CHEMBL1160294
7.82	IC50	15	nM	CHEMBL1160331
7.43	Ki	37	nM	CHEMBL1160328
6.82	IC50	150	nM	CHEMBL1160329
6.52	IC50	300	nM	CHEMBL1160332
6.12	Ki	750	nM	CHEMBL1160330

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
fatostatin	decreases expression, increases reaction, increases response to substance	4
bisphenol A	affects expression, decreases methylation, increases expression	3
Benzo(a)pyrene	decreases expression	3
Cisplatin	affects cotreatment, increases expression, decreases expression, affects expression	3
Cyclosporine	decreases expression, increases expression	3
Aflatoxin B1	affects expression, decreases expression	3
sodium arsenite	increases expression	2
nickel sulfate	increases expression	2
perfluorooctane sulfonic acid	decreases expression	2
Potassium Dichromate	increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Cadmium Chloride	increases abundance, increases expression	2
aristolochic acid I	increases expression	1
afuresertib	increases expression	1
bisphenol F	increases expression	1
22-hydroxycholesterol	decreases expression	1
methyleugenol	decreases expression	1
cupric chloride	decreases expression	1
cupric oxide	increases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
5-diphosphomevalonic acid	increases metabolic processing	1
avobenzone	increases expression	1
dinophysistoxin 1	decreases expression	1
tebuconazole	increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
obeticholic acid	decreases expression	1
bisphenol B	increases expression	1
quinocetone	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	affects expression	1
archazolid B	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL713612	Binding	Compound was evaluated for its inhibitory activity against MevPP decarboxylase	Inhibition of mevalonate 5-pyrophosphate decarboxylase by a proline-containing transition state analog — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06465641	PHASE4	RECRUITING	Methylphenidate in KBG Syndrome: N-of-1 Series
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families