CNP

Summary

CNP (2’,3’-cyclic nucleotide 3’ phosphodiesterase, HGNC:2158) is a protein-coding gene on chromosome 17q21.2, encoding 2’,3’-cyclic-nucleotide 3’-phosphodiesterase (P09543). Myelin-associated enzyme that catalyzes the phosphodiester hydrolysis of 2’,3’-cyclic nucleotides to 2’-nucleotides.

Predicted to enable 2’,3’-cyclic-nucleotide 3’-phosphodiesterase activity. Involved in substantia nigra development. Located in cytoplasm; extracellular space; and microtubule. Implicated in hypomyelinating leukodystrophy 20; multiple sclerosis; and schizophrenia. Biomarker of alcoholic liver cirrhosis; multiple sclerosis; and restless legs syndrome.

Source: NCBI Gene 1267 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukodystrophy, hypomyelinating, 20 (Limited, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 76 total — 5 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_033133

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2158
Approved symbol	CNP
Name	2’,3’-cyclic nucleotide 3’ phosphodiesterase
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	CN37
Ensembl gene	ENSG00000173786
Ensembl biotype	protein_coding
OMIM	123830
Entrez	1267

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000393888, ENST00000393892, ENST00000441615, ENST00000472031, ENST00000486438, ENST00000585452, ENST00000587679, ENST00000589772, ENST00000591945, ENST00000592105, ENST00000592446, ENST00000592861

RefSeq mRNA: 2 — MANE Select: NM_033133 NM_001330216, NM_033133

CCDS: CCDS11414, CCDS82123

Canonical transcript exons

ENST00000393892 — 4 exons

Exon	Start	End
ENSE00002336271	41968068	41968740
ENSE00002426903	41966795	41966887
ENSE00002862944	41973475	41977740
ENSE00003647193	41971892	41972031

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 80.7531 / max 7218.4624, expressed in 1819 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160893	58.9032	1807
160892	8.3433	1778
160894	6.3710	101
160891	4.2625	1684
208197	1.6247	1190
208196	0.6309	349
160899	0.3015	88
160904	0.2569	58
160895	0.0590	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior olivary complex	UBERON:0002127	99.76	gold quality
inferior vagus X ganglion	UBERON:0005363	99.72	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.68	gold quality
olfactory bulb	UBERON:0002264	99.67	gold quality
spinal cord	UBERON:0002240	99.64	gold quality
lateral globus pallidus	UBERON:0002476	99.61	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.58	gold quality
corpus callosum	UBERON:0002336	99.58	gold quality
subthalamic nucleus	UBERON:0001906	99.53	gold quality
medulla oblongata	UBERON:0001896	99.47	gold quality
cranial nerve II	UBERON:0000941	99.40	gold quality
globus pallidus	UBERON:0001875	99.38	gold quality
medial globus pallidus	UBERON:0002477	99.38	gold quality
ventral tegmental area	UBERON:0002691	99.36	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.29	gold quality
midbrain	UBERON:0001891	99.26	gold quality
superior vestibular nucleus	UBERON:0007227	99.25	gold quality
substantia nigra	UBERON:0002038	99.24	gold quality
substantia nigra pars compacta	UBERON:0001965	99.19	gold quality
putamen	UBERON:0001874	99.11	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.03	gold quality
middle frontal gyrus	UBERON:0002702	99.02	gold quality
amygdala	UBERON:0001876	98.93	gold quality
Ammon’s horn	UBERON:0001954	98.90	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.81	gold quality
caudate nucleus	UBERON:0001873	98.71	gold quality
tibial nerve	UBERON:0001323	98.63	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.58	gold quality
prefrontal cortex	UBERON:0000451	98.56	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.55	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	2500.63
E-GEOD-180759	yes	1367.95
E-GEOD-81547	yes	740.34
E-MTAB-7249	yes	184.94
E-HCAD-35	yes	87.71
E-HCAD-11	yes	26.50
E-GEOD-84465	yes	25.32
E-GEOD-81608	yes	15.80
E-ANND-3	yes	12.76
E-MTAB-7037	no	614.61
E-GEOD-124858	no	489.31

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 28)

• crystal structure of 2’,3’-cyclic nucleotide 3’-phosphohydrolase (PMID:15502338)
• crystal structure of the catalytic fragment (PMID:15713463)
• CNP interacts with tubulin and promotes microtubule assembly for process outgrowth in oligodendrocytes. (PMID:16103231)
• The larger CNP isoform, CNP2, contains an N-terminal mitochondrial targeting signal and is localized either in the cytoplasm or mitochondria. Mitochondrial localization is regulated by phosphorylation of the targeting signal by PKC. (PMID:16343930)
• reduced CNP expression in the schizophrenic brain is relevant to disease etiology and therefore provide support for the general hypothesis that altered oligodendrocyte function is an etiological factor in schizophrenia. (PMID:16389193)
• The crystal structure of the catalytic fragment of human CNP (hCNP-CF) at 1.3 A resolution, is determined. (PMID:17150526)
• study did not find an association between genetic variations in the CNP gene and schizophrenia in the Han Chinese population (PMID:17306456)
• MOBP and CNP protein in the white matter was not altered. (PMID:17964117)
• The effect of rs2070106 genotype on the CNP expression was transcript specific, and that the genotype was not associated with the expression of other oligodendrocyte-related genes. (PMID:18289148)
• This finding provides support for potential association of the CNP gene but not the MAG gene in schizophrenia in a Caucasian population. (PMID:18496213)
• Almost all multiple sclerosis patients had cerebrospinal fluid IgG directed to isoforms of one of the oligodendroglial molecules, transketolase, 2’,3’-cyclic-nucleotide 3’-phosphodiesterase type I, collapsin response mediator protein 2, and tubulin beta4. (PMID:18676363)
• This protein has been found differentially expressed in the temporal lobe from patients with schizophrenia. (PMID:19034380)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia (PMID:19165527)
• The results suggest that the CNP gene may not be involved in the etiology and pathology of schizophrenia in the Chinese population (PMID:19348671)
• verified the molecular interaction of Nogo-A with 2’, 3’-cyclic nucleotide 3’-phosphodiesterase (CNP), which could act as a conformational stabilizer for the intrinsically unstructured large segment of Amino-Nogo (PMID:19508346)
• The characteristic features in both humans and mice with their partial CNP ’loss-of-function’ genotype are best described as ‘catatonia-depression’ syndrome. (PMID:22473874)
• Differential CNP expression correlated with mouse model survival, and CNP immunoassay of a large GBM tissue microarray also showed significant differential patient survival (PMID:22589395)
• No Alzheimer disease-associated differences in CNP and DPYSL2 promoter DNA methylation were observed. (PMID:22954668)
• Bipolar I disorder and schizophrenia ahare a number of common genetic risk loci and susceptibility genes including the genes coding for 2’,3’-cyclic nucleotide 3’ phosphodiesterase enzyme. (PMID:23032943)
• CNP binds to the structural protein Gag and blocks HIV-1 particle assembly after Gag and viral RNA have associated with the plasma membrane. (PMID:23084924)
• 2’,3’-cyclic nucleotide 3’-phosphodiesterases inhibit hepatitis B virus replication. (PMID:24260477)
• kidneys express 2’,3’-cyclic nucleotide 3’-phosphodiesterase (CNPase), and renal CNPase mediates in part the renal 2’,3’-cAMP-adenosine pathway (PMID:24808540)
• This study showed that the expression of CNPase protein was significantly decreased but increase expression mrna in ventral prefrontal white matter in major depressive disorder. (PMID:25930075)
• CNP and RtcA fine-tune XBP1 output during ER stress (PMID:30355738)
• Catatonia-related executive dysfunction and brain atrophy of Cnp(-/-) mice fail to improve under PLX5622. (PMID:31090455)
• 2’,3’-Cyclic-nucleotide 3’-phosphodiesterase contributes to epithelial-mesenchymal transition of lens epithelial cells through the notch signalling pathway (PMID:31617266)
• CNP deficiency causes severe hypomyelinating leukodystrophy. (PMID:32128616)
• Circ-AFF2/miR-650/CNP axis promotes proliferation, inflammatory response, migration, and invasion of rheumatoid arthritis synovial fibroblasts. (PMID:33653372)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnp	ENSDARG00000070822
mus_musculus	Cnp	ENSMUSG00000006782
rattus_norvegicus	Cnp	ENSRNOG00000017496
caenorhabditis_elegans		WBGENE00017811

Protein

Protein identifiers

2’,3’-cyclic-nucleotide 3’-phosphodiesterase — P09543 (reviewed: P09543)

All UniProt accessions (6): P09543, C9K0L8, K7EN66, K7EQ27, K7ERC4, K7ERZ0

UniProt curated annotations — full annotation on UniProt →

Function. Myelin-associated enzyme that catalyzes the phosphodiester hydrolysis of 2’,3’-cyclic nucleotides to 2’-nucleotides. In the mitochondria, regulates the functioning of the mitochondrial permeability transition pore (mPTP), and thus is involved in the mechanisms of cell death, both apoptosis and necrosis. Acts as an antiviral factor by suppressing the assembly of SARS-CoV-2 virions. Acts as an antiviral factor by suppressing the assembly of HIV-1 virions through direct interaction with GAG.

Subunit / interactions. Exists as monomers and homodimers. (Microbial infection) Interacts with HIV-1 protein GAG; this interaction inhibits HIV-1 assembly.

Subcellular location. Melanosome. Mitochondrion Cell membrane.

Post-translational modifications. Acetylated. Acetylation suppresses enzymatic activity through restricting substrate accessibility. Deacetylated by SIRT3.

Disease relevance. Leukodystrophy, hypomyelinating, 20 (HLD20) [MIM:619071] An autosomal recessive disorder characterized by neuroregression and loss of motor, language and cognitive skills, after a normal early development. Disease onset is between 12 and 18 month of age. Patients show poor overall growth, microcephaly, feeding difficulties and spastic quadriplegia. Some patients may have seizures. Death in childhood may occur. Hypomyelinating leukodystrophy with subcortical and periventricular white matter abnormalities is seen on brain imaging. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the 2H phosphoesterase superfamily. CNPase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P09543-1	CNPII, DNAII	yes
P09543-2	CNPI, DNAI

RefSeq proteins (2): NP_001317145, NP_149124* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008431	CNPase	Family
IPR009097	Cyclic_Pdiesterase	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR047325	CNPase_cat	Domain

Pfam: PF05881, PF13671

Enzyme classification (BRENDA):

• EC 3.1.4.37 — 2’,3’-cyclic-nucleotide 3’-phosphodiesterase (BRENDA: 30 organisms, 71 substrates, 68 inhibitors, 90 Km, 72 kcat entries)
• EC 3.1.4.58 — RNA 2’,3’-cyclic 3’-phosphodiesterase (BRENDA: 6 organisms, 5 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
CYCLIC 2’,3’-AMP	0.49–100	19
2’,3’-CNADP	0.098–0.55	16
2’,3’-CAMP	0.25–13.1	13
2’,3’-CNADP+	0.483–39.648	13
2’,3’-CYCLIC AMP	0.553–1.305	5
2’,3’-CCMP	0.8–25.2	3
2’,3’-CGMP	0.57–9.2	3
2’,3’-CUMP	8.3–25.3	2
1,N6-ETHENO-2-AZAADENOSINE-2’,3’-CYCLIC MONOPHOS	10	1
1,N6-ETHENOADENOSINE-2’,3’-CYCLIC MONOPHOSPHATE	8.3	1
2’-AMP	0.76	1
3’-AMP	0.046	1
ADP	0.19	1
ATP	0.18	1
BIS-P-NITROPHENYL PHOSPHATE	0.16	1

Catalyzed reactions (Rhea), 1 shown:

• a nucleoside 2’,3’-cyclic phosphate + H2O = a nucleoside 2’-phosphate + H(+) (RHEA:14489)

UniProt features (38 total): modified residue 9, helix 9, strand 8, sequence variant 2, active site 2, binding site 2, chain 1, propeptide 1, lipid moiety-binding region 1, splice variant 1, mutagenesis site 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1WOJ	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P09543-F1	87.54	0.74

Functional residue map

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

Catalytic / active sites (2): 251 (proton acceptor); 330 (proton donor)

Ligand- & substrate-binding residues (2): 253; 332

Post-translational modifications (10): 170, 196, 359, 386, 418, 418, 6, 9, 110, 151

Mutagenesis-validated functional residues (1):

Position	Phenotype
418	loss of plasma membrane localization.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 346 (showing top): MYOGENIN_Q6, MODULE_274, GOBP_BEHAVIOR, GOBP_ADULT_BEHAVIOR, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CYCLIC_NUCLEOTIDE_METABOLIC_PROCESS, AP2_Q3, GOBP_ADULT_LOCOMOTORY_BEHAVIOR, CAGCTG_AP4_Q5, GOBP_CYCLIC_NUCLEOTIDE_CATABOLIC_PROCESS, GOBP_CELL_CELL_SIGNALING, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS

GO Biological Process (7): chemical synaptic transmission (GO:0007268), axonogenesis (GO:0007409), adult locomotory behavior (GO:0008344), cyclic nucleotide catabolic process (GO:0009214), response to toxic substance (GO:0009636), substantia nigra development (GO:0021762), oligodendrocyte differentiation (GO:0048709)

GO Molecular Function (4): RNA binding (GO:0003723), 2’,3’-cyclic-nucleotide 3’-phosphodiesterase activity (GO:0004113), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (8): obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), microtubule (GO:0005874), membrane (GO:0016020), melanosome (GO:0042470), myelin sheath (GO:0043209), synapse (GO:0045202), extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
anterograde trans-synaptic signaling	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
locomotory behavior	1
adult behavior	1
nucleotide catabolic process	1
cyclic nucleotide metabolic process	1
response to chemical	1
midbrain development	1
neural nucleus development	1
central nervous system development	1
glial cell differentiation	1
nucleic acid binding	1
cyclic-nucleotide phosphodiesterase activity	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
pigment granule	1
cell junction	1
extracellular vesicle	1

Protein interactions and networks

STRING

1303 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNP	MBP	P02686	894
CNP	GFAP	P14136	867
CNP	MAG	P20916	861
CNP	PLP1	P04400	831
CNP	OLIG2	Q13516	828
CNP	MOG	Q16653	818
CNP	DNAJC7	Q99615	765
CNP	GALC	P54803	758
CNP	OLIG1	Q8TAK6	733
CNP	MOBP	Q13875	725
CNP	RBFOX3	A6NFN3	712
CNP	PDGFRA	P16234	701
CNP	NES	P48681	689
CNP	CLDN11	O75508	675
CNP	AIF1	P55008	664

IntAct

172 interactions, top by confidence:

A	B	Type	Score
SMARCB1	ARID1A	psi-mi:“MI:0914”(association)	0.860
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PKN3	ARHGAP10	psi-mi:“MI:0914”(association)	0.680
CNP	HTT	psi-mi:“MI:0915”(physical association)	0.670
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
MTNR1A	PGRMC1	psi-mi:“MI:0914”(association)	0.530
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
RAB29	CNP	psi-mi:“MI:0915”(physical association)	0.400
CNP	SIRT3	psi-mi:“MI:0915”(physical association)	0.400
PPP1CA	CNP	psi-mi:“MI:0915”(physical association)	0.370
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
E7	AP2A1	psi-mi:“MI:0914”(association)	0.350
	VWA8	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
	IPO5	psi-mi:“MI:0914”(association)	0.350

BioGRID (240): CNP (Two-hybrid), CNP (Affinity Capture-Western), CNP (Affinity Capture-MS), CNP (Affinity Capture-MS), CNP (Affinity Capture-MS), SIRT3 (Affinity Capture-MS), CNP (Affinity Capture-MS), CNP (Affinity Capture-MS), CNP (Affinity Capture-MS), CNP (Affinity Capture-MS), CNP (Affinity Capture-MS), CNP (Affinity Capture-MS), SIRT3 (Affinity Capture-MS), CNP (Affinity Capture-MS), CNP (Affinity Capture-MS)

ESM2 similar proteins: A0A0M5K865, A0A2H5RJD4, A0JND4, A4RKC3, A8N5E5, A8NS89, B0D0N9, B4IB36, B4QL99, B6K0N7, E9M7A1, F4IF36, F4JPP0, G4YRT1, G4YUT3, P06623, P09543, P0CV73, P93042, Q0E0Q3, Q0JLS6, Q0UI93, Q1LZE8, Q2H0G2, Q2M3Z7, Q2M3Z8, Q2M405, Q2M408, Q2QMH2, Q2R224, Q2VF19, Q43827, Q5M888, Q5RFD0, Q5RFL4, Q6FLD4, Q75EG6, Q7S8J7, Q803H0, Q810J8

Diamond homologs: P06623, P09543, P13233, P16330, Q5RFD0, Q5TBK1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CNP	“down-regulates activity”	MBP

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 175 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
VEGFR2 mediated cell proliferation	5	22.1×	4e-04
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	20.1×	4e-04
RAS processing	5	18.4×	6e-04
Downstream signal transduction	6	17.7×	3e-04
Signaling by SCF-KIT	6	11.6×	9e-04
Signaling by FGFR1 in disease	5	11.3×	2e-03
NCAM signaling for neurite out-growth	5	10.5×	3e-03
Regulation of RAS by GAPs	7	10.5×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	7	19.3×	5e-05
vascular endothelial growth factor receptor signaling pathway	5	15.7×	3e-03
cell surface receptor protein tyrosine kinase signaling pathway	10	11.4×	3e-05
protein autophosphorylation	10	9.5×	5e-05
neuron apoptotic process	7	8.5×	3e-03
Ras protein signal transduction	6	8.1×	9e-03
MAPK cascade	7	7.0×	8e-03
positive regulation of MAPK cascade	12	6.3×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	0
Uncertain significance	56
Likely benign	10
Benign	2

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
693983	NM_033133.5(CNP):c.59A>C (p.Lys20Thr)	Pathogenic
834076	NM_033133.5(CNP):c.1034G>A (p.Gly345Asp)	Pathogenic
834077	NM_033133.5(CNP):c.59A>G (p.Lys20Arg)	Pathogenic
834079	NM_033133.5(CNP):c.-67C>T	Pathogenic
983536	NM_033133.5(CNP):c.245C>T (p.Ser82Leu)	Pathogenic

SpliceAI

1146 predictions. Top by Δscore:

Variant	Effect	Δscore
17:41968695:G:GT	donor_gain	1.0000
17:41968739:AT:A	donor_gain	1.0000
17:41968741:G:GG	donor_gain	1.0000
17:41971886:C:A	acceptor_gain	1.0000
17:41971888:GCA:G	acceptor_loss	1.0000
17:41971889:CAG:C	acceptor_loss	1.0000
17:41971890:A:AG	acceptor_gain	1.0000
17:41971890:AGTC:A	acceptor_gain	1.0000
17:41971890:AGTCG:A	acceptor_loss	1.0000
17:41971891:G:GA	acceptor_gain	1.0000
17:41971891:GT:G	acceptor_gain	1.0000
17:41971891:GTC:G	acceptor_gain	1.0000
17:41971891:GTCG:G	acceptor_gain	1.0000
17:41971891:GTCGT:G	acceptor_gain	1.0000
17:41972027:AAGAT:A	donor_gain	1.0000
17:41972028:AGAT:A	donor_gain	1.0000
17:41972029:GAT:G	donor_gain	1.0000
17:41972029:GATG:G	donor_gain	1.0000
17:41972030:AT:A	donor_gain	1.0000
17:41972030:ATG:A	donor_loss	1.0000
17:41972031:TG:T	donor_loss	1.0000
17:41972032:G:GG	donor_gain	1.0000
17:41977256:CCTA:C	donor_loss	1.0000
17:41977258:TA:T	donor_loss	1.0000
17:41977259:A:AT	donor_loss	1.0000
17:41977260:CCT:C	donor_loss	1.0000
17:41977337:CAAG:C	acceptor_gain	1.0000
17:41977338:A:T	acceptor_gain	1.0000
17:41977340:G:C	acceptor_gain	1.0000
17:41977340:G:GC	acceptor_gain	1.0000

AlphaMissense

2724 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:41968524:T:A	W154R	0.999
17:41968524:T:C	W154R	0.999
17:41968638:T:A	W192R	0.999
17:41968638:T:C	W192R	0.999
17:41968233:G:C	G57R	0.998
17:41968243:G:A	G60E	0.998
17:41968245:A:C	S61R	0.998
17:41968247:C:A	S61R	0.998
17:41968247:C:G	S61R	0.998
17:41968251:A:C	K63Q	0.998
17:41968253:G:C	K63N	0.998
17:41968253:G:T	K63N	0.998
17:41968513:C:A	P150H	0.998
17:41968546:T:A	L161H	0.998
17:41968546:T:C	L161P	0.998
17:41973586:T:A	W310R	0.998
17:41973586:T:C	W310R	0.998
17:41973701:T:C	L348P	0.998
17:41968249:G:A	G62D	0.997
17:41968252:A:T	K63M	0.997
17:41968636:G:A	G191D	0.997
17:41971971:C:G	C252W	0.997
17:41973551:C:A	A298D	0.997
17:41973796:T:A	W380R	0.997
17:41973796:T:C	W380R	0.997
17:41968251:A:G	K63E	0.996
17:41968545:C:T	L161F	0.996
17:41971969:T:C	C252R	0.996
17:41973563:T:C	L302S	0.996
17:41973644:C:A	A329D	0.996

dbSNP variants (sampled 300 via entrez): RS1000096123 (17:41967975 G>A), RS1000688978 (17:41969266 C>T), RS1001208996 (17:41969586 C>T), RS1001796470 (17:41975884 G>A), RS1001870381 (17:41972351 A>G), RS1001911122 (17:41976186 C>A), RS1004253826 (17:41973244 C>T), RS1004660030 (17:41965887 G>C,T), RS1004723915 (17:41967273 G>A), RS1004816291 (17:41971740 T>G), RS1005160562 (17:41968444 A>G), RS1005384414 (17:41977012 G>C), RS1007460964 (17:41965004 T>C), RS1007504845 (17:41969713 G>A), RS1007811506 (17:41975032 T>C)

Disease associations

OMIM: gene MIM:123830 | disease phenotypes: MIM:619071, MIM:100800, MIM:160700

GenCC curated gene-disease

Disease	Classification	Inheritance
leukodystrophy, hypomyelinating, 20	Limited	Autosomal recessive

Mondo (3): leukodystrophy, hypomyelinating, 20 (MONDO:0033657), achondroplasia (MONDO:0007037), myopia 2, autosomal dominant (MONDO:0008053)

Orphanet (1): Achondroplasia (Orphanet:15)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_110	Blood protein levels	4.000000e-12

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000130	Achondroplasia	C05.116.099.343.110; C05.116.099.708.017; C16.320.240.500
C563541	Myopia 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066309 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression	3
Tobacco Smoke Pollution	increases expression, affects expression	3
sodium arsenite	decreases expression, increases expression	2
perfluorooctanoic acid	decreases expression	2
Leflunomide	decreases expression	2
Tretinoin	increases expression	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
beauvericin	affects cotreatment, increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
enniatins	affects cotreatment, increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Amiodarone	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651141	Binding	Binding affinity to human CNP incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1NS	Abcam HeLa CNP KO	Cancer cell line	Female
CVCL_SJ41	HAP1 CNP (-) 1	Cancer cell line	Male
CVCL_XM90	HAP1 CNP (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05353192	PHASE4	UNKNOWN	A Study to Evaluate the Efficacy and Safety of Recombinant Human Growth Hormone in Children With Achondroplasia
NCT03197766	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of BMN 111 in Children With Achondroplasia
NCT03424018	PHASE3	ACTIVE_NOT_RECRUITING	An Extension Study to Evaluate the Efficacy and Safety of BMN 111 in Children With Achondroplasia
NCT06164951	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Infigratinib in Children and Adolescents With Achondroplasia
NCT06926491	PHASE3	RECRUITING	Evaluate the Efficacy and Safety of KK8398 in Patients With Achondroplasia（AOBA Study）
NCT02055157	PHASE2	COMPLETED	A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia
NCT02724228	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate Long-Term Safety, Tolerability, & Efficacy of BMN 111 in Children With Achondroplasia (ACH)
NCT03583697	PHASE2	COMPLETED	A Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children With Achondroplasia
NCT03989947	PHASE2	ACTIVE_NOT_RECRUITING	An Extension Study to Evaluate Safety and Efficacy of BMN 111 in Children With Achondroplasia
NCT04085523	PHASE2	COMPLETED	A Dose Escalation Trial Evaluating Safety, Efficacy, and Pharmacokinetics of TransCon CNP Administered Once Weekly in Prepubertal Children With Achondroplasia
NCT04265651	PHASE2	COMPLETED	Study of Infigratinib in Children With Achondroplasia
NCT04554940	PHASE2	ACTIVE_NOT_RECRUITING	A Clinical Trial to Evaluate Safety of Vosoritide in At-risk Infants With Achondroplasia
NCT04638153	PHASE2	TERMINATED	A Study Of Safety, Tolerability And Effectiveness Of Recifercept In Children With Achondroplasia
NCT05116046	PHASE2	TERMINATED	Continuation Study of Long-term Safety, Tolerability, Pharmacokinetics and Efficacy of Recifercept in Achondroplasia
NCT05145010	PHASE2	ENROLLING_BY_INVITATION	Extension Study of Infigratinib in Children With Achondroplasia (ACH)
NCT05246033	PHASE2	UNKNOWN	A Dose Escalation Trial Evaluating Safety, Efficacy, and Pharmacokinetics of Multiple Subcutaneous Doses of TransCon CNP Administered Once Weekly in Children With Achondroplasia
NCT06079398	PHASE2	RECRUITING	A Clinical Trial to Evaluate Efficacy and Safety of TransCon CNP Compared With Placebo in Infants (0 to <2 Years of Age) With Achondroplasia
NCT06433557	PHASE2	ACTIVE_NOT_RECRUITING	A Phase 2 Clinical Trial to Evaluate Efficacy, Safety, and Tolerability of Navepegritide in Combination With Lonapegsomatropin in Children With Achondroplasia
NCT06732895	PHASE2	RECRUITING	A Clinical Trial to Evaluate Efficacy and Safety of Navepegritide in Adolescents (12 - 18 Years of Age) With Achondroplasia.
NCT06842355	PHASE2	RECRUITING	A Study of TYRA-300 in Children With Achondroplasia: BEACH301
NCT07169279	PHASE2	RECRUITING	Interventional Study of Infigratinib in Children < 3 Years Old With Achondroplasia (ACH)
NCT01590446	PHASE1	COMPLETED	A Study to Evaluate Safety and Tolerability of BMN 111 Administered to Healthy Adult Volunteers
NCT05813314	PHASE1	TERMINATED	Bioequivalence Study to Compare Two Injection Devices for BMN 111 in Healthy Participants
NCT05598320	PHASE2/PHASE3	COMPLETED	A Clinical Trial to Evaluate Efficacy and Safety of TransCon CNP Compared With Placebo in Children With Achondroplasia
NCT05929807	PHASE2/PHASE3	ENROLLING_BY_INVITATION	A Clinical Trial to Investigate Long-term Safety, Tolerability, and Efficacy of Weekly Subcutaneous Doses With TransCon CNP in Children and Adolescents With Achondroplasia
NCT07441876	PHASE2/PHASE3	RECRUITING	Study to Evaluate the Efficacy and Safety of BMN 333 Versus Vosoritide in Children With Achondroplasia
NCT07297875	PHASE1/PHASE2	NOT_YET_RECRUITING	A Study of ABSK061 to Assess Safety, Tolerability, Pharmacokinetics, and Efficacy in Children With Achondroplasia
NCT00001536	Not specified	COMPLETED	Issues Surrounding Prenatal Genetic Testing for Achondroplasia
NCT01435629	Not specified	COMPLETED	A Survey Collecting Data on Adult Height in Patients With Achondroplasia Treated With Somatropin
NCT01516229	Not specified	COMPLETED	Special Survey for Long Term Application
NCT01541306	Not specified	COMPLETED	C-Type Natriuretic Peptide and Achondroplasia
NCT01603095	Not specified	COMPLETED	A Multicenter, Multinational Clinical Assessment Study for Pediatric Patients With Achondroplasia
NCT02597881	Not specified	RECRUITING	Achondroplasia Natural History Multicenter Clinical Study
NCT03449368	Not specified	COMPLETED	Lifetime Impact of Achondroplasia Study in Europe-LIAISE
NCT03780153	Not specified	COMPLETED	The Norwegian Adult Achondroplasia Study
NCT03794609	Not specified	TERMINATED	Observational Study Investigating Clinical & Anthropometric Characteristics of Children With Achondroplasia.
NCT03872531	Not specified	COMPLETED	Lifetime Impact Study for Achondroplasia
NCT03875534	Not specified	COMPLETED	A Multi-center, Longitudinal, Observational Study of Children With Achondroplasia
NCT04035811	Not specified	COMPLETED	Prospective Clinical Assessment Study in Children With Achondroplasia (ACH)
NCT04184817	Not specified	UNKNOWN	Radiological Analysis on Patients With Achondroplasia Disorder