PRUNE1

Summary

PRUNE1 (prune exopolyphosphatase 1, HGNC:13420) is a protein-coding gene on chromosome 1q21.3, encoding Exopolyphosphatase PRUNE1 (Q86TP1). Phosphodiesterase (PDE) that has higher activity toward cAMP than cGMP, as substrate. It is a selective cancer dependency (DepMap: 16.3% of cell lines).

This gene encodes a member of the DHH protein superfamily of phosphoesterases. This protein has been found to function as both a nucleotide phosphodiesterase and an exopolyphosphatase. This protein is believed to stimulate cancer progression and metastases through the induction of cell motility. A pseuodgene has been identified on chromosome 13. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 58497 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (Strong, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 147 total — 15 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 52
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 16.3% of screened cell lines
• MANE Select transcript: NM_021222

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13420
Approved symbol	PRUNE1
Name	prune exopolyphosphatase 1
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	DRES-17, HTCD37, H-PRUNE
Ensembl gene	ENSG00000143363
Ensembl biotype	protein_coding
OMIM	617413
Entrez	58497

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 12 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000271620, ENST00000368934, ENST00000368935, ENST00000368936, ENST00000368937, ENST00000431193, ENST00000450884, ENST00000462440, ENST00000467771, ENST00000475722, ENST00000650332, ENST00000895151, ENST00000895152, ENST00000895153, ENST00000916910

RefSeq mRNA: 4 — MANE Select: NM_021222 NM_001303229, NM_001303242, NM_001303243, NM_021222

CCDS: CCDS76211, CCDS977

Canonical transcript exons

ENST00000271620 — 8 exons

Exon	Start	End
ENSE00001387705	151033806	151035713
ENSE00003472812	151025515	151025673
ENSE00003476991	151027233	151027327
ENSE00003522652	151008449	151008671
ENSE00003611260	151024611	151024795
ENSE00003618078	151018467	151018669
ENSE00003666187	151017812	151017904
ENSE00003681196	151028786	151028944

Expression profiles

Bgee: expression breadth ubiquitous, 228 present calls, max score 91.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.1442 / max 130.8728, expressed in 1778 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5173	10.7427	1748
5174	2.4917	1207
5175	0.4742	236
5172	0.4356	249

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	91.59	gold quality
apex of heart	UBERON:0002098	90.06	gold quality
cortical plate	UBERON:0005343	89.94	gold quality
monocyte	CL:0000576	89.89	gold quality
mononuclear cell	CL:0000842	89.70	gold quality
right atrium auricular region	UBERON:0006631	89.65	gold quality
leukocyte	CL:0000738	89.64	gold quality
right lobe of thyroid gland	UBERON:0001119	89.58	gold quality
gastrocnemius	UBERON:0001388	89.41	gold quality
left lobe of thyroid gland	UBERON:0001120	89.30	gold quality
muscle of leg	UBERON:0001383	89.23	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.80	gold quality
heart left ventricle	UBERON:0002084	88.60	gold quality
thyroid gland	UBERON:0002046	88.22	gold quality
cardiac ventricle	UBERON:0002082	87.94	gold quality
cardiac atrium	UBERON:0002081	87.91	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.63	gold quality
ganglionic eminence	UBERON:0004023	86.97	gold quality
heart	UBERON:0000948	86.88	gold quality
mucosa of transverse colon	UBERON:0004991	86.37	gold quality
granulocyte	CL:0000094	86.33	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.02	gold quality
right testis	UBERON:0004534	85.86	gold quality
sperm	CL:0000019	85.74	gold quality
lower esophagus mucosa	UBERON:0035834	85.73	gold quality
mucosa of stomach	UBERON:0001199	85.46	gold quality
rectum	UBERON:0001052	85.28	gold quality
endocervix	UBERON:0000458	85.25	gold quality
descending thoracic aorta	UBERON:0002345	85.19	gold quality
left testis	UBERON:0004533	85.07	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, ESR2

miRNA regulators (miRDB)

82 targeting PRUNE1, 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-5692A	100.00	74.40	6850
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-8054	99.48	70.81	2084
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 16.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 20)

• prune has a role in breast neoplasm aggressiveness (PMID:15671547)
• GSK-3 and h-prune cooperatively regulate the disassembly of focal adhesions to promote cell migration and that h-prune is useful as a marker for tumor aggressiveness. (PMID:16428445)
• Prune is composed of two independent active sites and two interaction sites for the assembly of oligomeric signalling complexes (PMID:17655525)
• Increased amplification of PRUNE is associated with T4 breast carcinoma. (PMID:20735841)
• Data indicate that the D388A and D422A mutant h-Prune proteins interact weakly with Nm23-H1. (PMID:23448979)
• Authors assessed h-Prune levels in peripheral blood of lung cancer patients using ELISA assay, showing that h-Prune is an early diagnostic marker for lung cancer. (PMID:25026278)
• h-Prune expression is necessary for cancer cell motility and EMT and is associated with liver and lung metastasis in colorectal cancer cells. h-Prune could be a new prognostic marker and molecular target for CRLM. (PMID:27037526)
• h-prune is frequently expressed in anaplastic thyroid cancer cells and lymph nodes metastasis, and promotes migration and invasion of anaplastic thyroid cancer cells and metastasis in an anaplastic thyroid cancer model. (PMID:27109060)
• These results further delineate a new PRUNE1-related syndrome, and highlight the importance of periodic data re-annotation in individuals who remain without a diagnosis after undergoing genome-wide testing. (PMID:28211990)
• PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment. (PMID:28334956)
• Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation (PMID:28334956)
• This study demonstrated that the role for PRUNE1 in metastatic MBGroup3. (PMID:29490009)
• show that mutant PRUNE1 mRNA can be subject to nonsense-mediated mRNA decay (PMID:29797509)
• PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. (PMID:29940663)
• Exome sequencing and homozygosity mapping identified a homozygous PRUNE1 mutation in a canonical splice site, which produces two abnormal PRUNE1 mRNA products. Based on our studies and the histopathology and phenotypic data, we provide further evidence that this disorder leads to a neurodegenerative disease affecting both the peripheral and central nervous systems and suggest that the pathogenic c.521-2A>G mutation could (PMID:30556349)
• The PRUNE gene should be considered in all the individuals with non-5q spinal muscular atrophy. High creatine kinase values may be a part of PRUNE disease spectrum. (PMID:32134588)
• NMIHBA results from hypomorphic PRUNE1 variants that lack short-chain exopolyphosphatase activity. (PMID:33105479)
• An identical-by-descent novel splice-donor variant in PRUNE1 causes a neurodevelopmental syndrome with prominent dystonia in two consanguineous Sudanese families. (PMID:34111303)
• Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies in a consanguineous Iranian family is associated with a homozygous start loss variant in the PRUNE1 gene. (PMID:35379233)
• PRUNE1 (located on chromosome 1q21.3) promotes multiple myeloma with 1q21 Gain by enhancing the links between purine and mitochondrion. (PMID:37666675)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	prune	ENSDARG00000076246
mus_musculus	Prune1	ENSMUSG00000015711
rattus_norvegicus	Prune1	ENSRNOG00000021120
drosophila_melanogaster	pn	FBGN0003116

Protein

Protein identifiers

Exopolyphosphatase PRUNE1 — Q86TP1 (reviewed: Q86TP1)

Alternative names: Drosophila-related expressed sequence 17, HTcD37, Protein prune homolog 1

All UniProt accessions (4): Q86TP1, A0A3B3ITN0, Q5SZF2, Q5SZG1

UniProt curated annotations — full annotation on UniProt →

Function. Phosphodiesterase (PDE) that has higher activity toward cAMP than cGMP, as substrate. Plays a role in cell proliferation, migration and differentiation, and acts as a negative regulator of NME1. Plays a role in the regulation of neurogenesis. Involved in the regulation of microtubule polymerization.

Subunit / interactions. Homooligomer. Able to homodimerize via its C-terminal domain. Interacts with NME1. Interacts with GSK3; at focal adhesion complexes where paxillin and vinculin are colocalized. Interacts with alpha and beta tubulin.

Subcellular location. Cytoplasm. Nucleus. Cell junction. Focal adhesion.

Tissue specificity. Ubiquitously expressed. Seems to be overexpressed in aggressive sarcoma subtypes, such as leiomyosarcomas and malignant fibrous histiocytomas (MFH) as well as in the less malignant liposarcomas.

Disease relevance. Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) [MIM:617481] An autosomal recessive neurodevelopmental and degenerative disorder characterized by primary microcephaly, profound global developmental delay, and severe intellectual disability. Additional clinical features include dysmorphic features, truncal hypotonia, peripheral spasticity, and lack of independent ambulation or speech acquisition. Brain imaging shows cortical atrophy, thin corpus callosum, cerebellar hypoplasia, and delayed myelination. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by magnesium ions and inhibited by manganese ions. Inhibited by dipyridamole, moderately sensitive to IBMX and inhibited by vinpocetine.

Cofactor. Binds 2 manganese ions per subunit.

Similarity. Belongs to the PPase class C family. Prune subfamily.

Isoforms (7)

UniProt ID	Names	Canonical?
Q86TP1-1	1	yes
Q86TP1-2	2
Q86TP1-3	3
Q86TP1-4	4
Q86TP1-5	5
Q86TP1-6	6
Q86TP1-7	7

RefSeq proteins (4): NP_001290158, NP_001290171, NP_001290172, NP_067045* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001667	DDH_dom	Domain
IPR004097	DHHA2	Domain
IPR038222	DHHA2_dom_sf	Homologous_superfamily
IPR038763	DHH_sf	Homologous_superfamily

Pfam: PF01368, PF02833

Catalyzed reactions (Rhea), 1 shown:

• diphosphate + H2O = 2 phosphate + H(+) (RHEA:24576)

UniProt features (33 total): sequence variant 8, splice variant 5, binding site 5, modified residue 4, mutagenesis site 4, sequence conflict 3, region of interest 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86TP1-F1	85.61	0.75

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 (5): 28; 30; 106; 106; 179

Post-translational modifications (4): 399, 410, 414, 1

Mutagenesis-validated functional residues (4):

Position	Phenotype
28	partial loss of camp pde activity. partial loss of camp pde activity; when associated with d-106. partial loss of camp p
106	no change in camp pde activity. partial loss of camp pde activity; when associated with d-28. partial loss of camp pde a
126–129	partial loss of camp pde activity.
179	partial loss of camp pde activity. partial loss of camp pde activity; when associated with d-28 and d-106.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 299 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, CMYB_01, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GGAMTNNNNNTCCY_UNKNOWN, PATIL_LIVER_CANCER, TCF4_Q5, ONKEN_UVEAL_MELANOMA_UP, GOBP_REGULATION_OF_MICROTUBULE_POLYMERIZATION

GO Biological Process (2): regulation of microtubule polymerization (GO:0031113), regulation of neurogenesis (GO:0050767)

GO Molecular Function (8): exopolyphosphatase activity (GO:0004309), inorganic diphosphate phosphatase activity (GO:0004427), tubulin binding (GO:0015631), phosphatase activity (GO:0016791), metal ion binding (GO:0046872), protein binding (GO:0005515), pyrophosphatase activity (GO:0016462), hydrolase activity (GO:0016787)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), focal adhesion (GO:0005925), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
pyrophosphatase activity	2
cellular anatomical structure	2
regulation of microtubule polymerization or depolymerization	1
regulation of protein polymerization	1
microtubule polymerization	1
regulation of supramolecular fiber organization	1
neurogenesis	1
regulation of nervous system development	1
regulation of cell development	1
cytoskeletal protein binding	1
phosphoric ester hydrolase activity	1
cation binding	1
binding	1
hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
cell-substrate junction	1
cell junction	1

Protein interactions and networks

STRING

654 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRUNE1	NME1	P15531	912
PRUNE1	BNIP2	Q12982	632
PRUNE1	DHH	O43323	542
PRUNE1	GSK3B	P49841	534
PRUNE1	PPA1	Q15181	532
PRUNE1	SCIN	Q9Y6U3	523
PRUNE1	PPP4C	P33172	516
PRUNE1	GSN	P06396	511
PRUNE1	CYFIP1	Q7L576	443
PRUNE1	PPA2	Q9H2U2	441
PRUNE1	NME2	P22392	435
PRUNE1	ARHGAP1	Q07960	399
PRUNE1	ALDH7A1	P49419	394
PRUNE1	CDKL5	O76039	387
PRUNE1	IP6K1	Q92551	383

IntAct

35 interactions, top by confidence:

A	B	Type	Score
GSK3B	AXIN1	psi-mi:“MI:0914”(association)	0.980
GSK3A	AXIN1	psi-mi:“MI:0914”(association)	0.800
NPAS1	DNAJB5	psi-mi:“MI:0914”(association)	0.530
SCGB1D4	EGFR	psi-mi:“MI:0914”(association)	0.530
INSYN2A	CHUK	psi-mi:“MI:0914”(association)	0.530
CCL22	PLXNA2	psi-mi:“MI:0914”(association)	0.530
GMFG	PRUNE1	psi-mi:“MI:0914”(association)	0.530
PRUNE1	NME1	psi-mi:“MI:0915”(physical association)	0.510
NME1	PRUNE1	psi-mi:“MI:0915”(physical association)	0.510
CXorf66	PRUNE1	psi-mi:“MI:0915”(physical association)	0.500
GSK3B	SEC16A	psi-mi:“MI:2364”(proximity)	0.420
GSK3B	SEC16A	psi-mi:“MI:0914”(association)	0.420
PRUNE1	RUFY3	psi-mi:“MI:0915”(physical association)	0.400
RAB2B	UBA6	psi-mi:“MI:0914”(association)	0.350
PIANP	TCAF2	psi-mi:“MI:0914”(association)	0.350
INSYN2A	NOP56	psi-mi:“MI:0914”(association)	0.350
CCL22	HSPA12A	psi-mi:“MI:0914”(association)	0.350
GMPPB	PRMT3	psi-mi:“MI:0914”(association)	0.350
GMFG	HSPA14	psi-mi:“MI:0914”(association)	0.350
GSK3B	MYO1C	psi-mi:“MI:0914”(association)	0.350
hspa1a_hspa1b_human-1	SHTN1	psi-mi:“MI:0914”(association)	0.350
CXorf66	LRP4	psi-mi:“MI:0914”(association)	0.350
NPAS1	DNAJB6	psi-mi:“MI:0914”(association)	0.350
SPANXN5	USP1	psi-mi:“MI:0914”(association)	0.350
BORCS7	SNAPIN	psi-mi:“MI:0914”(association)	0.350

BioGRID (84): PRUNE (Affinity Capture-RNA), PRUNE (Affinity Capture-RNA), PRUNE (Affinity Capture-RNA), PRUNE (Affinity Capture-MS), PRUNE (Affinity Capture-MS), PRUNE (Affinity Capture-MS), PRUNE (Affinity Capture-MS), PRUNE (Affinity Capture-MS), PRUNE (Affinity Capture-MS), PRUNE (Affinity Capture-MS), PRUNE (Affinity Capture-MS), PRUNE (Affinity Capture-MS), PRUNE (Affinity Capture-MS), PRUNE (Affinity Capture-MS), PRUNE (Proximity Label-MS)

ESM2 similar proteins: A6H757, A6QPN6, B1H1P9, B3SP85, F1N2K1, O46559, O94952, O95479, P22413, P56201, P57075, P98192, Q13219, Q3U3W5, Q3V3E1, Q499T2, Q502B3, Q53H76, Q5E9H0, Q5NDE3, Q5NDE4, Q5R5S1, Q5R5X9, Q5R8C0, Q5RBQ5, Q6AYG3, Q6P2P2, Q7TNH6, Q865R1, Q86TP1, Q86UX2, Q8BGG7, Q8BP40, Q8CFX1, Q8CIY2, Q8HZK2, Q8HZK3, Q8IUF8, Q8IYR2, Q8R4K8

Diamond homologs: O54940, P85298, Q07960, Q0IHU9, Q12982, Q1M168, Q52KR3, Q54TH9, Q5BJR4, Q5CZL1, Q5E9Y6, Q5FWK3, Q5R4Q8, Q5XGM5, Q6AYG3, Q7Z465, Q86TP1, Q86WG3, Q8BHE3, Q8BIW1, Q8WUY3, Q99JU7, Q9CXP4, Q9GKT0, Q9P3B1, Q9VTU3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 41 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.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of cell migration	6	10.3×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	7
Uncertain significance	43
Likely benign	56
Benign	11

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
1711746	NM_021222.3(PRUNE1):c.50dup (p.Leu18fs)	Pathogenic
1711747	NM_021222.3(PRUNE1):c.540T>A (p.Cys180Ter)	Pathogenic
1711748	NM_021222.3(PRUNE1):c.515T>C (p.Leu172Pro)	Pathogenic
2579198	GRCh38/hg38 1q21.3(chr1:151017715-151018767)x0	Pathogenic
2717697	NM_021222.3(PRUNE1):c.723_726del (p.Tyr242fs)	Pathogenic
2721856	NM_021222.3(PRUNE1):c.285C>G (p.Tyr95Ter)	Pathogenic
3376986	NM_021222.3(PRUNE1):c.762T>A (p.Tyr254Ter)	Pathogenic
3382517	NM_021222.3(PRUNE1):c.446del (p.Ala149fs)	Pathogenic
3685892	NM_021222.3(PRUNE1):c.712C>T (p.Gln238Ter)	Pathogenic
3895660	NM_021222.3(PRUNE1):c.385_392dup (p.Glu131fs)	Pathogenic
427231	NM_021222.3(PRUNE1):c.160C>A (p.Pro54Thr)	Pathogenic
427232	NM_021222.3(PRUNE1):c.889C>T (p.Arg297Trp)	Pathogenic
521739	NM_021222.3(PRUNE1):c.3_7dup (p.Asp3fs)	Pathogenic
521740	NM_021222.3(PRUNE1):c.661del (p.Ala221fs)	Pathogenic
932732	NM_021222.3(PRUNE1):c.132+2T>C	Pathogenic
1184491	NM_021222.3(PRUNE1):c.3G>A (p.Met1Ile)	Likely pathogenic
1189774	NM_021222.3(PRUNE1):c.380A>G (p.His127Arg)	Likely pathogenic
265536	NM_021222.3(PRUNE1):c.521-2A>G	Likely pathogenic
2904135	NM_021222.3(PRUNE1):c.39+1G>T	Likely pathogenic
3029943	NM_021222.3(PRUNE1):c.382C>T (p.Arg128Ter)	Likely pathogenic
402132	NM_021222.3(PRUNE1):c.520G>T (p.Gly174Ter)	Likely pathogenic
450387	NM_021222.3(PRUNE1):c.809T>C (p.Leu270Pro)	Likely pathogenic

SpliceAI

1070 predictions. Top by Δscore:

Variant	Effect	Δscore
1:151008670:AGGT:A	donor_loss	1.0000
1:151008671:GG:G	donor_loss	1.0000
1:151008672:G:GA	donor_loss	1.0000
1:151008673:T:G	donor_loss	1.0000
1:151017811:GGA:G	acceptor_gain	1.0000
1:151018670:G:GG	donor_gain	1.0000
1:151024596:C:G	acceptor_gain	1.0000
1:151024609:A:AG	acceptor_gain	1.0000
1:151024610:G:GG	acceptor_gain	1.0000
1:151024610:GAA:G	acceptor_gain	1.0000
1:151024610:GAAGT:G	acceptor_gain	1.0000
1:151025511:ACAGG:A	acceptor_loss	1.0000
1:151025512:CAGGA:C	acceptor_loss	1.0000
1:151025513:A:AG	acceptor_gain	1.0000
1:151025513:A:T	acceptor_loss	1.0000
1:151025513:AG:A	acceptor_gain	1.0000
1:151025514:G:GG	acceptor_gain	1.0000
1:151025514:GG:G	acceptor_gain	1.0000
1:151025514:GGAA:G	acceptor_gain	1.0000
1:151025656:C:T	donor_gain	1.0000
1:151027229:CTAG:C	acceptor_loss	1.0000
1:151027230:TA:T	acceptor_loss	1.0000
1:151027231:A:AG	acceptor_gain	1.0000
1:151027231:A:T	acceptor_loss	1.0000
1:151027232:G:GC	acceptor_loss	1.0000
1:151027232:G:GG	acceptor_gain	1.0000
1:151027232:GGA:G	acceptor_gain	1.0000
1:151027324:GGAG:G	donor_gain	1.0000
1:151027325:GAG:G	donor_gain	1.0000
1:151027325:GAGG:G	donor_gain	1.0000

AlphaMissense

2943 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:151025574:G:C	D194H	0.995
1:151018498:T:A	V55D	0.994
1:151024719:T:G	C148W	0.994
1:151027304:A:C	S251R	0.993
1:151027306:T:A	S251R	0.993
1:151027306:T:G	S251R	0.993
1:151017855:A:T	D28V	0.991
1:151017856:T:A	D28E	0.991
1:151017856:T:G	D28E	0.991
1:151028901:G:C	R297P	0.991
1:151017855:A:C	D28A	0.990
1:151018651:A:T	D106V	0.990
1:151024654:C:G	H127D	0.989
1:151024656:T:A	H127Q	0.989
1:151024656:T:G	H127Q	0.989
1:151017862:C:A	D30E	0.988
1:151017862:C:G	D30E	0.988
1:151024658:G:C	R128P	0.988
1:151025531:C:A	D179E	0.988
1:151025531:C:G	D179E	0.988
1:151025647:T:C	L218P	0.988
1:151017861:A:T	D30V	0.987
1:151017863:T:C	S31P	0.987
1:151018652:C:A	D106E	0.987
1:151018652:C:G	D106E	0.987
1:151025575:A:C	D194A	0.987
1:151025596:T:C	L201P	0.987
1:151027254:T:C	L234P	0.987
1:151034112:A:C	S414R	0.987
1:151034114:C:A	S414R	0.987

dbSNP variants (sampled 300 via entrez): RS1000135973 (1:151033110 A>G), RS1000185357 (1:151036047 C>T), RS1000412972 (1:151021388 G>A,C), RS1000472043 (1:151012052 C>T), RS1000738815 (1:151012396 A>T), RS1000749320 (1:151029993 G>T), RS1000953654 (1:151016872 A>G), RS1000993435 (1:151010525 TGAAAG>T), RS1001104434 (1:151024617 C>T), RS1001316016 (1:151030770 G>C), RS1001634896 (1:151023789 C>T), RS1001946834 (1:151032945 T>C), RS1001976075 (1:151012462 C>G), RS1002055587 (1:151020303 T>G), RS1002086886 (1:151019915 C>G)

Disease associations

OMIM: gene MIM:617413 | disease phenotypes: MIM:617481

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies	Strong	Autosomal recessive

Mondo (1): neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (MONDO:0060490)

Orphanet (1): PRUNE1-related neurological syndrome (Orphanet:544469)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000189	Narrow palate
HP:0000252	Microcephaly
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000411	Protruding ear
HP:0000488	Retinopathy
HP:0000518	Cataract
HP:0000520	Proptosis
HP:0000648	Optic atrophy
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001285	Spastic tetraparesis
HP:0001308	Tongue fasciculations
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001357	Plagiocephaly
HP:0001558	Decreased fetal movement
HP:0001639	Hypertrophic cardiomyopathy
HP:0001762	Talipes equinovarus
HP:0001776	Bilateral talipes equinovarus
HP:0002020	Gastroesophageal reflux
HP:0002059	Cerebral atrophy
HP:0002079	Hypoplasia of the corpus callosum
HP:0002093	Respiratory insufficiency
HP:0002120	Cerebral cortical atrophy

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000649_7	Chronic kidney disease	1.000000e-12
GCST001966_1	Rhegmatogenous retinal detachment	1.000000e-07
GCST010173_178	Triglyceride levels	4.000000e-08
GCST90013405_133	Liver enzyme levels (alanine transaminase)	1.000000e-21
GCST90013663_104	Alanine aminotransferase levels	3.000000e-15
GCST90013664_26	Aspartate aminotransferase levels	3.000000e-08
GCST90020025_1215	Waist-to-hip ratio adjusted for BMI	4.000000e-08
GCST90020027_1800	Waist-hip index	4.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004736	aspartate aminotransferase measurement
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2079850 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 51,743 (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
CHEMBL932	DIPYRIDAMOLE	4	51,743

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.68	IC50	210	nM	CHEMBL348601
6.11	IC50	780	nM	DIPYRIDAMOLE

PubChem BioAssay actives

2 with measured affinity, of 11 total; 2 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
2-[[2-[bis(2-hydroxyethyl)amino]-4,8-bis[(4-methoxyphenyl)methylamino]pyrimido[5,4-d]pyrimidin-6-yl]-(2-hydroxyethyl)amino]ethanol	683135: Inhibition of purified human prune assessed as reduction of cAMP-phosphodiesterase activity by SPA	ic50	0.2100	uM
Dipyridamole	683134: Inhibition of human prune assessed as reduction of cAMP-phosphodiesterase activity	ic50	0.7800	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	affects response to substance, decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	increases methylation	2
triphenyl phosphate	affects expression	1
hydroxyhydroquinone	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
aflatoxin B2	increases methylation	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	decreases expression	1
Leflunomide	decreases expression	1
Cisplatin	increases expression	1
Ivermectin	increases expression	1
Lead	decreases expression	1
Phenobarbital	decreases expression	1
Quercetin	decreases expression	1
Rifampin	decreases expression	1
Selenium	affects cotreatment, increases expression	1
Thiram	decreases expression	1
Vitamin E	affects cotreatment, increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1
tert-Butylhydroperoxide	decreases 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
CHEMBL2091189	Binding	Inhibition of human prune assessed as reduction of cAMP-phosphodiesterase activity	Novel pyrimidopyrimidine derivatives for inhibition of cellular proliferation and motility induced by h-prune in breast cancer. — Eur J Med Chem

Clinical trials (associated diseases)

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