CLP1

Summary

CLP1 (cleavage factor polyribonucleotide kinase subunit 1, HGNC:16999) is a protein-coding gene on chromosome 11q12.1, encoding Polyribonucleotide 5’-hydroxyl-kinase Clp1 (Q92989). Polynucleotide kinase that can phosphorylate the 5’-hydroxyl groups of double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), double-stranded DNA (dsDNA) and double-stranded DNA:RNA hybrids. dsRNA is phosphorylated more efficiently than dsDNA, and the RNA component of a DNA:R…. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

This gene encodes a member of the Clp1 family. The encoded protein is a multifunctional kinase which is a component of the tRNA splicing endonuclease complex and a component of the pre-mRNA cleavage complex II. This protein is implicated in tRNA, mRNA, and siRNA maturation. Mutations in this gene are associated with pontocerebellar hypoplasia type 10 (PCH10). Alternatively splice transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10978 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pontocerebellar hypoplasia type 10 (Strong, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 135 total — 1 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 62
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_006831

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16999
Approved symbol	CLP1
Name	cleavage factor polyribonucleotide kinase subunit 1
Location	11q12.1
Locus type	gene with protein product
Status	Approved
Aliases	HEAB, hClp1
Ensembl gene	ENSG00000172409
Ensembl biotype	protein_coding
OMIM	608757
Entrez	10978

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 13 protein_coding

ENST00000302731, ENST00000525602, ENST00000529430, ENST00000529773, ENST00000533682, ENST00000533905, ENST00000681650, ENST00000859512, ENST00000859513, ENST00000927170, ENST00000927171, ENST00000927172, ENST00000927173

RefSeq mRNA: 2 — MANE Select: NM_006831 NM_001142597, NM_006831

CCDS: CCDS44600, CCDS7964

Canonical transcript exons

ENST00000533682 — 3 exons

Exon	Start	End
ENSE00002141900	57657762	57657860
ENSE00002179766	57660765	57661865
ENSE00003474384	57659455	57660082

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 90.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.4249 / max 110.6103, expressed in 1749 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114313	5.0678	1715
114314	1.3571	901

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	90.83	gold quality
oocyte	CL:0000023	90.81	gold quality
epithelium of nasopharynx	UBERON:0001951	89.09	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.80	gold quality
tongue squamous epithelium	UBERON:0006919	87.57	silver quality
amniotic fluid	UBERON:0000173	85.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.55	gold quality
sperm	CL:0000019	85.44	silver quality
esophagus squamous epithelium	UBERON:0006920	85.08	gold quality
blood	UBERON:0000178	85.05	gold quality
epithelium of esophagus	UBERON:0001976	85.05	gold quality
parietal pleura	UBERON:0002400	84.59	gold quality
bone marrow	UBERON:0002371	84.56	gold quality
islet of Langerhans	UBERON:0000006	84.53	gold quality
hair follicle	UBERON:0002073	84.39	silver quality
palpebral conjunctiva	UBERON:0001812	84.32	gold quality
pleura	UBERON:0000977	83.90	gold quality
male germ cell	CL:0000015	83.77	silver quality
mammary duct	UBERON:0001765	83.69	gold quality
leukocyte	CL:0000738	83.58	gold quality
mononuclear cell	CL:0000842	83.48	gold quality
epithelium of mammary gland	UBERON:0003244	83.42	gold quality
monocyte	CL:0000576	83.36	gold quality
germinal epithelium of ovary	UBERON:0001304	83.25	gold quality
stromal cell of endometrium	CL:0002255	82.93	gold quality
granulocyte	CL:0000094	82.86	gold quality
squamous epithelium	UBERON:0006914	82.74	gold quality
upper arm skin	UBERON:0004263	82.55	gold quality
bone element	UBERON:0001474	82.45	gold quality
eye	UBERON:0000970	82.30	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.17

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

44 targeting CLP1, 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-4500	99.99	72.72	2367
HSA-MIR-3662	99.99	73.82	5684
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-548B-3P	99.38	67.26	1000
HSA-MIR-183-5P	99.31	72.27	1164

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 8)

• HEAB is a pre-mRNA 3’-end processing factor, which bridges two other pre-mRNA processing factors (CF Im and CPSF) and is involved in cleavage of the pre-mRNA. It can be UV-crosslinked to GTP. (PMID:11060040)
• the kinase hClp1 phosphorylates and licenses synthetic siRNAs to become assembled into RISC for subsequent target RNA cleavage (PMID:17495927)
• Expression of hClp1 in budding yeast can complement conditional and lethal mutations in the essential 5’-OH RNA kinase module of yeast or plant tRNA ligases. (PMID:18648070)
• Study reports the identification of a human CLP1 mutation that impairs tRNA splicing in vitro and causes a neurological syndrome involving both the central nervous system (CNS) and peripheral nervous system (PNS). (PMID:24766809)
• Data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans. (PMID:24766810)
• We have reconstituted CF II as a heterodimer of hPcf11 and hClp1. The heterodimer is active in partially reconstituted cleavage reactions, whereas hClp1 by itself is not. Pcf11 moderately stimulates the RNA 5’ kinase activity of hClp1; the kinase activity is dispensable for RNA cleavage (PMID:30139799)
• RNA kinase CLP1/Cbc regulates meiosis initiation in spermatogenesis. (PMID:33864361)
• Modeling a human CLP1 mutation in mouse identifies an accumulation of tyrosine pre-tRNA fragments causing pontocerebellar hypoplasia type 10. (PMID:34273619)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	clp1	ENSDARG00000063663
mus_musculus	Clp1	ENSMUSG00000027079
rattus_norvegicus	Clp1	ENSRNOG00000007416
drosophila_melanogaster	cbc	FBGN0033842
caenorhabditis_elegans		WBGENE00010304

Paralogs (1): NOL9 (ENSG00000162408)

Protein

Protein identifiers

Polyribonucleotide 5’-hydroxyl-kinase Clp1 — Q92989 (reviewed: Q92989)

Alternative names: Polyadenylation factor Clp1, Polynucleotide kinase Clp1, Pre-mRNA cleavage complex II protein Clp1

All UniProt accessions (4): E9PJM4, E9PKV5, E9PL17, Q92989

UniProt curated annotations — full annotation on UniProt →

Function. Polynucleotide kinase that can phosphorylate the 5’-hydroxyl groups of double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), double-stranded DNA (dsDNA) and double-stranded DNA:RNA hybrids. dsRNA is phosphorylated more efficiently than dsDNA, and the RNA component of a DNA:RNA hybrid is phosphorylated more efficiently than the DNA component. Plays a key role in both tRNA splicing and mRNA 3’-end formation. Component of the tRNA splicing endonuclease complex: phosphorylates the 5’-terminus of the tRNA 3’-exon during tRNA splicing; this phosphorylation event is a prerequisite for the subsequent ligation of the two exon halves and the production of a mature tRNA. Its role in tRNA splicing and maturation is required for cerebellar development. Component of the pre-mRNA cleavage complex II (CF-II), which seems to be required for mRNA 3’-end formation. Also phosphorylates the 5’-terminus of exogenously introduced short interfering RNAs (siRNAs), which is a necessary prerequisite for their incorporation into the RNA-induced silencing complex (RISC). However, endogenous siRNAs and microRNAs (miRNAs) that are produced by the cleavage of dsRNA precursors by DICER1 already contain a 5’-phosphate group, so this protein may be dispensible for normal RNA-mediated gene silencing.

Subunit / interactions. Component of the tRNA splicing endonuclease complex, composed of CLP1, TSEN2, TSEN15, TSEN34 and TSEN54. Component of pre-mRNA cleavage complex II (CF-II). Also associates with numerous components of the pre-mRNA cleavage complex I (CF-I/CFIm), including NUDT21, CPSF2, CPSF3, CPSF6 and CPSF7. Interacts with CSTF2 and SYMPK.

Subcellular location. Nucleus.

Disease relevance. Pontocerebellar hypoplasia 10 (PCH10) [MIM:615803] A form of pontocerebellar hypoplasia, a disorder characterized by structural defects of the pons and cerebellum, evident upon brain imaging. PCH10 features include cortical dysgenesis marked by a simplified gyral pattern, cortical atrophy, mild or focal cerebellar vermian volume loss, delayed myelination, progressive microcephaly, global growth and developmental delays, severe intellectual disabilities, and seizures refractory to treatment. The disease is caused by variants affecting the gene represented in this entry. Neurodegeneration is due to defects in tRNA splicing.

Similarity. Belongs to the Clp1 family. Clp1 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92989-1	1	yes
Q92989-2	2

RefSeq proteins (2): NP_001136069, NP_006822* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010655	Clp1_C	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR028606	Clp1	Family
IPR032319	CLP1_P	Domain
IPR032324	Clp1_N	Domain
IPR038238	Clp1_C_sf	Homologous_superfamily
IPR038239	Clp1_N_sf	Homologous_superfamily
IPR045116	Clp1/Grc3	Family

Pfam: PF06807, PF16573, PF16575

Enzyme classification (BRENDA):

• EC 2.7.1.78 — polynucleotide 5’-hydroxyl-kinase (BRENDA: 23 organisms, 178 substrates, 91 inhibitors, 53 Km, 17 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ATP	0.0007–3.4	19
5’-OH-DNA	0.0027–0.046	7
5’-HYDROXYL POLY(A)	0.0025–0.0036	2
ADP	0.2	2
MG2+	0.5–2.5	2
R(A20)	0.0013–0.0015	2
[GAMMA-S]ATP	0.22–3.1	2
5’-DEPHOSPHO-GAAAA-RNA	0.099	1
5’-DEPHOSPHO-GC-RNA	0.109	1
5’-HO-CCGACCAACGAAGGT	0.0028	1
5’-HYDROXYL POLY(C)	0.0034	1
5’-OH DNA	0.016	1
5’-PHOSPHO-DNA	0.021	1
CTP	0.025	1
GGGCC(AG)10GGCCC-FLUORESCEIN	0.0006	1

Catalyzed reactions (Rhea), 2 shown:

• a 5’-end dephospho-2’-deoxyribonucleoside-DNA + ATP = a 5’-end 5’-phospho-2’-deoxyribonucleoside-DNA + ADP + H(+) (RHEA:15669)
• a 5’-end dephospho-ribonucleoside-RNA + ATP = a 5’-end 5’-phospho-ribonucleoside-RNA + ADP + H(+) (RHEA:54580)

UniProt features (46 total): strand 23, helix 10, turn 4, binding site 3, mutagenesis site 3, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8HMZ	ELECTRON MICROSCOPY	2.9
8HMY	ELECTRON MICROSCOPY	2.94

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92989-F1	93.95	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 (3): 22; 62; 124–129

Mutagenesis-validated functional residues (3):

Position	Phenotype
127–128	abrogates rna kinase activity. abrogates complementation of trna splicing activity in yeast; when associated with a-128.
127	abrogates rna kinase activity and trna splicing activity.
151	abrogates complementation of trna splicing activity in yeast.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-6784531	tRNA processing in the nucleus
R-HSA-72187	mRNA 3’-end processing
R-HSA-73856	RNA Polymerase II Transcription Termination
R-HSA-77595	Processing of Intronless Pre-mRNAs
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA

MSigDB gene sets: 297 (showing top): GOBP_HINDBRAIN_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_TRNA_METABOLIC_PROCESS, MORF_ATRX, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, PUJANA_CHEK2_PCC_NETWORK, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, SMITH_TERT_TARGETS_DN, GOBP_CEREBELLAR_CORTEX_DEVELOPMENT, GOBP_REGULATION_OF_MRNA_3_END_PROCESSING, MORF_PPP5C, REACTOME_MRNA_3_END_PROCESSING

GO Biological Process (8): tRNA splicing, via endonucleolytic cleavage and ligation (GO:0006388), cerebellar cortex development (GO:0021695), mRNA 3’-end processing (GO:0031124), RISC complex assembly (GO:0070922), global gene silencing by mRNA cleavage (GO:0098795), RNA processing (GO:0006396), mRNA processing (GO:0006397), tRNA processing (GO:0008033)

GO Molecular Function (9): ATP binding (GO:0005524), ATP-dependent polydeoxyribonucleotide 5’-hydroxyl-kinase activity (GO:0046404), polynucleotide 5’-hydroxyl-kinase activity (GO:0051731), ATP-dependent polyribonucleotide 5’-hydroxyl-kinase activity (GO:0051736), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), ATP-dependent polynucleotide 5’-hydroxyl-kinase activity (GO:0051734)

GO Cellular Component (5): tRNA-intron endonuclease complex (GO:0000214), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), mRNA cleavage factor complex (GO:0005849)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
tRNA processing	1
Processing of Capped Intron-Containing Pre-mRNA	1
RNA Polymerase II Transcription	1
Processing of Capped Intronless Pre-mRNA	1
mRNA 3’-end processing	1
Dengue Virus Infection	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
ATP-dependent polynucleotide 5’-hydroxyl-kinase activity	2
nuclear protein-containing complex	2
cellular anatomical structure	2
RNA splicing, via endonucleolytic cleavage and ligation	1
tRNA processing	1
cerebellum development	1
anatomical structure development	1
mRNA processing	1
RNA 3’-end processing	1
protein-RNA complex assembly	1
regulatory ncRNA-mediated gene silencing	1
post-transcriptional gene silencing	1
mRNA destabilization	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
mRNA metabolic process	1
tRNA metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
phosphotransferase activity, alcohol group as acceptor	1
nucleobase-containing compound kinase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
polynucleotide 5’-hydroxyl-kinase activity	1
endoribonuclease complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1

Protein interactions and networks

STRING

806 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLP1	PCF11	O94913	926
CLP1	CPSF6	Q16630	834
CLP1	MLLT10	P55197	778
CLP1	TSEN2	Q8NCE0	774
CLP1	MLLT6	P55198	669
CLP1	TSEN54	Q7Z6J9	587
CLP1	CSTF3	Q12996	560
CLP1	TSEN15	Q8WW01	547
CLP1	KNL1	Q8NG31	544
CLP1	GMPS	P49915	544
CLP1	RTCB	Q9Y3I0	543
CLP1	MLLT3	P42568	541
CLP1	TSEN34	Q9BSV6	522
CLP1	LASP1	Q14847	513
CLP1	SARNP	P82979	511

IntAct

86 interactions, top by confidence:

A	B	Type	Score
TSEN2	TSEN54	psi-mi:“MI:0914”(association)	0.830
TSEN15	TSEN54	psi-mi:“MI:0914”(association)	0.740
TSEN54	CLP1	psi-mi:“MI:0915”(physical association)	0.670
PCF11	CLP1	psi-mi:“MI:0407”(direct interaction)	0.590
CLP1	PCF11	psi-mi:“MI:0914”(association)	0.590
CLP1	FGF16	psi-mi:“MI:0915”(physical association)	0.560
CLP1	PRR3	psi-mi:“MI:0915”(physical association)	0.560
CLP1	PSMB5	psi-mi:“MI:0915”(physical association)	0.560
CLP1	FTO	psi-mi:“MI:0915”(physical association)	0.560
DAGLB	CLP1	psi-mi:“MI:0915”(physical association)	0.560
CLP1	CEP164	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	CLP1	psi-mi:“MI:0915”(physical association)	0.560
YJU2B	CLP1	psi-mi:“MI:0915”(physical association)	0.560
PCMT1	CLP1	psi-mi:“MI:0915”(physical association)	0.560
FGF16	CLP1	psi-mi:“MI:0915”(physical association)	0.560
CLP1	SNF8	psi-mi:“MI:0915”(physical association)	0.560
PRR3	CLP1	psi-mi:“MI:0915”(physical association)	0.560
PSMB5	CLP1	psi-mi:“MI:0915”(physical association)	0.560
MESD	CLP1	psi-mi:“MI:0915”(physical association)	0.560
CDKN2AIP	PCF11	psi-mi:“MI:0914”(association)	0.530
CLP1	DHRS2	psi-mi:“MI:0915”(physical association)	0.400
Clp1	TSEN34	psi-mi:“MI:0915”(physical association)	0.400
Cenpe	BBX	psi-mi:“MI:0914”(association)	0.350

BioGRID (90): CLP1 (Affinity Capture-MS), CLP1 (Co-fractionation), CLP1 (Co-fractionation), CLP1 (Affinity Capture-MS), CLP1 (Affinity Capture-MS), CLP1 (Affinity Capture-MS), CLP1 (Affinity Capture-MS), CLP1 (Affinity Capture-MS), CLP1 (Affinity Capture-MS), CLP1 (Affinity Capture-MS), CLP1 (Affinity Capture-MS), CLP1 (Affinity Capture-MS), TSEN2 (Affinity Capture-MS), TSEN54 (Affinity Capture-MS), TSEN34 (Affinity Capture-MS)

ESM2 similar proteins: A0A0K9RL25, A0A0U1WZ18, A0A1S4A695, B9N1F9, O15305, O35621, O80840, O88958, O97555, O97556, P21856, P31150, P46926, P50396, P50398, P50399, P60028, P78330, Q16HW7, Q1W374, Q1W375, Q1W376, Q1W377, Q259G4, Q2KHU0, Q3SZJ9, Q3UFY7, Q4R7R3, Q5E982, Q5R8T8, Q5RB83, Q5ZID6, Q5ZKF6, Q60HD6, Q61598, Q64422, Q6AYP7, Q6Q7J2, Q7SYN4, Q7XPW5

Diamond homologs: A1CB93, A1DE49, A2RAW3, A2VE01, A3LNJ3, A4QQE0, A6S936, A7RG82, B0CS49, B0VZR4, B0Y0Y6, B3MGZ0, B3NRK6, B4GGT6, B4HQJ2, B4JVN0, B4KML2, B4MCL6, B4MRZ9, B4P4H2, B4QEE3, E7F3I6, Q0CEZ9, Q0U2G5, Q10299, Q16WA6, Q1DKL9, Q28ZT4, Q2H1L0, Q2UEA6, Q4R7R3, Q4WVA5, Q54N48, Q5BH19, Q5PQL4, Q5ZJL4, Q6BU98, Q6BZT5, Q7K284, Q7QJW7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CLP1	“form complex”	“CFII complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 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
mRNA 3’-end processing	5	23.4×	4e-04
mRNA Polyadenylation	6	12.6×	6e-04
Processing of Capped Intron-Containing Pre-mRNA	5	9.8×	6e-03
Metabolism of RNA	9	8.9×	2e-04
Dengue Virus-Host Interactions	8	8.7×	4e-04
mRNA Splicing - Major Pathway	6	7.8×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
mRNA transport	6	25.5×	3e-05
mRNA splicing, via spliceosome	7	10.3×	5e-04
mRNA processing	8	10.2×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	3
Uncertain significance	72
Likely benign	46
Benign	7

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1076333	NC_000011.9:g.(?57235082)(57467503_?)del	Pathogenic
3599791	NM_006831.3(CLP1):c.121_122insG (p.Met41fs)	Likely pathogenic
3599792	NM_006831.3(CLP1):c.346C>T (p.Arg116Ter)	Likely pathogenic
3599793	NM_006831.3(CLP1):c.907G>T (p.Glu303Ter)	Likely pathogenic

SpliceAI

757 predictions. Top by Δscore:

Variant	Effect	Δscore
11:57659450:TCTA:T	acceptor_loss	1.0000
11:57659453:A:AG	acceptor_gain	1.0000
11:57659454:G:GC	acceptor_gain	1.0000
11:57659454:GGC:G	acceptor_gain	1.0000
11:57660760:TGCA:T	acceptor_loss	1.0000
11:57660761:GCAG:G	acceptor_loss	1.0000
11:57660762:CA:C	acceptor_loss	1.0000
11:57660763:A:AG	acceptor_gain	1.0000
11:57660763:AGATT:A	acceptor_loss	1.0000
11:57660764:G:A	acceptor_loss	1.0000
11:57660764:G:GG	acceptor_gain	1.0000
11:57660764:GATT:G	acceptor_gain	1.0000
11:57657858:CAGGT:C	donor_loss	0.9900
11:57657860:GGTG:G	donor_loss	0.9900
11:57657861:G:A	donor_loss	0.9900
11:57657862:T:A	donor_loss	0.9900
11:57659447:T:TA	acceptor_gain	0.9900
11:57659453:AG:A	acceptor_gain	0.9900
11:57659454:GG:G	acceptor_gain	0.9900
11:57659454:GGCA:G	acceptor_gain	0.9900
11:57659454:GGCAC:G	acceptor_gain	0.9900
11:57659818:TCCCC:T	donor_gain	0.9900
11:57660079:TAAG:T	donor_loss	0.9900
11:57660081:AGGT:A	donor_loss	0.9900
11:57660083:G:T	donor_loss	0.9900
11:57660084:T:G	donor_loss	0.9900
11:57660764:GA:G	acceptor_gain	0.9900
11:57660764:GAT:G	acceptor_gain	0.9900
11:57660764:GATTA:G	acceptor_gain	0.9900
11:57657857:GCAG:G	donor_gain	0.9800

AlphaMissense

2756 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:57659544:T:C	L23P	1.000
11:57659546:C:A	R24S	1.000
11:57659612:G:C	G46R	1.000
11:57659613:G:A	G46D	1.000
11:57659613:G:T	G46V	1.000
11:57659667:C:A	A64D	1.000
11:57659670:T:A	V65D	1.000
11:57659672:T:C	F66L	1.000
11:57659674:C:A	F66L	1.000
11:57659674:C:G	F66L	1.000
11:57659689:T:G	C71W	1.000
11:57659723:T:C	Y83H	1.000
11:57659837:G:C	G121R	1.000
11:57659838:G:A	G121D	1.000
11:57659838:G:T	G121V	1.000
11:57659852:G:C	G126R	1.000
11:57659853:G:A	G126D	1.000
11:57659853:G:T	G126V	1.000
11:57659856:A:T	K127M	1.000
11:57659857:G:C	K127N	1.000
11:57659857:G:T	K127N	1.000
11:57659957:G:C	G161R	1.000
11:57659958:G:A	G161D	1.000
11:57659958:G:T	G161V	1.000
11:57660041:G:C	G189R	1.000
11:57660042:G:A	G189D	1.000
11:57660831:G:C	G225R	1.000
11:57660832:G:A	G225D	1.000
11:57660838:T:A	V227D	1.000
11:57660841:T:A	I228N	1.000

dbSNP variants (sampled 300 via entrez): RS1000383693 (11:57658482 C>A,G,T), RS1000909961 (11:57659340 C>T), RS1000920002 (11:57659083 G>T), RS1001462246 (11:57659102 G>A,T), RS1002424488 (11:57658351 A>G), RS1002951492 (11:57662280 G>A), RS1003043015 (11:57656078 G>A), RS1003093943 (11:57655770 A>T), RS1003375470 (11:57657466 C>A,G), RS1003429536 (11:57657219 T>A,C), RS1003737662 (11:57662319 C>T), RS1004441657 (11:57661495 C>G,T), RS1004931692 (11:57657100 G>A), RS1005109260 (11:57656781 C>T), RS1005292042 (11:57657589 G>A,C)

Disease associations

OMIM: gene MIM:608757 | disease phenotypes: MIM:615803, MIM:607596

GenCC curated gene-disease

Disease	Classification	Inheritance
pontocerebellar hypoplasia type 10	Strong	Autosomal recessive

Mondo (2): pontocerebellar hypoplasia type 10 (MONDO:0014349), pontocerebellar hypoplasia (MONDO:0020135)

Orphanet (2): Pontocerebellar hypoplasia type 10 (Orphanet:411493), Non-syndromic pontocerebellar hypoplasia (Orphanet:98523)

HPO phenotypes

62 total (30 of 62 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000341	Narrow forehead
HP:0000414	Bulbous nose
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000470	Short neck
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000520	Proptosis
HP:0000527	Long eyelashes
HP:0000540	Hypermetropia
HP:0000565	Esotropia
HP:0000637	Long palpebral fissure
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000664	Synophrys
HP:0000687	Widely spaced teeth
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0000817	Reduced eye contact
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002539_6	Schizophrenia	2.000000e-09
GCST004521_290	Autism spectrum disorder or schizophrenia	5.000000e-08
GCST005232_71	Neuroticism	7.000000e-11
GCST006803_71	Schizophrenia	1.000000e-09
GCST90002390_30	Mean corpuscular hemoglobin	1.000000e-17
GCST90002392_346	Mean corpuscular volume	3.000000e-14

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0004527	mean corpuscular hemoglobin

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C580383	Pontocerebellar Hypoplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, decreases methylation	5
trichostatin A	affects cotreatment, decreases expression	2
Cisplatin	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression	1
zinc chromate	increases abundance, increases expression	1
sulindac sulfide	decreases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
chromium hexavalent ion	increases abundance, increases expression	1
entinostat	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression, affects cotreatment	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Leflunomide	decreases expression	1
Panobinostat	affects cotreatment, decreases expression	1
Arsenic	increases methylation	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1

Clinical trials (associated diseases)

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