Pontocerebellar hypoplasia type 10

Summary

Pontocerebellar hypoplasia type 10 (MONDO:0014349) is a disease caused by CLP1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CLP1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 16
• Phenotypes (HPO): 27

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		23	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002194	Delayed gross motor development	Very frequent (80-99%)
HP:0010862	Delayed fine motor development	Very frequent (80-99%)
HP:0000430	Underdeveloped nasal alae	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0000527	Long eyelashes	Frequent (30-79%)
HP:0000637	Long palpebral fissure	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0002538	Abnormality of the cerebral cortex	Frequent (30-79%)
HP:0002553	Highly arched eyebrow	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0002363	Abnormal brainstem morphology	Occasional (5-29%)
HP:0009879	Simplified gyral pattern	Occasional (5-29%)
HP:0025405	Visual fixation instability	Occasional (5-29%)
HP:0000486	Strabismus	Very rare (<1-4%)
HP:0000505	Visual impairment	Very rare (<1-4%)
HP:0000648	Optic atrophy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia type 10
Mondo ID	MONDO:0014349
OMIM	615803
Orphanet	411493
DOID	DOID:0060279
UMLS	C5190575
MedGen	1676575
GARD	0017680
Is cancer (heuristic)	no

Also known as: CLP1 non-syndromic pontocerebellar hypoplasia · CLP1-related pontocerebellar hypoplasia · non-syndromic pontocerebellar hypoplasia caused by mutation in CLP1 · PCH10 · pontocerebellar hypoplasia, type 10

Data availability: 16 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › pontocerebellar hypoplasia › pontocerebellar hypoplasia type 10

Related subtypes (20): pontocerebellar hypoplasia type 4, pontocerebellar hypoplasia type 3, pontocerebellar hypoplasia type 5, pontocerebellar hypoplasia type 6, pontocerebellar hypoplasia type 8, pontocerebellar hypoplasia type 7, pontocerebellar hypoplasia type 9, pontocerebellar hypoplasia type 2E, pontocerebellar hypoplasia type 1, pontocerebellar hypoplasia type 2, pontocerebellar hypoplasia, type 14, pontocerebellar hypoplasia, type 15, pontocerebellar hypoplasia, type 1E, pontocerebellar hypoplasia, type 1F, pontocerebellar hypoplasia, type 16, pontocerebellar hypoplasia, IIA 17, pontocerebellar hypoplasia, type 12, pontocerebellar hypoplasia, type 13, pontocerebellar hypoplasia, type 11, pontocerebellar hypoplasia, type 1D

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

16 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 4 likely pathogenic, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
143934	NM_006831.3(CLP1):c.419G>A (p.Arg140His)	CLP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3338459	GRCh37/hg19 11q12.1(chr11:57003258-57596656)x3	APLNR	Likely pathogenic	no assertion criteria provided
3599791	NM_006831.3(CLP1):c.121_122insG (p.Met41fs)	CLP1	Likely pathogenic	criteria provided, single submitter
3599792	NM_006831.3(CLP1):c.346C>T (p.Arg116Ter)	CLP1	Likely pathogenic	criteria provided, single submitter
3599793	NM_006831.3(CLP1):c.907G>T (p.Glu303Ter)	CLP1	Likely pathogenic	criteria provided, single submitter
1804783	NM_006831.3(CLP1):c.55C>T (p.Arg19Ter)	CLP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030159	NM_006831.3(CLP1):c.178G>T (p.Gly60Cys)	CLP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030160	NM_006831.3(CLP1):c.310C>G (p.Arg104Gly)	CLP1	Uncertain significance	criteria provided, single submitter
1030161	NM_006831.3(CLP1):c.422T>A (p.Leu141Ter)	CLP1	Uncertain significance	criteria provided, single submitter
1030162	NM_006831.3(CLP1):c.427C>T (p.Arg143Cys)	CLP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032495	NM_006831.3(CLP1):c.159_161del (p.Lys54del)	CLP1	Uncertain significance	criteria provided, single submitter
2440148	NM_006831.3(CLP1):c.293C>G (p.Thr98Arg)	CLP1	Uncertain significance	criteria provided, single submitter
2503502	NM_006831.3(CLP1):c.784C>G (p.Leu262Val)	CLP1	Uncertain significance	criteria provided, single submitter
2585595	NM_006831.3(CLP1):c.1214C>T (p.Ala405Val)	CLP1	Uncertain significance	criteria provided, single submitter
4073417	NM_006831.3(CLP1):c.617G>A (p.Arg206His)	CLP1	Uncertain significance	no assertion criteria provided
4073459	NM_006831.3(CLP1):c.410A>G (p.Tyr137Cys)	CLP1	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CLP1	Strong	Autosomal recessive	pontocerebellar hypoplasia type 10	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLP1	Orphanet:411493	Pontocerebellar hypoplasia type 10

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CLP1	HGNC:16999	ENSG00000172409	Q92989	Polyribonucleotide 5’-hydroxyl-kinase Clp1	gencc,clinvar
APLNR	HGNC:339	ENSG00000134817	P35414	Apelin receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLP1	Polyribonucleotide 5’-hydroxyl-kinase Clp1	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…
APLNR	Apelin receptor	G protein-coupled receptor for peptide hormones apelin (APLN) and apelin receptor early endogenous ligand (APELA/ELA), that plays a role in the regulation of normal cardiovascular function and fluid homeostasis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
GPCR	1	12.0×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLP1	Enzyme (other)	yes	2.7.1.78	Clp1_C, P-loop_NTPase, Clp1
APLNR	GPCR	yes		GPCR_Rhodpsn, Apelin_rcpt, GPCR_Rhodpsn_7TM

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelium of nasopharynx	1
oocyte	1
secondary oocyte	1
cranial nerve II	1
dorsal motor nucleus of vagus nerve	1
inferior olivary complex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLP1	275	ubiquitous	yes	secondary oocyte, oocyte, epithelium of nasopharynx
APLNR	232	broad	marker	cranial nerve II, inferior olivary complex, dorsal motor nucleus of vagus nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APLNR	2,099
CLP1	982

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APLNR	P35414	37
CLP1	Q92989	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Processing of Intronless Pre-mRNAs	1	285.5×	0.033	CLP1
RNA Polymerase II Transcription Termination	1	109.8×	0.033	CLP1
tRNA processing in the nucleus	1	98.5×	0.033	CLP1
mRNA 3’-end processing	1	98.5×	0.033	CLP1
mRNA Polyadenylation	1	43.9×	0.050	CLP1
Class A/1 (Rhodopsin-like receptors)	1	37.1×	0.050	APLNR
Peptide ligand-binding receptors	1	37.1×	0.050	APLNR
GPCR ligand binding	1	32.1×	0.050	APLNR
Dengue Virus-Host Interactions	1	22.8×	0.055	CLP1
GPCR downstream signalling	1	21.7×	0.055	APLNR
Signaling by GPCR	1	20.0×	0.055	APLNR
G alpha (i) signalling events	1	19.5×	0.055	APLNR
Signal Transduction	1	5.1×	0.187	APLNR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete negative regulation of cAMP-mediated signaling	1	8426.0×	0.002	APLNR
regulation of gap junction assembly	1	8426.0×	0.002	APLNR
vascular associated smooth muscle cell differentiation	1	2808.7×	0.002	APLNR
apelin receptor signaling pathway	1	2808.7×	0.002	APLNR
global gene silencing by mRNA cleavage	1	2808.7×	0.002	CLP1
positive regulation of cardiac muscle hypertrophy in response to stress	1	2808.7×	0.002	APLNR
positive regulation of G protein-coupled receptor internalization	1	2808.7×	0.002	APLNR
atrioventricular valve development	1	2106.5×	0.002	APLNR
regulation of body fluid levels	1	2106.5×	0.002	APLNR
venous blood vessel development	1	1685.2×	0.002	APLNR
cerebellar cortex development	1	1053.2×	0.003	CLP1
negative regulation of cardiac muscle hypertrophy in response to stress	1	936.2×	0.003	APLNR
positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	842.6×	0.003	APLNR
RISC complex assembly	1	766.0×	0.003	CLP1
endocardial cushion formation	1	702.2×	0.003	APLNR
tRNA splicing, via endonucleolytic cleavage and ligation	1	702.2×	0.003	CLP1
adult heart development	1	601.9×	0.003	APLNR
vasculature development	1	561.7×	0.003	APLNR
gastrulation	1	351.1×	0.005	APLNR
coronary vasculature development	1	312.1×	0.005	APLNR
mRNA 3’-end processing	1	280.9×	0.005	CLP1
aorta development	1	280.9×	0.005	APLNR
positive regulation of release of sequestered calcium ion into cytosol	1	247.8×	0.006	APLNR
ventricular septum morphogenesis	1	216.1×	0.007	APLNR
blood vessel development	1	187.2×	0.007	APLNR
heart looping	1	133.8×	0.010	APLNR
vasculogenesis	1	127.7×	0.010	APLNR
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	109.4×	0.011	APLNR
positive regulation of angiogenesis	1	57.7×	0.020	APLNR
regulation of gene expression	1	41.7×	0.027	APLNR

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
APLNR	DIHYDROERGOTAMINE MESYLATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APLNR	9	4
CLP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DIHYDROERGOTAMINE MESYLATE	4	APLNR
FLUOXETINE HYDROCHLORIDE	4	APLNR
PIMAVANSERIN	4	APLNR
ELAGOLIX SODIUM	4	APLNR
PERPHENAZINE	4	APLNR
FORETINIB	2	APLNR
NIGULDIPINE	2	APLNR
AZELAPRAG	1	APLNR
BMS-986224	1	APLNR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
APLNR	139	Binding:70, Functional:65, ADMET:2, Unclassified:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CLP1	2.7.1.78	polynucleotide 5’-hydroxyl-kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
APLNR	139

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

9 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
DIHYDROERGOTAMINE MESYLATE	4	APLNR
FLUOXETINE HYDROCHLORIDE	4	APLNR
PIMAVANSERIN	4	APLNR
ELAGOLIX SODIUM	4	APLNR
PERPHENAZINE	4	APLNR
FORETINIB	2	APLNR
NIGULDIPINE	2	APLNR
AZELAPRAG	1	APLNR
BMS-986224	1	APLNR

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	APLNR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	CLP1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CLP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.