pontocerebellar hypoplasia type 1B

Summary

pontocerebellar hypoplasia type 1B (MONDO:0013853) is a disease caused by EXOSC3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: EXOSC3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 248

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia type 1B
Mondo ID	MONDO:0013853
OMIM	614678
DOID	DOID:0060266
UMLS	C3553449
MedGen	766363
GARD	0015834
Is cancer (heuristic)	no

Also known as: EXOSC3 non-syndromic pontocerebellar hypoplasia · non-syndromic pontocerebellar hypoplasia caused by mutation in EXOSC3 · PCH1B · pontocerebellar hypoplasia type 1B · pontocerebellar hypoplasia, type 1B

Data availability: 248 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › pontocerebellar hypoplasia type 1 › pontocerebellar hypoplasia type 1B

Related subtypes (2): pontocerebellar hypoplasia type 1A, pontocerebellar hypoplasia, type 1C

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

248 retrieved; paginated sample, class counts are floors:

121 likely benign, 57 uncertain significance, 21 pathogenic, 14 conflicting classifications of pathogenicity, 13 likely pathogenic, 12 pathogenic/likely pathogenic, 8 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
129023	NM_016042.4(EXOSC3):c.112del (p.Glu38fs)	EXOSC3	Pathogenic	criteria provided, multiple submitters, no conflicts
129024	NM_016042.4(EXOSC3):c.238G>T (p.Val80Phe)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322842	NM_016042.4(EXOSC3):c.382dup (p.Ile128fs)	EXOSC3	Pathogenic	criteria provided, single submitter
1324354	NM_016042.4(EXOSC3):c.428_431del (p.Tyr143fs)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1525013	NM_016042.4(EXOSC3):c.404_407del (p.Gly135fs)	EXOSC3	Pathogenic	criteria provided, single submitter
1723242	NM_016042.4(EXOSC3):c.556C>T (p.Arg186Ter)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183048	NM_016042.4(EXOSC3):c.571G>T (p.Gly191Cys)	EXOSC3	Pathogenic	no assertion criteria provided
1878333	NM_016042.4(EXOSC3):c.312_313del (p.Gln105fs)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1996188	NM_016042.4(EXOSC3):c.301del (p.Trp101fs)	EXOSC3	Pathogenic	criteria provided, single submitter
2159070	NM_016042.4(EXOSC3):c.151C>T (p.Arg51Ter)	EXOSC3	Pathogenic	criteria provided, single submitter
2735274	NM_016042.4(EXOSC3):c.551del (p.Cys184fs)	EXOSC3	Pathogenic	criteria provided, single submitter
2757620	NM_016042.4(EXOSC3):c.422del (p.Leu141fs)	EXOSC3	Pathogenic	criteria provided, single submitter
2767586	NM_016042.4(EXOSC3):c.714G>A (p.Trp238Ter)	EXOSC3	Pathogenic	criteria provided, single submitter
2771413	NM_016042.4(EXOSC3):c.1A>G (p.Met1Val)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280004	NM_016042.4(EXOSC3):c.155del (p.Pro52fs)	EXOSC3	Pathogenic	criteria provided, multiple submitters, no conflicts
2829110	NM_016042.4(EXOSC3):c.180del (p.Ser61fs)	EXOSC3	Pathogenic	criteria provided, single submitter
2855937	NM_016042.4(EXOSC3):c.174_183del (p.Arg58fs)	EXOSC3	Pathogenic	criteria provided, single submitter
2866577	NM_016042.4(EXOSC3):c.129del (p.Gly44fs)	EXOSC3	Pathogenic	criteria provided, single submitter
2873713	NM_016042.4(EXOSC3):c.226dup (p.Asp76fs)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2908421	NM_016042.4(EXOSC3):c.297_298insG (p.Tyr100fs)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2912064	NM_016042.4(EXOSC3):c.1A>T (p.Met1Leu)	EXOSC3	Pathogenic	criteria provided, single submitter
2962578	NM_016042.4(EXOSC3):c.3G>T (p.Met1Ile)	EXOSC3	Pathogenic	criteria provided, single submitter
3003295	NM_016042.4(EXOSC3):c.167_174del (p.Asn56fs)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3016443	NM_016042.4(EXOSC3):c.3G>A (p.Met1Ile)	EXOSC3	Pathogenic	criteria provided, single submitter
31688	NM_016042.4(EXOSC3):c.395A>C (p.Asp132Ala)	EXOSC3	Pathogenic	criteria provided, multiple submitters, no conflicts
31690	NM_016042.4(EXOSC3):c.294_303del (p.Val99fs)	EXOSC3	Pathogenic	criteria provided, multiple submitters, no conflicts
31691	NM_016042.4(EXOSC3):c.92G>C (p.Gly31Ala)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3597346	NM_016042.4(EXOSC3):c.672_673del (p.Tyr225fs)	EXOSC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3641160	NM_016042.4(EXOSC3):c.395_397del (p.Asp132del)	EXOSC3	Pathogenic	criteria provided, single submitter
3706994	NM_016042.4(EXOSC3):c.419_422del (p.Ser140fs)	EXOSC3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
EXOSC3	Definitive	Autosomal recessive	pontocerebellar hypoplasia type 1B	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EXOSC3	Orphanet:2254	Pontocerebellar hypoplasia type 1
VRK1	Orphanet:2254	Pontocerebellar hypoplasia type 1
VRK1	Orphanet:423894	Microcephaly-complex motor and sensory axonal neuropathy syndrome

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
EXOSC3	HGNC:17944	ENSG00000107371	Q9NQT5	Exosome complex component RRP40	gencc,clinvar
VRK1	HGNC:12718	ENSG00000100749	Q99986	Serine/threonine-protein kinase VRK1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EXOSC3	Exosome complex component RRP40	Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events.
VRK1	Serine/threonine-protein kinase VRK1	Serine/threonine kinase involved in the regulation of key cellular processes including the cell cycle, nuclear condensation, transcription regulation, and DNA damage response.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EXOSC3	Other/Unknown	no		KH_dom_type_1, NA-bd_OB-fold, Exosome_RNA_bind1/RRP40/RRP4
VRK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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
oocyte	2
secondary oocyte	2
tendon of biceps brachii	1
bone marrow	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EXOSC3	246	ubiquitous	marker	oocyte, secondary oocyte, tendon of biceps brachii
VRK1	286	ubiquitous	marker	oocyte, bone marrow, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VRK1	3,022
EXOSC3	2,330

Intra-cohort edges

A	B	Sources
EXOSC3	VRK1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VRK1	Q99986	26
EXOSC3	Q9NQT5	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
mRNA decay by 3’ to 5’ exoribonuclease	1	356.9×	0.006	EXOSC3
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	1	317.2×	0.006	EXOSC3
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	1	317.2×	0.006	EXOSC3
KSRP (KHSRP) binds and destabilizes mRNA	1	317.2×	0.006	EXOSC3
Initiation of Nuclear Envelope (NE) Reformation	1	300.5×	0.006	VRK1
Nuclear Envelope Breakdown	1	228.4×	0.006	VRK1
ATF4 activates genes in response to endoplasmic reticulum stress	1	203.9×	0.006	EXOSC3
Nuclear RNA decay	1	154.3×	0.007	EXOSC3
Major pathway of rRNA processing in the nucleolus and cytosol	1	30.9×	0.032	EXOSC3

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
positive regulation of protein localization to chromatin	1	2808.7×	0.002	VRK1
Cajal body organization	1	2106.5×	0.002	VRK1
DNA deamination	1	2106.5×	0.002	EXOSC3
CUT catabolic process	1	2106.5×	0.002	EXOSC3
Golgi disassembly	1	1404.3×	0.002	VRK1
exonucleolytic trimming to generate mature 3’-end of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1	1203.7×	0.002	EXOSC3
nuclear polyadenylation-dependent rRNA catabolic process	1	1203.7×	0.002	EXOSC3
TRAMP-dependent tRNA surveillance pathway	1	1203.7×	0.002	EXOSC3
U4 snRNA 3’-end processing	1	1053.2×	0.002	EXOSC3
poly(A)-dependent snoRNA 3’-end processing	1	1053.2×	0.002	EXOSC3
mitotic nuclear membrane disassembly	1	936.2×	0.003	VRK1
positive regulation of isotype switching	1	648.1×	0.003	EXOSC3
isotype switching	1	421.3×	0.005	EXOSC3
nuclear-transcribed mRNA catabolic process	1	383.0×	0.005	EXOSC3
regulation of neuron migration	1	312.1×	0.006	VRK1
mRNA catabolic process	1	247.8×	0.007	EXOSC3
RNA catabolic process	1	227.7×	0.007	EXOSC3
RNA processing	1	109.4×	0.013	EXOSC3
protein autophosphorylation	1	72.6×	0.018	VRK1
rRNA processing	1	70.8×	0.018	EXOSC3
neuron projection development	1	61.1×	0.020	VRK1
chromatin remodeling	1	36.5×	0.032	VRK1
protein phosphorylation	1	34.0×	0.033	VRK1
DNA damage response	1	26.8×	0.040	VRK1
cell division	1	23.1×	0.045	VRK1
signal transduction	1	8.0×	0.121	VRK1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EXOSC3	0	0
VRK1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
VRK1	74	Binding:74

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	VRK1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	EXOSC3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EXOSC3	0	—
VRK1	74	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.