pontocerebellar hypoplasia type 1A

Summary

pontocerebellar hypoplasia type 1A (MONDO:0011866) is a disease caused by VRK1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: VRK1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 518

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia type 1A
Mondo ID	MONDO:0011866
OMIM	607596
DOID	DOID:0060265
UMLS	C1843504
MedGen	335969
GARD	0015416
Is cancer (heuristic)	no

Also known as: non-syndromic pontocerebellar hypoplasia caused by mutation in VRK1 · PCH1A · pontocerebellar hypoplasia, type 1A · VRK1 non-syndromic pontocerebellar hypoplasia

Data availability: 518 ClinVar variants · 5 GenCC gene-disease records.

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 1A

Related subtypes (2): pontocerebellar hypoplasia type 1B, 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

518 retrieved; paginated sample, class counts are floors:

254 likely benign, 140 uncertain significance, 42 pathogenic, 32 likely pathogenic, 20 pathogenic/likely pathogenic, 16 conflicting classifications of pathogenicity, 12 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067636	NM_003384.3(VRK1):c.1096_1097insTGAAGCA (p.Lys366fs)	VRK1	Pathogenic	criteria provided, single submitter
1071258	NM_003384.3(VRK1):c.110G>A (p.Trp37Ter)	VRK1	Pathogenic	criteria provided, single submitter
1071599	NM_003384.3(VRK1):c.222del (p.Ser75fs)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076855	NM_003384.3(VRK1):c.387dup (p.Ile130fs)	VRK1	Pathogenic	criteria provided, single submitter
1383284	NM_003384.3(VRK1):c.783G>A (p.Trp261Ter)	VRK1	Pathogenic	criteria provided, single submitter
1399359	NM_003384.3(VRK1):c.542_543insGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGTGGATCATGAGGTCAGGAGATCNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGGCCTC (p.Ser181_Asn182insArgGlyGlySerArgLeuTer)	VRK1	Pathogenic	criteria provided, single submitter
1403721	NM_003384.3(VRK1):c.897del (p.Ile299fs)	VRK1	Pathogenic	criteria provided, single submitter
1408344	NM_003384.3(VRK1):c.913dup (p.Thr305fs)	VRK1	Pathogenic	criteria provided, single submitter
1431709	NM_003384.3(VRK1):c.733G>T (p.Glu245Ter)	VRK1	Pathogenic	criteria provided, single submitter
1453030	NM_003384.3(VRK1):c.179_180del (p.Glu60fs)	VRK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1453248	NM_003384.3(VRK1):c.1133_1136del (p.Thr378fs)	VRK1	Pathogenic	criteria provided, single submitter
1453431	NM_003384.3(VRK1):c.1124G>A (p.Trp375Ter)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455719	NC_000014.8:g.(?97326874)(97327092_?)del	VRK1	Pathogenic	criteria provided, single submitter
1456740	NM_003384.3(VRK1):c.652A>T (p.Lys218Ter)	VRK1	Pathogenic	criteria provided, single submitter
1457447	NC_000014.8:g.(?97299809)(97327092_?)del	VRK1	Pathogenic	criteria provided, single submitter
1459674	NM_003384.3(VRK1):c.103_104del (p.Lys35fs)	VRK1	Pathogenic	criteria provided, single submitter
1460187	NC_000014.8:g.(?97319158)(97322933_?)del	VRK1	Pathogenic	criteria provided, single submitter
1970380	NM_003384.3(VRK1):c.1144dup (p.Glu382fs)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2003519	NM_003384.3(VRK1):c.1061dup (p.Thr355fs)	VRK1	Pathogenic	criteria provided, single submitter
2036712	NM_003384.3(VRK1):c.950_951dup (p.Glu318fs)	VRK1	Pathogenic	criteria provided, single submitter
2039561	NM_003384.3(VRK1):c.500del (p.Tyr167fs)	VRK1	Pathogenic	criteria provided, single submitter
2062005	NM_003384.3(VRK1):c.1149del (p.Ile384fs)	VRK1	Pathogenic	criteria provided, single submitter
209204	NM_003384.3(VRK1):c.356A>G (p.His119Arg)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209205	NM_003384.3(VRK1):c.961C>T (p.Arg321Cys)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2101376	NM_003384.3(VRK1):c.22C>T (p.Gln8Ter)	VRK1	Pathogenic	criteria provided, single submitter
2108163	NM_003384.3(VRK1):c.159_160insCATATATCTT (p.Ala54fs)	VRK1	Pathogenic	criteria provided, single submitter
2150009	NM_003384.3(VRK1):c.160+1del	VRK1	Pathogenic	criteria provided, single submitter
2164156	NM_003384.3(VRK1):c.1081_1084del (p.Glu361fs)	VRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2167963	NM_003384.3(VRK1):c.633_636del (p.Lys211fs)	VRK1	Pathogenic	criteria provided, single submitter
2428131	NM_003384.3(VRK1):c.105_108del (p.Lys35fs)	VRK1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
VRK1	Strong	Autosomal recessive	pontocerebellar hypoplasia type 1A	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VRK1	Orphanet:2254	Pontocerebellar hypoplasia type 1
VRK1	Orphanet:423894	Microcephaly-complex motor and sensory axonal neuropathy syndrome
CHMP1A	Orphanet:324569	Pontocerebellar hypoplasia type 8

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
VRK1	HGNC:12718	ENSG00000100749	Q99986	Serine/threonine-protein kinase VRK1	gencc,clinvar
CHMP1A	HGNC:8740	ENSG00000131165	Q9HD42	Charged multivesicular body protein 1a	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
CHMP1A	Charged multivesicular body protein 1a	Probable peripherally associated component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs.

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)
VRK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
CHMP1A	Other/Unknown	no		Snf7_fam

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
bone marrow	1
oocyte	1
secondary oocyte	1
endometrium epithelium	1
lower esophagus mucosa	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VRK1	286	ubiquitous	marker	oocyte, bone marrow, secondary oocyte
CHMP1A	293	ubiquitous	marker	endometrium epithelium, lower esophagus mucosa, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VRK1	3,022
CHMP1A	1,793

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VRK1	Q99986	26
CHMP1A	Q9HD42	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Initiation of Nuclear Envelope (NE) Reformation	1	300.5×	0.007	VRK1
Nuclear Envelope Breakdown	1	228.4×	0.007	VRK1
HCMV Late Events	1	49.2×	0.020	CHMP1A

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×	0.005	VRK1
Cajal body organization	1	2106.5×	0.005	VRK1
Golgi disassembly	1	1404.3×	0.005	VRK1
mitotic nuclear membrane disassembly	1	936.2×	0.005	VRK1
endosome transport via multivesicular body sorting pathway	1	936.2×	0.005	CHMP1A
late endosome to vacuole transport	1	936.2×	0.005	CHMP1A
ESCRT III complex disassembly	1	842.6×	0.005	CHMP1A
vesicle fusion with vacuole	1	766.0×	0.005	CHMP1A
multivesicular body-lysosome fusion	1	702.2×	0.005	CHMP1A
viral budding from plasma membrane	1	648.1×	0.005	CHMP1A
cell division	2	46.2×	0.005	VRK1, CHMP1A
mitotic chromosome condensation	1	495.6×	0.005	CHMP1A
nuclear membrane reassembly	1	495.6×	0.005	CHMP1A
late endosome to lysosome transport	1	495.6×	0.005	CHMP1A
viral budding via host ESCRT complex	1	401.2×	0.005	CHMP1A
multivesicular body sorting pathway	1	401.2×	0.005	CHMP1A
regulation of centrosome duplication	1	366.4×	0.005	CHMP1A
midbody abscission	1	366.4×	0.005	CHMP1A
regulation of mitotic spindle assembly	1	366.4×	0.005	CHMP1A
regulation of neuron migration	1	312.1×	0.006	VRK1
plasma membrane repair	1	290.6×	0.006	CHMP1A
nucleus organization	1	280.9×	0.006	CHMP1A
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	1	271.8×	0.006	CHMP1A
multivesicular body assembly	1	263.3×	0.006	CHMP1A
membrane fission	1	205.5×	0.007	CHMP1A
mitotic metaphase chromosome alignment	1	191.5×	0.007	CHMP1A
autophagosome maturation	1	175.5×	0.008	CHMP1A
protein autophosphorylation	1	72.6×	0.018	VRK1
neuron projection development	1	61.1×	0.021	VRK1
autophagy	1	55.1×	0.022	CHMP1A

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VRK1	0	0
CHMP1A	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
CHMP1A	6	Binding:6

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	CHMP1A

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)
VRK1	74	—
CHMP1A	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.