Pontocerebellar hypoplasia type 8

Summary

Pontocerebellar hypoplasia type 8 (MONDO:0013990) is a disease caused by CHMP1A (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CHMP1A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia type 8
Mondo ID	MONDO:0013990
OMIM	614961
Orphanet	324569
DOID	DOID:0060277
SNOMED CT	718611007
UMLS	C3554209
MedGen	767123
GARD	0017488
Is cancer (heuristic)	no

Also known as: CHMP1A non-syndromic pontocerebellar hypoplasia · non-syndromic pontocerebellar hypoplasia caused by mutation in CHMP1A · PCH8 · pontocerebellar hypoplasia due to CHMP1A mutation · pontocerebellar hypoplasia type 8 · pontocerebellar hypoplasia, type 8

Data availability: 14 ClinVar variants · 3 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 8

Related subtypes (20): pontocerebellar hypoplasia type 4, pontocerebellar hypoplasia type 3, pontocerebellar hypoplasia type 5, pontocerebellar hypoplasia type 6, pontocerebellar hypoplasia type 7, pontocerebellar hypoplasia type 10, 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

14 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 5 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
39838	NM_002768.5(CHMP1A):c.28-13G>A	CHMP1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2442121	NM_002768.5(CHMP1A):c.28-2A>G	CHMP1A	Likely pathogenic	criteria provided, single submitter
3377250	NM_002768.5(CHMP1A):c.34del (p.Ala12fs)	CHMP1A	Likely pathogenic	criteria provided, single submitter
128732	NM_002768.5(CHMP1A):c.51G>A (p.Lys17=)	CHMP1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3065748	NM_002768.5(CHMP1A):c.65C>T (p.Ala22Val)	CHMP1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
39837	NM_002768.5(CHMP1A):c.88C>T (p.Gln30Ter)	CHMP1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
510863	NM_002768.5(CHMP1A):c.204C>T (p.Arg68=)	CHMP1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522948	NM_002768.5(CHMP1A):c.346G>A (p.Glu116Lys)	CHMP1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028044	NM_002768.5(CHMP1A):c.106-3C>T	CHMP1A	Uncertain significance	criteria provided, single submitter
1028045	NM_002768.5(CHMP1A):c.130T>A (p.Cys44Ser)	CHMP1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032086	NM_002768.5(CHMP1A):c.*93G>A	CHMP1A	Uncertain significance	criteria provided, single submitter
1032087	NM_002768.5(CHMP1A):c.277A>G (p.Thr93Ala)	CHMP1A	Uncertain significance	criteria provided, single submitter
3391148	NM_002768.5(CHMP1A):c.559C>G (p.Leu187Val)	CHMP1A	Uncertain significance	criteria provided, single submitter
4819156	NM_002768.5(CHMP1A):c.299T>G (p.Leu100Arg)	CHMP1A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CHMP1A	Strong	Autosomal recessive	pontocerebellar hypoplasia type 8	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHMP1A	Orphanet:324569	Pontocerebellar hypoplasia type 8

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CHMP1A	HGNC:8740	ENSG00000131165	Q9HD42	Charged multivesicular body protein 1a	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CHMP1A	Other/Unknown	no		Snf7_fam

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
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
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
CHMP1A	1,793

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHMP1A	Q9HD42	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
HCMV Late Events	1	98.5×	0.010	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
endosome transport via multivesicular body sorting pathway	1	1872.4×	0.003	CHMP1A
late endosome to vacuole transport	1	1872.4×	0.003	CHMP1A
ESCRT III complex disassembly	1	1685.2×	0.003	CHMP1A
vesicle fusion with vacuole	1	1532.0×	0.003	CHMP1A
multivesicular body-lysosome fusion	1	1404.3×	0.003	CHMP1A
viral budding from plasma membrane	1	1296.3×	0.003	CHMP1A
mitotic chromosome condensation	1	991.3×	0.003	CHMP1A
nuclear membrane reassembly	1	991.3×	0.003	CHMP1A
late endosome to lysosome transport	1	991.3×	0.003	CHMP1A
viral budding via host ESCRT complex	1	802.5×	0.003	CHMP1A
multivesicular body sorting pathway	1	802.5×	0.003	CHMP1A
regulation of centrosome duplication	1	732.7×	0.003	CHMP1A
midbody abscission	1	732.7×	0.003	CHMP1A
regulation of mitotic spindle assembly	1	732.7×	0.003	CHMP1A
plasma membrane repair	1	581.1×	0.003	CHMP1A
nucleus organization	1	561.7×	0.003	CHMP1A
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	1	543.6×	0.003	CHMP1A
multivesicular body assembly	1	526.6×	0.003	CHMP1A
membrane fission	1	411.0×	0.003	CHMP1A
mitotic metaphase chromosome alignment	1	383.0×	0.003	CHMP1A
autophagosome maturation	1	351.1×	0.004	CHMP1A
autophagy	1	110.1×	0.011	CHMP1A
vesicle-mediated transport	1	96.3×	0.012	CHMP1A
negative regulation of gene expression	1	69.1×	0.016	CHMP1A
cell division	1	46.2×	0.023	CHMP1A
protein transport	1	43.9×	0.023	CHMP1A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
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
CHMP1A	6	Binding:6

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CHMP1A

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)
CHMP1A	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.