Pontocerebellar hypoplasia, type 14

Summary

Pontocerebellar hypoplasia, type 14 (MONDO:0030258) is a disease caused by PPIL1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PPIL1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		18	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia, type 14
Mondo ID	MONDO:0030258
OMIM	619301
Orphanet	613274
DOID	DOID:0112325
UMLS	C5543322
MedGen	1778516
GARD	0018032
Is cancer (heuristic)	no

Also known as: PCH14 · pontocerebellar hypoplasia, type 14

Data availability: 12 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 14

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 10, pontocerebellar hypoplasia type 9, pontocerebellar hypoplasia type 2E, pontocerebellar hypoplasia type 1, pontocerebellar hypoplasia type 2, 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

12 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065399	NM_016059.5(PPIL1):c.295G>A (p.Ala99Thr)	PPIL1	Pathogenic/Likely pathogenic	no assertion criteria provided
1065400	NM_016059.5(PPIL1):c.319A>G (p.Thr107Ala)	PPIL1	Pathogenic/Likely pathogenic	no assertion criteria provided
4073533	NM_016059.5(PPIL1):c.41_42delinsG (p.Val14fs)	C6orf89	Likely pathogenic	criteria provided, single submitter
1065403	NM_016059.5(PPIL1):c.280+1G>A	PPIL1	Likely pathogenic	criteria provided, single submitter
929944	NM_016059.5(PPIL1):c.133C>T (p.Arg45Ter)	PPIL1	Likely pathogenic	criteria provided, single submitter
930026	NM_016059.5(PPIL1):c.379A>G (p.Thr127Ala)	PPIL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1701722	NM_016059.5(PPIL1):c.316G>A (p.Asp106Asn)	PPIL1	Uncertain significance	criteria provided, single submitter
2499595	NM_016059.5(PPIL1):c.277A>C (p.Thr93Pro)	PPIL1	Uncertain significance	criteria provided, single submitter
2500348	NM_016059.5(PPIL1):c.349G>A (p.Ala117Thr)	PPIL1	Uncertain significance	criteria provided, single submitter
2500349	NM_016059.5(PPIL1):c.350C>A (p.Ala117Asp)	PPIL1	Uncertain significance	criteria provided, single submitter
3377734	NM_016059.5(PPIL1):c.188A>C (p.Gln63Pro)	PPIL1	Uncertain significance	criteria provided, single submitter
3377735	NM_016059.5(PPIL1):c.344C>A (p.Thr115Asn)	PPIL1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 0 · 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
PPIL1	Strong	Autosomal recessive	pontocerebellar hypoplasia, type 14	4

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
PPIL1	HGNC:9260	ENSG00000137168	Q9Y3C6	Peptidyl-prolyl cis-trans isomerase-like 1	gencc,clinvar
C6orf89	HGNC:21114	ENSG00000198663	Q6UWU4	Bombesin receptor-activated protein C6orf89	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PPIL1	Peptidyl-prolyl cis-trans isomerase-like 1	Involved in pre-mRNA splicing as component of the spliceosome.
C6orf89	Bombesin receptor-activated protein C6orf89	Exhibits histone deacetylase (HDAC) enhancer properties.

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PPIL1	Enzyme (other)	yes	5.2.1.8	Cyclophilin-type_PPIase_dom, Cyclophilin-type_PPIase_CS, Cyclophilin-type_PPIase
C6orf89	Other/Unknown	no		BRAP

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
left ventricle myocardium	2
heart right ventricle	1
oocyte	1
cardiac muscle of right atrium	1
islet of Langerhans	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PPIL1	251	ubiquitous	marker	heart right ventricle, left ventricle myocardium, oocyte
C6orf89	256	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PPIL1	3,219
C6orf89	448

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PPIL1	Q9Y3C6	28

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C6orf89	Q6UWU4	72.24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
mRNA Splicing - Major Pathway	1	54.6×	0.022	PPIL1
Dengue Virus-Host Interactions	1	45.7×	0.022	PPIL1

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
protein peptidyl-prolyl isomerization	1	2808.7×	0.004	PPIL1
response to bleomycin	1	1685.2×	0.004	C6orf89
connective tissue replacement	1	1203.7×	0.004	C6orf89
collagen metabolic process	1	526.6×	0.006	C6orf89
embryonic brain development	1	401.2×	0.006	PPIL1
positive regulation of cell cycle	1	221.7×	0.009	C6orf89
fibroblast proliferation	1	195.9×	0.009	C6orf89
epithelial cell proliferation	1	156.0×	0.010	C6orf89
wound healing	1	113.9×	0.013	C6orf89
autophagy	1	55.1×	0.023	C6orf89
protein folding	1	51.7×	0.023	PPIL1
mRNA splicing, via spliceosome	1	45.8×	0.024	PPIL1
chromatin remodeling	1	36.5×	0.027	C6orf89

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
PPIL1	0	0
C6orf89	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PPIL1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PPIL1	5.2.1.8	peptidylprolyl isomerase

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	PPIL1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	C6orf89

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)
PPIL1	2	—
C6orf89	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.