Pontocerebellar hypoplasia type 3

Summary

Pontocerebellar hypoplasia type 3 (MONDO:0011948) is a disease caused by PCLO (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PCLO (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 78

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia type 3
Mondo ID	MONDO:0011948
MeSH	C548072
OMIM	608027
Orphanet	97249
DOID	DOID:0060272
ICD-11	378477807
SNOMED CT	718609003
UMLS	C1842687
MedGen	334225
GARD	0010708
Is cancer (heuristic)	no

Also known as: cerebellar atrophy with progressive microcephaly · clam · non-syndromic pontocerebellar hypoplasia caused by mutation in PCLO · PCH with optic atrophy · PCH without dyskinesia · PCH3 · PCLO non-syndromic pontocerebellar hypoplasia · pontocerebellar hypoplasia, type 3

Data availability: 78 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 3

Related subtypes (20): pontocerebellar hypoplasia type 4, 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 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

78 retrieved; paginated sample, class counts are floors:

50 uncertain significance, 12 conflicting classifications of pathogenicity, 7 benign, 4 pathogenic, 2 benign/likely benign, 2 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
193026	NM_033026.6(PCLO):c.10624C>T (p.Arg3542Ter)	PCLO	Pathogenic	no assertion criteria provided
2506068	NM_033026.6(PCLO):c.1451del (p.Pro484fs)	PCLO	Pathogenic	criteria provided, single submitter
3381839	PCLO, GLN901TER	PCLO	Pathogenic	no assertion criteria provided
3381840	PCLO, TYR2360TER	PCLO	Pathogenic	no assertion criteria provided
3594915	NM_033026.6(PCLO):c.14055dup (p.Gly4686fs)	PCLO	Likely pathogenic	criteria provided, single submitter
800508	NM_033026.6(PCLO):c.2532dup (p.Gln845fs)	PCLO	Likely pathogenic	criteria provided, single submitter
1013552	NM_033026.6(PCLO):c.1297G>A (p.Ala433Thr)	PCLO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028490	NM_033026.6(PCLO):c.13571C>T (p.Pro4524Leu)	PCLO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029004	NM_033026.6(PCLO):c.8069G>A (p.Gly2690Asp)	PCLO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029005	NM_033026.6(PCLO):c.9373G>A (p.Asp3125Asn)	PCLO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032312	NM_033026.6(PCLO):c.5267G>A (p.Arg1756His)	PCLO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032313	NM_033026.6(PCLO):c.6532C>T (p.Pro2178Ser)	PCLO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1392116	NM_033026.6(PCLO):c.6167G>A (p.Arg2056Lys)	PCLO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1410421	NM_033026.6(PCLO):c.824_826del (p.Gln275del)	PCLO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1448156	NM_033026.6(PCLO):c.7585A>G (p.Ile2529Val)	PCLO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1978713	NM_033026.6(PCLO):c.14501A>C (p.His4834Pro)	PCLO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2689670	NM_033026.6(PCLO):c.4849A>G (p.Thr1617Ala)	PCLO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
708091	NM_033026.6(PCLO):c.13495A>G (p.Ile4499Val)	PCLO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028487	NM_033026.6(PCLO):c.10918T>C (p.Phe3640Leu)	PCLO	Uncertain significance	criteria provided, single submitter
1028489	NM_033026.6(PCLO):c.11578C>T (p.Pro3860Ser)	PCLO	Uncertain significance	criteria provided, single submitter
1028491	NM_033026.6(PCLO):c.1585C>A (p.Pro529Thr)	PCLO	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028492	NM_033026.6(PCLO):c.3367C>T (p.Arg1123Cys)	PCLO	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028493	NM_033026.6(PCLO):c.4697A>G (p.Asp1566Gly)	PCLO	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028494	NM_033026.6(PCLO):c.4892A>T (p.Asp1631Val)	PCLO	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029003	NM_033026.6(PCLO):c.6533C>A (p.Pro2178His)	PCLO	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029006	NM_033026.6(PCLO):c.9494T>C (p.Leu3165Ser)	PCLO	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031531	NM_033026.6(PCLO):c.10780A>G (p.Thr3594Ala)	PCLO	Uncertain significance	criteria provided, single submitter
1031532	NM_033026.6(PCLO):c.11671T>C (p.Ser3891Pro)	PCLO	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032311	NM_033026.6(PCLO):c.2576A>G (p.Gln859Arg)	PCLO	Uncertain significance	criteria provided, single submitter
1032314	NM_033026.6(PCLO):c.7375G>T (p.Val2459Phe)	PCLO	Uncertain significance	criteria provided, single submitter

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
PCLO	Strong	Autosomal recessive	pontocerebellar hypoplasia type 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PCLO	Orphanet:97249	Pontocerebellar hypoplasia type 3

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
PCLO	HGNC:13406	ENSG00000186472	Q9Y6V0	Protein piccolo	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PCLO	Protein piccolo	Scaffold protein of the presynaptic cytomatrix at the active zone (CAZ) which is the place in the synapse where neurotransmitter is released.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PCLO	Transcription factor	no		C2_dom, PDZ, Znf_piccolo

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
Brodmann (1909) area 23	1
cerebellar vermis	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PCLO	235	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, cerebellar vermis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PCLO	2,389

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PCLO	Q9Y6V0	1

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
Sensory processing of sound by inner hair cells of the cochlea	1	163.1×	0.006	PCLO

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
presynaptic active zone assembly	1	5617.3×	0.001	PCLO
presynaptic actin cytoskeleton organization	1	3370.4×	0.001	PCLO
synaptic vesicle clustering	1	1404.3×	0.002	PCLO
synaptic vesicle exocytosis	1	766.0×	0.002	PCLO
protein localization to synapse	1	766.0×	0.002	PCLO
regulation of exocytosis	1	702.2×	0.002	PCLO
insulin secretion	1	432.1×	0.003	PCLO
cytoskeleton organization	1	132.7×	0.008	PCLO

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PCLO	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	PCLO

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)
PCLO	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.