Pontocerebellar hypoplasia, type 12

Summary

Pontocerebellar hypoplasia, type 12 (MONDO:0032643) is a disease caused by COASY (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COASY (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia, type 12
Mondo ID	MONDO:0032643
OMIM	618266
Orphanet	611256
DOID	DOID:0112327
UMLS	C4748873
MedGen	1648343
GARD	0018030
Is cancer (heuristic)	no

Also known as: COASY-related pontocerebellar hypoplasia · PCH12 · PONTOCEREBELLAR HYPOPLASIA, TYPE 12

Data availability: 16 ClinVar variants · 2 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 12

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 14, pontocerebellar hypoplasia, type 15, pontocerebellar hypoplasia, type 1E, pontocerebellar hypoplasia, type 1F, pontocerebellar hypoplasia, type 16, pontocerebellar hypoplasia, IIA 17, 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

16 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 4 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 3 likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2043445	NM_025233.7(COASY):c.1129C>T (p.Arg377Ter)	COASY	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
599341	NM_025233.7(COASY):c.1486-3C>G	COASY	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
599342	NM_025233.7(COASY):c.1549_1550del (p.Ser517fs)	COASY	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2050208	NM_025233.7(COASY):c.1388-2A>G	COASY	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3581965	NM_025233.7(COASY):c.1387+1G>A	COASY	Likely pathogenic	criteria provided, single submitter
3775291	NM_025233.7(COASY):c.586_587del (p.Val196fs)	COASY	Likely pathogenic	criteria provided, single submitter
1472390	NM_025233.7(COASY):c.1015C>T (p.Arg339Ter)	COASY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2079887	NM_025233.7(COASY):c.53dup (p.Ala19fs)	COASY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
421057	NM_025233.7(COASY):c.1403_1404dup (p.Ile469Ter)	COASY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
808273	NM_025233.7(COASY):c.1237+1G>C	COASY	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1018770	NM_025233.7(COASY):c.118C>T (p.His40Tyr)	COASY	Uncertain significance	criteria provided, multiple submitters, no conflicts
1480948	NM_025233.7(COASY):c.1628G>A (p.Arg543His)	COASY	Uncertain significance	criteria provided, multiple submitters, no conflicts
1727237	NM_025233.7(COASY):c.1238-24_1238-20del	COASY	Uncertain significance	criteria provided, single submitter
2506397	NM_025233.7(COASY):c.1664G>A (p.Arg555His)	COASY	Uncertain significance	criteria provided, multiple submitters, no conflicts
379956	NM_025233.7(COASY):c.164C>A (p.Ser55Tyr)	COASY	Benign	criteria provided, multiple submitters, no conflicts
379957	NM_025233.7(COASY):c.972A>G (p.Thr324=)	COASY	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
COASY	Strong	Autosomal recessive	pontocerebellar hypoplasia, type 12	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COASY	Orphanet:397725	COASY protein-associated neurodegeneration

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
COASY	HGNC:29932	ENSG00000068120	Q13057	Bifunctional coenzyme A synthase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COASY	Bifunctional coenzyme A synthase	Bifunctional enzyme that catalyzes the fourth step of the coenzyme A biosynthetic pathway, the adenylation of 4’-phosphopantetheine, and the fifth step, the phosphorylation of dephospho-CoA to CoA.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COASY	Kinase	yes	2.7.1.24	Depp_CoAkinase, Cyt_trans-like, Rossmann-like_a/b/a_fold

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
lower esophagus mucosa	1
mucosa of transverse colon	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COASY	280	ubiquitous	marker	parotid gland, mucosa of transverse colon, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COASY	3,273

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COASY	Q13057	89.51

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
Coenzyme A biosynthesis	1	1427.5×	7e-04	COASY

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
coenzyme A biosynthetic process	1	1532.0×	7e-04	COASY

Therapeutics

Drug target analysis

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

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
COASY	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	COASY

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
COASY	10	Binding:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
COASY	2.7.1.24, 2.7.7.3	dephospho-CoA kinase, pantetheine-phosphate adenylyltransferase

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	COASY

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	1	COASY
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.