Pontocerebellar hypoplasia type 9

Summary

Pontocerebellar hypoplasia type 9 (MONDO:0014351) is a disease caused by AMPD2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AMPD2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 396

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pontocerebellar hypoplasia type 9
Mondo ID	MONDO:0014351
OMIM	615809
Orphanet	369920
DOID	DOID:0060278
UMLS	C4014354
MedGen	862791
GARD	0017590
Is cancer (heuristic)	no

Also known as: AMPD2 non-syndromic pontocerebellar hypoplasia · non-syndromic pontocerebellar hypoplasia caused by mutation in AMPD2 · PCH9 · pontocerebellar hypoplasia, type 9

Data availability: 396 ClinVar variants · 5 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 9

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 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

396 retrieved; paginated sample, class counts are floors:

194 likely benign, 127 uncertain significance, 18 pathogenic, 15 likely pathogenic, 14 benign, 11 benign/likely benign, 10 conflicting classifications of pathogenicity, 7 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1098293	NM_001368809.2(AMPD2):c.247G>T (p.Glu83Ter)	AMPD2	Pathogenic	criteria provided, single submitter
132810	NM_001368809.2(AMPD2):c.2172G>C (p.Glu724Asp)	AMPD2	Pathogenic	criteria provided, single submitter
132811	NM_001368809.2(AMPD2):c.885C>A (p.Tyr295Ter)	AMPD2	Pathogenic	no assertion criteria provided
132812	NM_001368809.2(AMPD2):c.2215G>T (p.Asp739Tyr)	AMPD2	Pathogenic	no assertion criteria provided
132813	NM_001368809.2(AMPD2):c.1859G>A (p.Arg620His)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339563	NM_001368809.2(AMPD2):c.895C>T (p.Gln299Ter)	AMPD2	Pathogenic	no assertion criteria provided
1508575	NM_001368809.2(AMPD2):c.1698+1G>A	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705300	NM_001368809.2(AMPD2):c.1057C>T (p.Arg353Ter)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723362	NM_001368809.2(AMPD2):c.646del (p.Leu216fs)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1991577	NM_001368809.2(AMPD2):c.-43_-24dup	AMPD2	Pathogenic	criteria provided, single submitter
2004862	NM_001368809.2(AMPD2):c.319C>T (p.Gln107Ter)	AMPD2	Pathogenic	criteria provided, single submitter
225763	NM_001368809.2(AMPD2):c.2094C>G (p.Tyr698Ter)	AMPD2	Pathogenic	no assertion criteria provided
3758013	NM_001368809.2(AMPD2):c.42del (p.Lys14fs)	AMPD2	Pathogenic	criteria provided, single submitter
426650	NM_001368809.2(AMPD2):c.102_103del (p.Gly35fs)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4785536	NM_001368809.2(AMPD2):c.2007C>A (p.Tyr669Ter)	AMPD2	Pathogenic	criteria provided, single submitter
4787223	NM_001368809.2(AMPD2):c.886_887del (p.Tyr295_Pro296insTer)	AMPD2	Pathogenic	criteria provided, single submitter
4789804	NM_001368809.2(AMPD2):c.-90_-69dup	AMPD2	Pathogenic	criteria provided, single submitter
4790266	NM_001368809.2(AMPD2):c.-42dup	AMPD2	Pathogenic	criteria provided, single submitter
488467	NM_001368809.2(AMPD2):c.2165T>G (p.Leu722Arg)	AMPD2	Pathogenic	criteria provided, single submitter
620339	NM_001368809.2(AMPD2):c.520G>T (p.Glu174Ter)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
810627	NM_001368809.2(AMPD2):c.333del (p.Gln112fs)	AMPD2	Pathogenic	no assertion criteria provided
813899	NM_001368809.2(AMPD2):c.1345C>T (p.Arg449Ter)	AMPD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
975089	NM_001368809.2(AMPD2):c.1198C>T (p.Gln400Ter)	AMPD2	Pathogenic	criteria provided, single submitter
2424031	NC_000001.10:g.(?108679275)(111674176_?)del	EPS8L3	Pathogenic	criteria provided, single submitter
132809	NM_001368809.2(AMPD2):c.1492del (p.Asp498fs)	LOC126805822	Pathogenic	no assertion criteria provided
1098294	NM_001368809.2(AMPD2):c.1859G>T (p.Arg620Leu)	AMPD2	Likely pathogenic	criteria provided, single submitter
1325790	NM_001368809.2(AMPD2):c.2366G>A (p.Arg789His)	AMPD2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2031731	NM_001368809.2(AMPD2):c.1408-3_1418del	AMPD2	Likely pathogenic	criteria provided, single submitter
2503047	NM_001368809.2(AMPD2):c.1858C>A (p.Arg620Ser)	AMPD2	Likely pathogenic	criteria provided, single submitter
3382962	NM_001368809.2(AMPD2):c.269del (p.Pro90fs)	AMPD2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
AMPD2	Definitive	Autosomal recessive	pontocerebellar hypoplasia type 9	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AMPD2	Orphanet:369920	Pontocerebellar hypoplasia type 9
AMPD2	Orphanet:401805	Autosomal recessive spastic paraplegia type 63
EPS8L3	Orphanet:444	Marie Unna hereditary hypotrichosis

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
AMPD2	HGNC:469	ENSG00000116337	Q01433	AMP deaminase 2	gencc,clinvar
EPS8L3	HGNC:21297	ENSG00000198758	Q8TE67	Epidermal growth factor receptor kinase substrate 8-like protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AMPD2	AMP deaminase 2	AMP deaminase plays a critical role in energy metabolism.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	8.6×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AMPD2	Enzyme (other)	yes	3.5.4.6	AMPD, A/AMP_deam_AS, Metal_Hydrolase
EPS8L3	Scaffold/PPI	no		SH3_domain, PH-like_dom_sf, PTB

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
adenohypophysis	1
granulocyte	1
pituitary gland	1
ileal mucosa	1
mucosa of transverse colon	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AMPD2	262	ubiquitous	marker	adenohypophysis, pituitary gland, granulocyte
EPS8L3	161	tissue_specific	marker	mucosa of transverse colon, rectum, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AMPD2	2,024
EPS8L3	632

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AMPD2	Q01433	4
EPS8L3	Q8TE67	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Nucleotide salvage	1	1142.0×	0.002	AMPD2
Purine salvage	1	878.5×	0.002	AMPD2
Metabolism of nucleotides	1	300.5×	0.004	AMPD2
Metabolism	1	11.6×	0.086	AMPD2

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
cyclic purine nucleotide metabolic process	1	8426.0×	0.002	AMPD2
IMP biosynthetic process	1	2808.7×	0.002	AMPD2
IMP salvage	1	1685.2×	0.002	AMPD2
GMP salvage	1	1404.3×	0.002	AMPD2
regulation of hair cycle	1	1203.7×	0.002	EPS8L3
AMP metabolic process	1	936.2×	0.002	AMPD2
podocyte development	1	766.0×	0.003	AMPD2
GTP metabolic process	1	561.7×	0.003	AMPD2
positive regulation of ruffle assembly	1	495.6×	0.003	EPS8L3
regulation of Rho protein signal transduction	1	255.3×	0.005	EPS8L3
ATP metabolic process	1	234.1×	0.005	AMPD2
energy homeostasis	1	135.9×	0.009	AMPD2
Rho protein signal transduction	1	123.9×	0.009	EPS8L3
cholesterol homeostasis	1	78.0×	0.013	AMPD2

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
AMPD2	0	0
EPS8L3	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
AMPD2	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AMPD2	3.5.4.6	AMP deaminase

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	AMPD2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	EPS8L3

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)
AMPD2	4	—
EPS8L3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.