Neurodegeneration, childhood-onset, with cerebellar atrophy

Summary

Neurodegeneration, childhood-onset, with cerebellar atrophy (MONDO:0032650) is a disease caused by AGTPBP1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: AGTPBP1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegeneration, childhood-onset, with cerebellar atrophy
Mondo ID	MONDO:0032650
OMIM	618276
UMLS	C4748934
MedGen	1648286
GARD	0027270
Is cancer (heuristic)	no

Also known as: CONDCA

Data availability: 34 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 disorder › neurodegenerative disease › inherited neurodegenerative disorder › neurodegeneration, childhood-onset, with cerebellar atrophy

Related subtypes (81): Huntington disease and related disorders, agenesis of the corpus callosum with peripheral neuropathy, striatonigral degeneration, angioid streaks of choroid, amyotrophic lateral sclerosis-parkinsonism-dementia complex, inherited Creutzfeldt-Jakob disease, mitochondrial DNA depletion syndrome 4a, cerebellar ataxia-hypogonadism syndrome, myoclonic cerebellar dyssynergia, cerebral sclerosis similar to Pelizaeus-Merzbacher disease, Chediak-Higashi syndrome, encephalopathy due to beta-mercaptolactate-cysteine disulfiduria, PEHO syndrome, deafness dystonia syndrome, Kennedy disease, fatal familial insomnia, Huntington disease-like 1, neuronal intranuclear inclusion disease, ataxia-telangiectasia-like disorder, radiation sensitivity/chromosome instability syndrome, autosomal dominant, Huntington disease-like 2, microphthalmia-brain atrophy syndrome, neurodegenerative syndrome due to cerebral folate transport deficiency, hereditary sensory neuropathy-deafness-dementia syndrome, infantile cerebellar-retinal degeneration, Alzheimer disease 17, hypotonia, infantile, with psychomotor retardation and characteristic facies, Alzheimer disease 18, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, severe neurodegenerative syndrome with lipodystrophy, developmental and epileptic encephalopathy, 35, combined oxidative phosphorylation deficiency 29, neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, neuronal ceroid lipofuscinosis, frontotemporal dementia with motor neuron disease, frontotemporal dementia, GM2 gangliosidosis, attenuated Chédiak-Higashi syndrome, autosomal recessive cerebral atrophy, neurodegeneration with brain iron accumulation, fatal post-viral neurodegenerative disorder, ferro-cerebro-cutaneous syndrome, PRKAR1B-related neurodegenerative dementia with intermediate filaments, ITM2B amyloidosis, corticobasal syndrome, infantile-onset axonal motor and sensory neuropathy-optic atrophy-neurodegenerative syndrome, recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, posterior cortical atrophy, progressive supranuclear palsy, leukodystrophy, hereditary spastic paraplegia, facial onset sensory and motor neuronopathy, X-linked neurodegenerative syndrome, Bertini type, X-linked neurodegenerative syndrome, Hamel type, boylan dew greco syndrome, hereditary motor neuron disease, neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, frontotemporal dementia and/or amyotrophic lateral sclerosis, neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities, neurodegeneration with ataxia and late-onset optic atrophy, neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, neurodegeneration, infantile-onset, biotin-responsive, hereditary optic atrophy, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, familial Alzheimer disease, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, hereditary cerebellar ataxia, DCTN1-related neurodegeneration, early-childhood-onset neurodegeneration with retinitis pigmentosa, sensorineural hearing loss, and demyelinating peripheral neuropathy, TUBB4A-related neurologic disorder, neurodegeneration, childhood-onset, with progressive microcephaly, neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, neurodegeneration and seizures due to copper transport defect, neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairment, neurodegenerative disorder with cerebellar and caudate atrophy, APP-related brain and vascular amyloidosis

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

34 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 9 pathogenic, 7 likely pathogenic, 3 conflicting classifications of pathogenicity, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2577529	NM_001330701.2(AGTPBP1):c.910-1G>A	AGTPBP1	Pathogenic	criteria provided, single submitter
522816	NM_001330701.2(AGTPBP1):c.2336-1G>T	AGTPBP1	Pathogenic	criteria provided, single submitter
522817	NM_001286715.1(AGTPBP1):c.2892del (p.Tyr964Terfs)	AGTPBP1	Pathogenic	criteria provided, single submitter
599365	NM_001330701.2(AGTPBP1):c.2566C>T (p.Gln856Ter)	AGTPBP1	Pathogenic	no assertion criteria provided
599366	NM_001330701.2(AGTPBP1):c.2552C>T (p.Thr851Met)	AGTPBP1	Pathogenic	criteria provided, single submitter
599367	NM_001330701.2(AGTPBP1):c.2969A>T (p.His990Leu)	AGTPBP1	Pathogenic	no assertion criteria provided
599370	NM_001330701.2(AGTPBP1):c.2080T>G (p.Tyr694Asp)	AGTPBP1	Pathogenic	no assertion criteria provided
983264	NM_001330701.2(AGTPBP1):c.1240C>T (p.Arg414Ter)	AGTPBP1	Pathogenic	criteria provided, single submitter
984979	NM_001330701.2(AGTPBP1):c.820_821del (p.Gln274fs)	AGTPBP1	Pathogenic	criteria provided, single submitter
1029296	NM_001330701.2(AGTPBP1):c.1606C>T (p.Arg536Ter)	AGTPBP1	Likely pathogenic	criteria provided, single submitter
1323865	NM_001330701.2(AGTPBP1):c.2481T>A (p.Tyr827Ter)	AGTPBP1	Likely pathogenic	criteria provided, single submitter
2440454	NM_001330701.2(AGTPBP1):c.-34+1G>A	AGTPBP1	Likely pathogenic	criteria provided, single submitter
2444496	NM_001330701.2(AGTPBP1):c.2833C>T (p.Gln945Ter)	AGTPBP1	Likely pathogenic	criteria provided, single submitter
2690507	NM_001330701.2(AGTPBP1):c.2016-2A>G	AGTPBP1	Likely pathogenic	criteria provided, single submitter
599368	NM_001330701.2(AGTPBP1):c.2362C>T (p.Gln788Ter)	AGTPBP1	Likely pathogenic	criteria provided, single submitter
983265	NM_001330701.2(AGTPBP1):c.2396G>T (p.Arg799Leu)	AGTPBP1	Likely pathogenic	criteria provided, single submitter
1201667	NM_001330701.2(AGTPBP1):c.-66del	AGTPBP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3391206	NM_001330701.2(AGTPBP1):c.2420A>G (p.Tyr807Cys)	AGTPBP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
599369	NM_001330701.2(AGTPBP1):c.2752C>T (p.Arg918Trp)	AGTPBP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029297	NM_001330701.2(AGTPBP1):c.2843G>A (p.Arg948Gln)	AGTPBP1	Uncertain significance	criteria provided, single submitter
1029298	NM_001330701.2(AGTPBP1):c.437-3C>A	AGTPBP1	Uncertain significance	criteria provided, single submitter
1308442	NM_001330701.2(AGTPBP1):c.-206G>A	AGTPBP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438928	NM_001330701.2(AGTPBP1):c.2738T>A (p.Val913Asp)	AGTPBP1	Uncertain significance	criteria provided, single submitter
2438929	NM_001330701.2(AGTPBP1):c.3206G>T (p.Cys1069Phe)	AGTPBP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2584838	NM_001330701.2(AGTPBP1):c.1096G>A (p.Val366Ile)	AGTPBP1	Uncertain significance	criteria provided, single submitter
3065792	NM_001330701.2(AGTPBP1):c.3013G>A (p.Ala1005Thr)	AGTPBP1	Uncertain significance	criteria provided, single submitter
3602597	NM_001330701.2(AGTPBP1):c.521G>A (p.Arg174His)	AGTPBP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3602598	NM_001330701.2(AGTPBP1):c.2904-7_2904-2dup	AGTPBP1	Uncertain significance	criteria provided, single submitter
3602599	NM_001330701.2(AGTPBP1):c.55G>A (p.Val19Ile)	AGTPBP1	Uncertain significance	criteria provided, single submitter
3892969	NM_001330701.2(AGTPBP1):c.675_677del (p.Thr226del)	AGTPBP1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
AGTPBP1	Definitive	Autosomal recessive	neurodegeneration, childhood-onset, with cerebellar atrophy	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AGTPBP1	Orphanet:2254	Pontocerebellar hypoplasia type 1

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
AGTPBP1	HGNC:17258	ENSG00000135049	Q9UPW5	Cytosolic carboxypeptidase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AGTPBP1	Cytosolic carboxypeptidase 1	Metallocarboxypeptidase that mediates protein deglutamylation of tubulin and non-tubulin target proteins.

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AGTPBP1	Protease	yes	3.4.17.24	Peptidase_M14, ARM-like, ARM-type_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
corpus callosum	1
cortical plate	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AGTPBP1	280	ubiquitous	marker	cortical plate, corpus callosum, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AGTPBP1	815

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AGTPBP1	Q9UPW5	75.95

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Carboxyterminal post-translational modifications of tubulin	1	237.9×	0.013	AGTPBP1
Post-translational protein modification	1	19.2×	0.078	AGTPBP1
Metabolism of proteins	1	12.4×	0.081	AGTPBP1

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
anterograde axonal transport of mitochondrion	1	8426.0×	8e-04	AGTPBP1
protein deglutamylation	1	5617.3×	8e-04	AGTPBP1
retrograde axonal transport of mitochondrion	1	5617.3×	8e-04	AGTPBP1
eye photoreceptor cell differentiation	1	4213.0×	8e-04	AGTPBP1
C-terminal protein deglutamylation	1	4213.0×	8e-04	AGTPBP1
protein side chain deglutamylation	1	2808.7×	9e-04	AGTPBP1
cerebellar Purkinje cell differentiation	1	1053.2×	0.002	AGTPBP1
central nervous system neuron development	1	802.5×	0.002	AGTPBP1
olfactory bulb development	1	766.0×	0.002	AGTPBP1
positive regulation of ubiquitin-dependent protein catabolic process	1	561.7×	0.003	AGTPBP1
neuromuscular process	1	526.6×	0.003	AGTPBP1
adult walking behavior	1	495.6×	0.003	AGTPBP1
retina development in camera-type eye	1	255.3×	0.005	AGTPBP1
mitochondrion organization	1	151.8×	0.008	AGTPBP1
negative regulation of cell population proliferation	1	42.1×	0.025	AGTPBP1
proteolysis	1	34.2×	0.029	AGTPBP1

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
AGTPBP1	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
AGTPBP1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AGTPBP1	3.4.17.24	tubulin-glutamate carboxypeptidase

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	1	AGTPBP1
E	Difficult family or no structure, no drug	0

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)
AGTPBP1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.