AGTPBP1
protein-codingATP/GTP binding carboxypeptidase 1, the group of M14 carboxypeptidases|Armadillo like helical domain containing
Gene summary
NNA1 is a zinc carboxypeptidase that contains nuclear localization signals and an ATP/GTP-binding motif that was initially cloned from regenerating spinal cord neurons of the mouse.[supplied by OMIM, Jul 2002]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~195.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0032650
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0032650
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0032650
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0032650
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0032650
Submitter: ClinGen
*AGTPBP1* was first reported in relation to autosomal recessive neurodegeneration, childhood-onset, with cerebellar atrophy (also known as Childhood-onset neurodegeneration with cerebellar atrophy (CONDCA)) in 2018 (Shashi et al., PMID: 30420557). Neurodegeneration, childhood-onset, with cerebellar atrophy is a severe neurodevelopmental disorder which presents in the first year of life with global developmental delay, impaired intellectual development, poor or absent speech, and motor abnormalities. Brain imaging shows cerebellar atrophy in patients with this disease. Biallelic variants in *AGTPBP1* are reported to cause this disease through a loss of function mechanism. Variants in this gene have also been associated with Pontocerebellar hypoplasia type 1. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the two disease entities have been lumped under neurodegeneration, childhood-onset, with cerebellar atrophy. At least 13 unique variants (nonsense, missense, splice-site) that have been reported in 10 probands from 4 publications (PMIDs: 28600779, 30420557, 30976113, 38153683) are included in this curation. More information is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. This gene-disease relationship is also supported by biochemical function, functional alteration studies, and a knockout mouse model recapitulating the disease phenotype (PMIDs: 28325758, 30420557). In summary, there is definitive evidence to support the relationship between *AGTPBP1* and autosomal recessive neurodegeneration, childhood-onset, with cerebellar atrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on July 21st, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0016396
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to AGTPBP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001330701.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 17 | 2 | 20 | ||
| missense | 3 | 4 | 117 | 8 | 132 | |
| nonsense | 5 | 4 | 9 | |||
| start loss | 0 | |||||
| frameshift | 3 | 1 | 4 | |||
| splice donor/acceptor (+/-2bp) | 2 | 5 | 7 | 14 | ||
| Total | 13 | 13 | 126 | 25 | 2 | 179 |
Highest pathogenic variant AF is 0.0000068585505
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001317630.1 | 25 | MANE Select | |
| Ensembl | ENSP00000349592.3 | 25 | MANE Select | |
| RefSeq | NP_001273644.1 | 25 | Standard | |
| RefSeq | NP_001273646.1 | 25 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| agtpbp1 | Danio rerio | Structure: ventricular system Quality: edematous abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Olfactory bulb development and olfactory learning
- Post-translational protein modification
- Metabolism of proteins
- Carboxyterminal post-translational modifications of tubulin
Biological Process
- eye photoreceptor cell differentiation
- proteolysis
- mitochondrion organization
- cerebellar Purkinje cell differentiation
- olfactory bulb development
Molecular Function
- metallocarboxypeptidase activity
- zinc ion binding
- tubulin binding
Cellular Component
- nucleus
- nucleolus
- cytoplasm
- mitochondrion
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000376083
- Coding exons
- 25
- Length
- 195490
- Individuals with no LoFs
- 125709
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 37
- Defined
- 125746
- p
- 0.000147
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.01 | 477 | 618 | 0.772 | 0.0000314 | 7799 |
| Missense (PolyPhen) | 98 | 184.6 | 0.53089 | 2308 | ||
| Synonymous | 0.527 | 208 | 218 | 0.955 | 0.0000113 | 2200 |
| Loss of Function | 5.68 | 14 | 62.4 | 0.224 | 0.00000348 | 811 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000088 | 0.000087 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00015 | 0.00015 | rare |
| South Asian | 0.00024 | 0.00023 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Metallocarboxypeptidase that mediates deglutamylation of target proteins. Catalyzes the deglutamylation of polyglutamate side chains generated by post-translational polyglutamylation in proteins such as tubulins. Also removes gene-encoded polyglutamates from the carboxy-terminus of target proteins such as MYLK. Acts as a long-chain deglutamylase and specifically shortens long polyglutamate chains, while it is not able to remove the branching point glutamate, a process catalyzed by AGBL5/CCP5. {ECO:0000250|UniProtKB:Q641K1}.;
Recessive Scores
- pRec
- 0.143
Intolerance Scores
- LoFtool
- 0.604
- RVIS EVS
- -1.08
- RVIS percentile EVS
- 7.2
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.172
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |