AGBL5
protein-codingAGBL carboxypeptidase 5, the group of M14 carboxypeptidases
Gene summary
This gene encodes a metallocarboxypeptidase involved in protein deglutamylation and a member of the peptidase M14 family of proteins. The encoded protein has been described as a "dual-functional" deglutamylase that can remove glutamate residues from both carboxyl termini and side chains of protein substrates. This deglutamylase activity may be important in antiviral immunity. Mutations in this gene are associated with retinitis pigmentosa. [provided by RefSeq, Jul 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~28.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014871
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014871
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014871
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0019118
Submitter: ClinGen
*AGBL5* was first described in relation to retinitis pigmentosa in 2015 (Kastner et al., PMID: 26720455). Patients diagnosed with the specific disease entity, retinitis pigmentosa 75 (MONDO:0014871, OMIM:615900), most commonly exhibited rod-cone dystrophy, nyctalopia, reduced visual acuity, bone spicule pigmentation of the retina, cataracts, and/or constriction of peripheral visual fields. All of the probands were diagnosed during adulthood, although onset of ocular symptoms could occur during childhood. Many probands were also found to have hearing loss. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (biallelic loss of function in the AGBL5 gene product) and mode of inheritance (autosomal recessive) were found to be consistent among unrelated patients with this diagnosis. The phenotypic variability among the diverse cases appeared to represent a spectrum of disease rather than separate disease entities. Therefore, these cases have been lumped for the purposes of this gene curation into a single disease entity, referred to as AGBL5-related retinopathy. This curation includes 16 variants (9 missense, 2 frameshift, 4 nonsense, and 1 non-canonical splicing disruption) that have been collectively reported in 15 probands in 7 publications (PMID: 26720455, PMID: 26355662, PMID: 39672920, PMID: 35892439, PMID: 27764769, PMID: 27842159, and PMID: 38078364). Overall, the variant types suggest that the mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by multiple forms of experimental evidence, including biochemical studies indicating that *AGBL5* encodes an enzyme (also known as CCP5) that is responsible for deglutamylating tubulin (PMID: 24022482). Mouse models of *Agbl5* loss show disruption of this post-translational modification in the retinal cilia and recapitulate the abnormal retinal morphology in human probands (PMID: 39528655). In conclusion, *AGBL5* has a Definitive association with AGBL5-related retinopathy. This classification has been clearly demonstrated in both research and diagnostic settings and has been upheld over time without the emergence of conflicting evidence. This classification was approved by the Retina GCEP on March 6th, 2025 (SOP Version 11).
Clinical Genomic Database (CGD)
Manifestation: Ophthalmologic
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 AGBL5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_021831.6. 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 | 9 | 194 | 3 | 206 | ||
| missense | 2 | 7 | 397 | 20 | 2 | 428 |
| nonsense | 11 | 3 | 2 | 16 | ||
| start loss | 0 | |||||
| frameshift | 13 | 9 | 5 | 27 | ||
| splice donor/acceptor (+/-2bp) | 9 | 10 | 19 | |||
| Total | 26 | 28 | 423 | 214 | 5 | 696 |
Highest pathogenic variant AF is 0.00001734715
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_068603.4 | 14 | MANE Select | |
| Ensembl | ENSP00000353249.4 | 14 | MANE Select | |
| RefSeq | NP_001030584.1 | 10 | Standard | |
| Ensembl | ENSP00000323681.8 | 10 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| agbl5 | Danio rerio | Structure: ventricular system Quality: edematous abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Post-translational protein modification
- Metabolism of proteins
- Carboxyterminal post-translational modifications of tubulin
Biological Process
- proteolysis
- protein deglutamylation
- protein branching point deglutamylation
- defense response to virus
Molecular Function
- metallocarboxypeptidase activity
- zinc ion binding
- tubulin binding
Cellular Component
- nucleus
- cytoplasm
- cytosol
- microtubule cytoskeleton
- midbody
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000360131
- Coding exons
- 14
- Length
- 28259
- Individuals with no LoFs
- 125622
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 126
- Defined
- 125748
- p
- 0.000501
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.29 | 462 | 547 | 0.844 | 0.0000346 | 5753 |
| Missense (PolyPhen) | 101 | 157.29 | 0.64213 | 1502 | ||
| Synonymous | -0.604 | 217 | 206 | 1.05 | 0.0000118 | 1874 |
| Loss of Function | 3.23 | 20 | 42.8 | 0.467 | 0.00000290 | 418 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00038 | 0.00037 | rare |
| Latino/Admixed American | 0.00035 | 0.00035 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00050 | 0.00049 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00032 | 0.00027 | rare |
| South Asian | 0.0020 | 0.0020 | notable |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Metallocarboxypeptidase that mediates protein deglutamylation. Specifically catalyzes the deglutamylation of the branching point glutamate side chains generated by post- translational glutamylation in proteins such as tubulins. In contrast, it is not able to act as a long-chain deglutamylase that shortens long polyglutamate chains, a process catalyzed by AGTPBP1/CCP1, AGBL2/CCP2, AGBL3/CCP3, AGBL1/CCP4 and AGBL4/CCP6. Mediates deglutamylation of CGAS, regulating the antiviral activity of CGAS. {ECO:0000250|UniProtKB:Q09M02}.;
Intolerance Scores
- LoFtool
- 0.737
- RVIS EVS
- -0.99
- RVIS percentile EVS
- 8.6
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.0761
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |