ATG5
protein-codingautophagy related 5, the group of Autophagy related
Gene summary
The protein encoded by this gene, in combination with autophagy protein 12, functions as an E1-like activating enzyme in a ubiquitin-like conjugating system. The encoded protein is involved in several cellular processes, including autophagic vesicle formation, mitochondrial quality control after oxidative damage, negative regulation of the innate antiviral immune response, lymphocyte development and proliferation, MHC II antigen presentation, adipocyte differentiation, and apoptosis. Several transcript variants encoding different protein isoforms have been found for this gene. [provided by RefSeq, Sep 2015]
- APG5L
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~280.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0033115
Submitter: ClinGen
The relationship between the ATG5 gene and spinocerebellar ataxia, autosomal recessive 25 (SCAR25), was evaluated using the ClinGen Clinical Validity Framework as of July 13, 2022 and re-evaluated on October 23, 2025. ATG5 encodes autophagy 5 protein, a protein involved in cellular autophagy via binding the ATG12 protein (PMID: 9759731, PMID: 9852036) to form a complex needed for formation of the autophagic isolation membrane, which helps deliver cytoplasmic components to lysosomes for degradation in macroautophagy (PMID: 11266458). The lymphoblastoid cells of patients with biallelic ATG5 variants reported showed reduced levels of the ATG5-ATG12 protein complex and decreased autophagic flux, consistent with impaired autophagy due to impeded ATG5-ATG12 interaction (PMID: 26812546). The disease mechanism of SCAR25 is loss of function. SCAR25 was first reported in 2005 (PMID:15981765) and the first report of biallelic variants in ATG5 among patients with SCAR25 was in 2016 (PMID: 26812546). In this report, a homozygous missense variant, c.366A>T (p.E122D), was reported to segregate in a consanguineous Turkish family with two affected members; as noted above, lymphoblastoid cells of patients (who were homozygous for this ATG5 variant) showed reduced levels of the ATG5-ATG12 protein complex and decreased autophagic flux, supporting that the variant resulted in impaired autophagy due to impeded ATG5-ATG12 interaction (PMID: 26812546).To date, this first report (PMID: 26812546) appears to be the only report of biallelic ATG5 variants among patients with SCAR25. In addition to the case-level (genetic) evidence (4 points; including 2 points for the variant and 2 points for segregation), there is also experimental evidence supporting the relationship between SCAR25 and ATG5 (6 points total). Experimental evidence for the relationship between ATG5 and SCAR25 includes the biochemical function of the gene product (autophagy 5) being consistent with the reduced autophagic flux found in individuals with SCAR25 (PMID: 26812546), the biochemical and clinical features of a ATG5 knockout Drosophila model (PMID: 26812546), and rescue of a a ATG5 knockout Drosophila model via reexpression of a wild-type ATG5 transgene (PMID: 26812546). In summay, the relationship between ATG5 and SCAR25 is limited. While the total points awarded (10 points) would allow for the classificaiton of "moderate", only a single family with a homozygous single variant has been reported. Therefore, additional case-level evidence is needed to support a causal role. This clinical validity classification of limited was first approved by the ClinGen Lysosomal Diseases GCEP on July 21, 2022 (SOP v9), and re-evaluated by the ClinGen General IEM GCEP on October 24, 2025 (SOP v11).
Inheritance Pattern: AR
Disease ID:MONDO:0033115
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0033115
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0033115
Submitter: PanelApp Australia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ATG5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004849.4. 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 | 2 | 3 | |||
| missense | 13 | 1 | 2 | 16 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 0 | 0 | 17 | 1 | 4 | 22 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004840.1 | 7 | MANE Select | |
| Ensembl | ENSP00000358072.3 | 7 | MANE Select | |
| RefSeq | NP_001273035.1 | 7 | Standard | |
| RefSeq | NP_001273036.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| atg5 | Danio rerio | Structure: dopaminergic neuron Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Longevity regulating pathway - multiple species - Homo sapiens (human)
- Autophagy - animal - Homo sapiens (human)
- Autophagy - other - Homo sapiens (human)
- Mitophagy - animal - Homo sapiens (human)
- Longevity regulating pathway - Homo sapiens (human)
Biological Process
- autophagosome assembly
- autophagy of mitochondrion
- blood vessel remodeling
- regulation of cytokine secretion involved in immune response
- C-terminal protein lipidation
Molecular Function
- protein binding
- Atg8 ligase activity
Cellular Component
- cytoplasm
- autophagosome
- cytosol
- axoneme
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000369076
- Coding exons
- 7
- Length
- 141316
- Individuals with no LoFs
- 125630
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125632
- p
- 0.00000796
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.82 | 81 | 142 | 0.570 | 0.00000689 | 1842 |
| Missense (PolyPhen) | 21 | 52.425 | 0.40057 | 681 | ||
| Synonymous | 0.891 | 38 | 45.7 | 0.832 | 0.00000228 | 475 |
| Loss of Function | 3.48 | 1 | 16.1 | 0.0623 | 8.24e-7 | 194 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000037 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in autophagic vesicle formation. Conjugation with ATG12, through a ubiquitin-like conjugating system involving ATG7 as an E1-like activating enzyme and ATG10 as an E2-like conjugating enzyme, is essential for its function. The ATG12-ATG5 conjugate acts as an E3-like enzyme which is required for lipidation of ATG8 family proteins and their association to the vesicle membranes. Involved in mitochondrial quality control after oxidative damage, and in subsequent cellular longevity. Plays a critical role in multiple aspects of lymphocyte development and is essential for both B and T lymphocyte survival and proliferation. Required for optimal processing and presentation of antigens for MHC II. Involved in the maintenance of axon morphology and membrane structures, as well as in normal adipocyte differentiation. Promotes primary ciliogenesis through removal of OFD1 from centriolar satellites and degradation of IFT20 via the autophagic pathway. {ECO:0000250|UniProtKB:Q99J83, ECO:0000269|PubMed:12207896, ECO:0000269|PubMed:20580051, ECO:0000269|PubMed:22170153, ECO:0000269|PubMed:26812546}.; FUNCTION: (Microbial infection) May act as a proviral factor. In association with ATG12, negatively regulates the innate antiviral immune response by impairing the type I IFN production pathway upon vesicular stomatitis virus (VSV) infection (PubMed:17709747). Required for the translation of incoming hepatitis C virus (HCV) RNA and, thereby, for initiation of HCV replication, but not required once infection is established (PubMed:19666601). {ECO:0000269|PubMed:17709747, ECO:0000269|PubMed:19666601}.;
- Disease
- DISEASE: Spinocerebellar ataxia, autosomal recessive, 25 (SCAR25) [MIM:617584]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR25 patients manifest delayed psychomotor development with delayed walking, truncal ataxia, dysmetria, and nystagmus, Cerebellar hypoplasia is seen on brain imaging. {ECO:0000269|PubMed:26812546}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.171
Intolerance Scores
- LoFtool
- 0.0998
- RVIS EVS
- 0.1
- RVIS percentile EVS
- 61.28
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.741
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |