ATG5

Summary

ATG5 (autophagy related 5, HGNC:589) is a protein-coding gene on chromosome 6q21, encoding Autophagy protein 5 (Q9H1Y0). Involved in autophagic vesicle formation.

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.

Source: NCBI Gene 9474 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia, autosomal recessive 25 (Moderate, GenCC)
• GWAS associations: 30
• Clinical variants (ClinVar): 39 total
• Phenotypes (HPO): 13
• MANE Select transcript: NM_004849

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:589
Approved symbol	ATG5
Name	autophagy related 5
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	ASP, APG5, hAPG5
Ensembl gene	ENSG00000057663
Ensembl biotype	protein_coding
OMIM	604261
Entrez	9474

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000343245, ENST00000360666, ENST00000369070, ENST00000369076, ENST00000475645, ENST00000476518, ENST00000613993, ENST00000635758, ENST00000636335, ENST00000636437, ENST00000646025, ENST00000855918, ENST00000855919, ENST00000855920, ENST00000855921, ENST00000855922, ENST00000939176, ENST00000939177, ENST00000939178, ENST00000958077, ENST00000958078

RefSeq mRNA: 5 — MANE Select: NM_004849 NM_001286106, NM_001286107, NM_001286108, NM_001286111, NM_004849

CCDS: CCDS5055, CCDS69159, CCDS75498

Canonical transcript exons

ENST00000369076 — 8 exons

Exon	Start	End
ENSE00000974890	106308364	106308491
ENSE00003664444	106316101	106316266
ENSE00003681713	106184476	106186676
ENSE00003801831	106248150	106248244
ENSE00003804703	106279661	106279823
ENSE00003808200	106201972	106202089
ENSE00003811127	106293028	106293106
ENSE00003849930	106325526	106325760

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 95.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.6741 / max 179.6531, expressed in 1818 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74899	15.8220	1798
74901	12.8081	1790
74900	0.5729	299
74898	0.4710	230

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.43	gold quality
colonic mucosa	UBERON:0000317	93.31	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.93	gold quality
calcaneal tendon	UBERON:0003701	92.00	gold quality
jejunal mucosa	UBERON:0000399	91.34	gold quality
endothelial cell	CL:0000115	90.85	gold quality
oocyte	CL:0000023	90.77	gold quality
adrenal tissue	UBERON:0018303	90.68	gold quality
rectum	UBERON:0001052	90.65	gold quality
islet of Langerhans	UBERON:0000006	90.34	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.22	gold quality
duodenum	UBERON:0002114	89.73	gold quality
ileal mucosa	UBERON:0000331	89.68	gold quality
oral cavity	UBERON:0000167	89.57	gold quality
middle temporal gyrus	UBERON:0002771	89.57	gold quality
secondary oocyte	CL:0000655	89.25	gold quality
bronchial epithelial cell	CL:0002328	89.10	gold quality
mucosa of transverse colon	UBERON:0004991	89.08	gold quality
right adrenal gland cortex	UBERON:0035827	89.08	gold quality
right adrenal gland	UBERON:0001233	89.00	gold quality
left adrenal gland	UBERON:0001234	88.99	gold quality
adrenal gland	UBERON:0002369	88.86	gold quality
endometrium	UBERON:0001295	88.68	gold quality
left adrenal gland cortex	UBERON:0035825	88.41	gold quality
bone marrow	UBERON:0002371	88.37	gold quality
colonic epithelium	UBERON:0000397	88.24	gold quality
granulocyte	CL:0000094	88.15	gold quality
tendon	UBERON:0000043	88.13	gold quality
adrenal cortex	UBERON:0001235	88.06	gold quality
leukocyte	CL:0000738	87.99	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	10511.96
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, DDIT3, E2F1, TP73

miRNA regulators (miRDB)

104 targeting ATG5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-3529-3P	99.90	73.55	3045

Literature-anchored findings (GeneRIF, showing 40)

• Human Apg3p/Aut1p homologue is an authentic E2 enzyme for multiple substrates, GATE-16, GABARAP, and MAP-LC3, and facilitates the conjugation of hApg12p to hApg5p (PMID:11825910)
• the Apg12p.Apg5p conjugate does not facilitate LC3 processing (PMID:12207896)
• Apg5 and the apoptosis-specific protein p45ASP are distinct proteins although they do share some common characteristics. (PMID:12417306)
• results suggest that autophagy 5-like Atg5 plays a crucial role in interferon-gamma-induced autophagic cell death by interacting with Fas-associated protein with death domain (FADD) (PMID:15778222)
• Our data show that ATG5 protein is required to execute Denge Virus 2-induced autophagy. (PMID:18353420)
• Increased T cell expression of Atg5 may contribute to inflammatory demyelination in multiple sclerosis. (PMID:19066443)
• Knockdown of p300 reduces acetylation of Atg5, Atg7, Atg8, and Atg12, although overexpressed p300 increases the acetylation of these same proteins. (PMID:19124466)
• The UBQLN protective effect requires the autophagy-related genes ATG5 and ATG7, two essential components of autophagy. (PMID:19148225)
• tumor-promoting effect of deletion in 6q21, that included genes PRDM1, ATG5 and AIM1 (PMID:19194464)
• Data show that silencing of ATG5 or beclin-1 reduced autophagy in 17alpha-AED treated malignant gliomas and attenuated its cytotoxic effects. (PMID:19375507)
• upregulation of Atg5 is required for the oncogenic H-ras-induced autophagic cell death in normal fibroblasts and that activation of Rac1/MKK7/JNK-signaling pathway leads to upregulation of Atg5 in response to oncogenic H-ras (PMID:19783847)
• Data show that proteasome inhibition promoted autophagosome formation, stimulated autophagic flux, and upregulated expression of the autophagy-specific genes ATG5 and ATG7. (PMID:19881538)
• Calpain1 plays an important role in controlling the levels of autophagy in normal living cells by regulating the levels of a key signaling molecule, ATG12-ATG5 conjugate. (PMID:19901552)
• The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. (PMID:20038797)
• Data reveal that Beclin 1 and ATG5 play key roles in morphine-induced autophagy, which may contribute to morphine-induced neuronal injury. (PMID:20190558)
• Atg5 knockdown reduces gossypol-mediated autophagy. (PMID:20529838)
• This study identified ATG5 as an interacting protein for the hepacivirus NS5B protein. (PMID:20580051)
• study demonstrated that polymorphisms in the intergenic region of PRDM1-ATG5 were associated with systemic lupus erythematosus susceptibility in a Chinese population (PMID:21622776)
• Data show that both EGFR-TKIs increased ATG5 and ATG7 at the mRNA or protein levels (Figure 3), confirming the induction of autophagy by EGFR-TKIs. (PMID:21655094)
• Somatic mutation and loss of expression of ATG5 gene might play a role in gastrointestinal cancer pathogenesis by altering autophagic and apoptotic cell death. (PMID:21664058)
• These findings suggest that toxin sensitivity correlates with caspase and calpain activation, leading to Atg5 and Beclin-1 cleavage. (PMID:21722286)
• ULK1 negatively regulates the kinase activity of mTORC1 and cell proliferation in a manner independent of Atg5 and TSC2 (PMID:21795849)
• overexpression of ATG5 gene may be related to autophagy and might play a role in prostate tumorigenesis. (PMID:21995634)
• Results showed no involvement of rs548234 at PRDM1-ATG5 region in the susceptibility or clinical relevance of RA in Chinese Han population. (PMID:22040493)
• doxorubicin switches protective autophagy in SPP1-depleted cells to apoptosis by calpain-mediated Atg5 cleavage. (PMID:22052905)
• These data relate LC3B, ATG5 and ATG12 to mitochondrial quality control after oxidative damage, and to cellular longevity. (PMID:22170153)
• Genetic variants in ATG5, including a functional promotor variant, are associated with childhood asthma. (PMID:22536318)
• Immunohistochemical analysis of colorectal cancer tissues indicated that increased ATG5 expression is associated with lymphovascular invasion. (PMID:22993366)
• Autophagy is differentially induced in prostate cancer LNCaP, DU145 and PC-3 cells via distinct splicing profiles of ATG5. (PMID:23075929)
• study to identify role of conjugation between ATG12 and ATG5 in LC3 lipidation; structural and mutational analyses of ATG12~ATG5-ATG16N revealed the conjugation generates a patch across ATG12 and ATG5 required for E3 activity (PMID:23202584)
• MAPK14-mediated phosphorylation of ATG5 has a role in inhibiting autophagocytosis (PMID:23235332)
• These results suggested that calpain, Bak and Atg5 were molecular links between autophagy and apoptosis and revealed novel aspects of the crosstalk between these two processes. (PMID:23242420)
• ATG-5 down-regulation is associated with hepatocellular carcinoma infected with hepatitis C virus. (PMID:23317196)
• MIR181A is a novel and important regulator of autophagy and ATG5 is a rate-limiting miRNA target in this effect (PMID:23322078)
• the variant identified in PD patient may change ATG5 protein levels and alter autophagy activities, contributing to Parkinson’s disease onset as a risk factor. (PMID:23384565)
• Data suggest that activated autophagy is associated with the progression of pancreatic ductal adenocarcinoma and that the overexpression of autophagy-related proteins Atg5, Ambra1, beclin-1, LC3B and Bif-1 is significantly correlated with poor outcome. (PMID:23429496)
• PDCD4 negatively regulates autophagy by targeting ATG5. (PMID:23486359)
• sublethal concentrations of DNA-damaging drugs, such as etoposide and cisplatin, induce the expression of autophagy-related protein 5, which is both necessary and sufficient for the subsequent induction of mitotic catastrophe. (PMID:23945651)
• In dopaminergic cells, Atg5-dependent autophagy acts as a protective mechanism during apoptotic cell death induced by paraquat and MPP but not during rotenone or 6-OHDA toxicity. (PMID:23997112)
• down-regulation of ATG5 contributes to tumorigenesis in early-stage cutaneous melanoma. (PMID:24027027)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	atg5	ENSDARG00000023396
mus_musculus	Atg5	ENSMUSG00000038160
rattus_norvegicus	Atg5	ENSRNOG00000000322
drosophila_melanogaster	Atg5	FBGN0029943
caenorhabditis_elegans	atg-5	WBGENE00022152

Protein

Protein identifiers

Autophagy protein 5 — Q9H1Y0 (reviewed: Q9H1Y0)

Alternative names: APG5-like, Apoptosis-specific protein

All UniProt accessions (8): Q9H1Y0, A0A1B0GUS1, A0A1B0GV54, A0A2R8Y718, A9UGY9, L7UMD8, L7UQJ2, Q7Z3H3

UniProt curated annotations — full annotation on UniProt →

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. As part of the ATG8 conjugation system with ATG12 and ATG16L1, required for recruitment of LRRK2 to stressed lysosomes and induction of LRRK2 kinase activity in response to lysosomal stress. May play an important role in the apoptotic process, possibly within the modified cytoskeleton. Its expression is a relatively late event in the apoptotic process, occurring downstream of caspase activity. Plays a crucial role in IFN-gamma-induced autophagic cell death by interacting with FADD. (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. 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.

Subunit / interactions. Forms a conjugate with ATG12. Part of the minor complex composed of 4 sets of ATG12-ATG5 and ATG16L1 (400 kDa); this complex interacts with ATG3 leading to disruption of ATG7 interaction and promotion of ATG8-like proteins lipidation. Forms an 800-kDa complex composed of ATG12-ATG5 and ATG16L2. The ATG12-ATG5 conjugate interacts with RAB33A; this interaction is bridged by ATG16L1 and promotes ATG12-ATG5-ATG16L1 complex recruitment to phagophores. Interacts with TECPR1; the interaction is direct and does not take place when ATG16L1 is associated with the ATG5-ATG12 conjugate. Interacts with DHX58/RIG-1, IFIH1/MDA5 and MAVS/IPS-1 in monomeric form as well as in ATG12-ATG5 conjugate form. The interaction with MAVS is further enhanced upon vesicular stomatitis virus (VSV) infection. Interacts with ATG3. Interacts with ATG7 and ATG10. Interacts with FADD. Interacts with Bassoon/BSN; this interaction is important for the regulation of presynaptic autophagy. Interacts with ATG16L2. (Microbial infection) Interacts transiently interacts with hepatitis C virus (HCV) protein NS5B during HCV infection. (Microbial infection) Interacts with S.flexneri IcsA; bacterial IcsB inhibits this interaction.

Subcellular location. Cytoplasm. Preautophagosomal structure membrane.

Tissue specificity. Ubiquitous. The mRNA is present at similar levels in viable and apoptotic cells, whereas the protein is dramatically highly expressed in apoptotic cells.

Post-translational modifications. Conjugated to ATG12; which is essential for autophagy, but is not required for association with isolation membrane. Acetylated by EP300.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry.

Induction. By apoptotic stimuli.

Similarity. Belongs to the ATG5 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H1Y0-1	Long	yes
Q9H1Y0-2	Short, APG5beta

RefSeq proteins (5): NP_001273035, NP_001273036, NP_001273037, NP_001273040, NP_004840* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007239	Atg5	Family
IPR042526	Atg5_HR	Homologous_superfamily
IPR042527	Atg5_UblA_dom_sf	Homologous_superfamily
IPR048318	ATG5_UblB	Domain
IPR048939	ATG5_UblA	Domain
IPR048940	ATG5_HBR	Domain

Pfam: PF04106, PF20637, PF20638

UniProt features (35 total): helix 14, strand 12, turn 2, sequence variant 2, chain 1, modified residue 1, cross-link 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
4TQ1	X-RAY DIFFRACTION	1.8
4NAW	X-RAY DIFFRACTION	2.19
4TQ0	X-RAY DIFFRACTION	2.7
4GDK	X-RAY DIFFRACTION	2.7
4GDL	X-RAY DIFFRACTION	2.88
5D7G	X-RAY DIFFRACTION	3
7W36	X-RAY DIFFRACTION	3
5NPV	X-RAY DIFFRACTION	3.1
5NPW	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H1Y0-F1	93.53	0.83

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 1, 130

Mutagenesis-validated functional residues (1):

Position	Phenotype
130	loss of conjugaction with atg12. does affect interaction with dhx58, nor with mavs.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy
R-HSA-5205685	PINK1-PRKN Mediated Mitophagy
R-HSA-8934903	Receptor Mediated Mitophagy
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta
R-HSA-5205647	Mitophagy
R-HSA-9612973	Autophagy
R-HSA-9663891	Selective autophagy

MSigDB gene sets: 444 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, WENDT_COHESIN_TARGETS_UP, ATF_B, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_AXO_DENDRITIC_TRANSPORT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_VACUOLE_ORGANIZATION, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, GOBP_THYMIC_T_CELL_SELECTION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (53): autophagosome assembly (GO:0000045), mitophagy (GO:0000423), blood vessel remodeling (GO:0001974), regulation of cytokine production involved in immune response (GO:0002718), chromatin organization (GO:0006325), autophagy (GO:0006914), cellular response to nitrogen starvation (GO:0006995), response to xenobiotic stimulus (GO:0009410), response to fungus (GO:0009620), response to iron(II) ion (GO:0010040), positive regulation of autophagy (GO:0010508), cardiac muscle cell apoptotic process (GO:0010659), negative regulation of cardiac muscle cell apoptotic process (GO:0010667), macroautophagy (GO:0016236), protein ubiquitination (GO:0016567), antigen processing and presentation of endogenous antigen (GO:0019883), negative regulation of protein ubiquitination (GO:0031397), negative regulation of type I interferon production (GO:0032480), piecemeal microautophagy of the nucleus (GO:0034727), aggrephagy (GO:0035973), negative stranded viral RNA replication (GO:0039689), vasodilation (GO:0042311), post-translational protein modification (GO:0043687), negative thymic T cell selection (GO:0045060), innate immune response (GO:0045087), negative regulation of innate immune response (GO:0045824), otolith development (GO:0048840), negative regulation of defense response to virus (GO:0050687), negative regulation of phagocytosis (GO:0050765), regulation of release of sequestered calcium ion into cytosol (GO:0051279), defense response to virus (GO:0051607), ventricular cardiac muscle cell development (GO:0055015), heart contraction (GO:0060047), chaperone-mediated autophagy (GO:0061684), positive regulation of stress granule assembly (GO:0062029), mucus secretion (GO:0070254), positive regulation of mucus secretion (GO:0070257), cellular response to nitrosative stress (GO:0071500), axonal transport (GO:0098930), regulation of postsynaptic membrane neurotransmitter receptor levels (GO:0099072)

GO Molecular Function (2): Atg8-family ligase activity (GO:0019776), protein binding (GO:0005515)

GO Cellular Component (17): cytoplasm (GO:0005737), autophagosome (GO:0005776), cytosol (GO:0005829), axoneme (GO:0005930), membrane (GO:0016020), axon (GO:0030424), phagocytic vesicle membrane (GO:0030670), protein-containing complex (GO:0032991), phagophore assembly site membrane (GO:0034045), Atg12-Atg5-Atg16 complex (GO:0034274), mitochondria-associated endoplasmic reticulum membrane contact site (GO:0044233), phagophore (GO:0061908), Schaffer collateral - CA1 synapse (GO:0098685), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), transferase complex (GO:1990234), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Mitophagy	2
Autophagy	1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1
Immune System	1
Innate Immune System	1
Selective autophagy	1
Macroautophagy	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	3
synapse	3
macroautophagy	2
autophagy	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
autophagy of mitochondrion	1
tissue remodeling	1
regulation of cytokine production	1
cytokine production involved in immune response	1
regulation of production of molecular mediator of immune response	1
cellular component organization	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
cellular response to starvation	1
cellular response to nitrogen levels	1
response to chemical	1
response to other organism	1
response to iron ion	1
positive regulation of catabolic process	1
regulation of autophagy	1
striated muscle cell apoptotic process	1
cardiac muscle cell apoptotic process	1
negative regulation of striated muscle cell apoptotic process	1
regulation of cardiac muscle cell apoptotic process	1
autophagosome assembly	1
protein modification by small protein conjugation	1
antigen processing and presentation	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
negative regulation of cytokine production	1
regulation of type I interferon production	1

Protein interactions and networks

STRING

4056 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATG5	ATG7	O95352	999
ATG5	ATG12	O94817	999
ATG5	ATG16L1	Q676U5	999
ATG5	GABARAPL2	P60520	998
ATG5	ATG10	Q9H0Y0	997
ATG5	ATG3	Q9NT62	996
ATG5	F5GZY7	F5GZY7	996
ATG5	TECPR1	Q7Z6L1	992
ATG5	FADD	Q13158	991
ATG5	SIRT1	Q96EB6	990
ATG5	WDFY3	Q8IZQ1	990
ATG5	RIGI	O95786	990
ATG5	BCL2L1	Q07817	990
ATG5	VIPR1	P32241	988
ATG5	IRGM	A1A4Y4	988

IntAct

196 interactions, top by confidence:

A	B	Type	Score
ATG101	ATG13	psi-mi:“MI:0914”(association)	0.950
ULK1	ATG13	psi-mi:“MI:0914”(association)	0.940
ATG13	ULK1	psi-mi:“MI:0914”(association)	0.940
ATG5	ATG16L1	psi-mi:“MI:0407”(direct interaction)	0.850
TECPR1	ATG5	psi-mi:“MI:0915”(physical association)	0.820
RB1CC1	ATG13	psi-mi:“MI:0914”(association)	0.820
ATG5	ATG12	psi-mi:“MI:0914”(association)	0.800
ATG16L1	RB1CC1	psi-mi:“MI:0914”(association)	0.800
HTT	SQSTM1	psi-mi:“MI:0914”(association)	0.770
CCDC12	ATG5	psi-mi:“MI:0915”(physical association)	0.740
CCT2	TXNDC9	psi-mi:“MI:0914”(association)	0.730
UCHL1	ATG5	psi-mi:“MI:0915”(physical association)	0.680
ATG5	TEKT4	psi-mi:“MI:0915”(physical association)	0.670
TEKT4	ATG5	psi-mi:“MI:0915”(physical association)	0.670
WIPI2	BNIP3L	psi-mi:“MI:0914”(association)	0.640
ATG5	MAVS	psi-mi:“MI:0407”(direct interaction)	0.630
ATG5	MAVS	psi-mi:“MI:0915”(physical association)	0.630
MAVS	ATG5	psi-mi:“MI:0915”(physical association)	0.630

BioGRID (547): FADD (Reconstituted Complex), ATG5 (Affinity Capture-Western), ATG5 (Co-localization), ATG5 (Affinity Capture-Western), ATG5 (Two-hybrid), ATG5 (Two-hybrid), KEAP1 (Two-hybrid), CCHCR1 (Two-hybrid), TEKT4 (Two-hybrid), ATG5 (Biochemical Activity), ATG5 (Biochemical Activity), ATG5 (Affinity Capture-Western), ATG16L1 (Co-crystal Structure), ATG5 (Affinity Capture-MS), ATG16L1 (Co-fractionation)

ESM2 similar proteins: F1LNJ2, O18756, O75643, O94923, P11881, P16446, P29994, P34942, P48603, P48738, P48739, P53810, P53811, P53812, Q00169, Q0E908, Q0VEJ0, Q14643, Q28C34, Q2HJ54, Q3MQ04, Q3MQ06, Q3MQ24, Q3ZT31, Q5BJI9, Q5EAV6, Q5M7Y0, Q5R6F0, Q5R6M6, Q5R792, Q5RCP7, Q6IQC7, Q6NRD0, Q6NRZ4, Q6P3Q6, Q6P4T2, Q6VVX2, Q7K556, Q7ZYD9, Q8N6S4

Diamond homologs: A1CE93, A1DMA1, A2X052, A6RE26, A7EJG6, A7KAL6, I1S039, J5JH39, Q0CRF3, Q0UXN8, Q1DP17, Q2HGZ8, Q2UBM1, Q3MQ04, Q3MQ06, Q3MQ24, Q4WNA5, Q525E4, Q5B2Q6, Q5R792, Q6C4Q6, Q6ZGL4, Q872C6, Q99J83, Q9FFI2, Q9H1Y0, A7KAI4, A3LR68, Q6BVI8, Q6CKE2, Q59VY1, A5DWA7, Q3V5I7, Q9W3R7, Q54GT9

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
ATG5	“form complex”	ATG12/5/16L1	binding
TUFM	“down-regulates activity”	ATG5	binding
WDFY3	“up-regulates quantity”	ATG5	binding
PAK1	“up-regulates quantity by stabilization”	ATG5	phosphorylation
USP13	“up-regulates quantity by stabilization”	ATG5	deubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 134 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Macroautophagy	17	18.9×	8e-15
TBC/RABGAPs	7	17.5×	2e-05
Autophagy	11	15.7×	2e-08
Proteasome assembly	8	15.7×	6e-06
Regulation of RUNX3 expression and activity	6	13.4×	4e-04
Regulation of activated PAK-2p34 by proteasome mediated degradation	5	13.4×	1e-03
Regulation of ornithine decarboxylase (ODC)	5	13.1×	1e-03
Vpu mediated degradation of CD4	5	12.8×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome assembly	21	37.5×	6e-25
piecemeal microautophagy of the nucleus	5	37.1×	2e-05
autophagy of mitochondrion	6	34.9×	2e-06
mitophagy	13	32.8×	4e-14
autophagosome maturation	9	25.1×	2e-08
macroautophagy	9	17.2×	5e-07
regulation of macroautophagy	5	11.7×	4e-03
positive regulation of autophagy	7	11.6×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

39 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	1
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

3597 predictions. Top by Δscore:

Variant	Effect	Δscore
6:106088197:CCAG:C	acceptor_loss	1.0000
6:106088198:CAGGC:C	acceptor_loss	1.0000
6:106088199:A:AG	acceptor_gain	1.0000
6:106088199:A:T	acceptor_loss	1.0000
6:106088200:G:GA	acceptor_loss	1.0000
6:106088200:G:GG	acceptor_gain	1.0000
6:106088200:GGCT:G	acceptor_gain	1.0000
6:106095611:TTA:T	acceptor_loss	1.0000
6:106095613:A:AG	acceptor_gain	1.0000
6:106095613:A:AT	acceptor_loss	1.0000
6:106095613:AG:A	acceptor_gain	1.0000
6:106095614:G:GA	acceptor_gain	1.0000
6:106095614:GG:G	acceptor_gain	1.0000
6:106095614:GGT:G	acceptor_gain	1.0000
6:106095614:GGTT:G	acceptor_gain	1.0000
6:106095719:G:GT	donor_gain	1.0000
6:106095730:GGAGG:G	donor_gain	1.0000
6:106095731:GAGG:G	donor_gain	1.0000
6:106095731:GAGGG:G	donor_gain	1.0000
6:106095732:AGG:A	donor_gain	1.0000
6:106095733:GG:G	donor_gain	1.0000
6:106095733:GGG:G	donor_gain	1.0000
6:106095734:GG:G	donor_gain	1.0000
6:106095735:G:C	donor_loss	1.0000
6:106095735:G:GG	donor_gain	1.0000
6:106095736:T:G	donor_loss	1.0000
6:106097025:G:GT	donor_gain	1.0000
6:106099293:T:A	acceptor_gain	1.0000
6:106099294:G:A	acceptor_gain	1.0000
6:106099297:CA:C	acceptor_loss	1.0000

AlphaMissense

1849 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:106279673:C:G	G156R	1.000
6:106279673:C:T	G156R	1.000
6:106279681:A:G	L153P	1.000
6:106279745:C:G	A132P	1.000
6:106293051:A:G	W98R	1.000
6:106293051:A:T	W98R	1.000
6:106316175:A:G	W12R	1.000
6:106316175:A:T	W12R	1.000
6:106186574:A:G	L265P	0.999
6:106186574:A:T	L265H	0.999
6:106186576:A:C	F264L	0.999
6:106186576:A:T	F264L	0.999
6:106186578:A:G	F264L	0.999
6:106186579:A:C	N263K	0.999
6:106186579:A:T	N263K	0.999
6:106186584:C:G	D262H	0.999
6:106186607:A:G	L254P	0.999
6:106186611:A:G	W253R	0.999
6:106186611:A:T	W253R	0.999
6:106202010:A:G	L218P	0.999
6:106248166:G:T	P186H	0.999
6:106248228:A:C	F165L	0.999
6:106248228:A:T	F165L	0.999
6:106248229:A:G	F165S	0.999
6:106248230:A:G	F165L	0.999
6:106279672:C:T	G156E	0.999
6:106279679:A:G	W154R	0.999
6:106279679:A:T	W154R	0.999
6:106279731:T:A	K136N	0.999
6:106279731:T:G	K136N	0.999

dbSNP variants (sampled 300 via entrez): RS1000031275 (6:106211094 A>G), RS1000050530 (6:106224135 T>A), RS1000055845 (6:106259446 T>A,C), RS1000092719 (6:106231331 G>A), RS1000119892 (6:106225898 GAA>G), RS1000140385 (6:106209782 A>C), RS1000162625 (6:106248259 A>G), RS1000171959 (6:106192637 T>A), RS1000178821 (6:106325899 C>G,T), RS1000211229 (6:106201249 T>C), RS1000213349 (6:106276623 A>G), RS1000217405 (6:106187756 G>A), RS1000243647 (6:106296708 C>T), RS1000266720 (6:106192340 A>C), RS1000268656 (6:106276327 G>A,C)

Disease associations

OMIM: gene MIM:604261 | disease phenotypes: MIM:617584

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia, autosomal recessive 25	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
spinocerebellar ataxia, autosomal recessive 25	Limited	AR

Mondo (1): spinocerebellar ataxia, autosomal recessive 25 (MONDO:0033115)

Orphanet (0):

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000666	Horizontal nystagmus
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001310	Dysmetria
HP:0001321	Cerebellar hypoplasia
HP:0001348	Brisk reflexes
HP:0002078	Truncal ataxia
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0003680	Nonprogressive
HP:0031936	Delayed ability to walk

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST000507_12	Systemic lupus erythematosus	5.000000e-12
GCST001795_22	Systemic lupus erythematosus	4.000000e-06
GCST002069_4	Systemic lupus erythematosus and Systemic sclerosis	5.000000e-07
GCST002318_8	Rheumatoid arthritis	8.000000e-10
GCST002318_9	Rheumatoid arthritis	4.000000e-08
GCST002726_13	Glucose homeostasis traits	4.000000e-06
GCST003155_3	Systemic lupus erythematosus	5.000000e-14
GCST003156_8	Systemic lupus erythematosus	5.000000e-14
GCST003620_4	Systemic lupus erythematosus or rheumatoid arthritis	1.000000e-07
GCST003622_31	Systemic lupus erythematosus	4.000000e-12
GCST003622_47	Systemic lupus erythematosus	3.000000e-06
GCST003996_46	Monobrow	5.000000e-14
GCST004483_2	Multiple myeloma	9.000000e-15
GCST005038_110	Allergic disease (asthma, hay fever or eczema)	4.000000e-11
GCST005533_3	Limited cutaneous systemic scleroderma	8.000000e-07
GCST005534_3	Systemic sclerosis	4.000000e-08
GCST005752_16	Systemic lupus erythematosus	4.000000e-15
GCST006959_108	Rheumatoid arthritis	1.000000e-07
GCST007400_47	Systemic lupus erythematosus	6.000000e-15
GCST007797_28	Asthma onset (childhood vs adult)	3.000000e-07
GCST007798_77	Asthma	1.000000e-06
GCST007800_9	Asthma (childhood onset)	9.000000e-21
GCST008473_3	Visceral fat	1.000000e-09
GCST008473_4	Visceral fat	4.000000e-10
GCST009131_12	Systemic sclerosis	3.000000e-09
GCST010043_144	Asthma	7.000000e-10
GCST011011_24	Youthful appearance (self-reported)	4.000000e-08
GCST012396_7	Multiple myeloma	2.000000e-06
GCST90002381_157	Eosinophil count	1.000000e-14
GCST90002382_349	Eosinophil percentage of white cells	2.000000e-14

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004471	insulin sensitivity measurement
EFO:0007906	synophrys measurement
EFO:1001017	limited scleroderma
EFO:0004847	age at onset
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs510432	Efficacy	3	adalimumab	Inflammatory Bowel Diseases
rs9373839	Efficacy	3	adalimumab	Inflammatory Bowel Diseases

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs510432	ATG5	3	2.25	1	adalimumab
rs9373839	ATG5	3	2.25	1	adalimumab

CTD chemical–gene interactions

154 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects reaction, decreases reaction, increases expression, affects cotreatment, affects response to substance (+2 more)	6
Cisplatin	affects response to substance, decreases expression, decreases response to substance, affects cotreatment, increases expression (+1 more)	6
sodium arsenite	increases methylation, affects reaction, increases activity, increases cleavage, increases expression (+1 more)	5
3-methyladenine	decreases reaction, increases expression, decreases expression, affects reaction, increases activity	5
Arsenic Trioxide	increases expression, affects binding, increases reaction, increases degradation, affects reaction (+1 more)	5
Acetylcysteine	decreases reaction, increases expression, affects binding, increases reaction	5
Particulate Matter	increases expression, increases abundance, decreases reaction	5
Paraquat	increases expression, affects response to substance, affects binding, affects abundance, increases activity (+4 more)	4
Rotenone	affects response to substance, decreases expression, affects reaction, decreases reaction, increases cleavage	4
Sirolimus	increases cleavage, affects cotreatment, increases expression, affects reaction, decreases reaction	4
Vorinostat	affects binding, decreases reaction, increases reaction, affects cotreatment, increases cleavage (+2 more)	3
Acrolein	affects cotreatment, decreases expression, increases abundance, decreases reaction, increases expression	3
Ethanol	increases activity, increases reaction, increases expression, decreases response to substance, decreases expression (+1 more)	3
Valproic Acid	affects expression, decreases expression, increases expression	3
methylmercuric chloride	decreases expression	2
bisphenol A	affects cotreatment, increases expression, decreases expression	2
tetrandrine	decreases expression, increases expression	2
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	2
epigallocatechin gallate	affects reaction, increases expression, affects cotreatment, decreases expression	2
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases reaction, increases expression, decreases expression	2
Erlotinib Hydrochloride	decreases response to substance, increases expression	2
Vehicle Emissions	affects reaction, increases expression, increases abundance	2
Chloroquine	decreases reaction, increases expression, increases reaction	2
Doxorubicin	decreases expression, increases expression, decreases reaction	2
Nickel	affects cotreatment, increases expression	2
Oleanolic Acid	increases expression	2
Ozone	affects cotreatment, decreases expression, increases abundance	2
Tretinoin	increases expression, affects localization, affects reaction, increases metabolic processing, affects binding (+1 more)	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cadmium Chloride	affects reaction, decreases expression, increases abundance, increases expression	2

Cellosaurus cell lines

9 cell lines: 8 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1A5	Abcam THP-1 ATG5 KO	Cancer cell line	Male
CVCL_D7KQ	Ubigene A-549 ATG5 KO	Cancer cell line	Male
CVCL_D8HP	Ubigene HCT 116 ATG5 KO	Cancer cell line	Male
CVCL_D8ZM	Ubigene HEK293 ATG5 KO	Transformed cell line	Female
CVCL_D9Y4	Ubigene HeLa ATG5 KO	Cancer cell line	Female
CVCL_E0VF	Ubigene Huh-7 ATG5 KO	Cancer cell line	Male
CVCL_E0ZG	Ubigene NCI-H1299 ATG5 KO	Cancer cell line	Male
CVCL_SE00	HAP1 ATG5 (-) 1	Cancer cell line	Male
CVCL_SE01	HAP1 ATG5 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.