ATG3

Summary

ATG3 (autophagy related 3, HGNC:20962) is a protein-coding gene on chromosome 3q13.2, encoding Ubiquitin-like-conjugating enzyme ATG3 (Q9NT62). E2 conjugating enzyme that catalyzes the covalent conjugation of the C-terminal Gly of ATG8-like proteins (GABARAP, GABARAPL1, GABARAPL2 or MAP1LC3A) to the amino group of phosphatidylethanolamine (PE)-containing lipids in the membrane resulting in membrane-bound ATG8-like prote….

This gene encodes a ubiquitin-like-conjugating enzyme and is a component of ubiquitination-like systems involved in autophagy, the process of degradation, turnover and recycling of cytoplasmic constituents in eukaryotic cells. This protein is known to play a role in regulation of autophagy during cell death. A pseudogene of this gene is located on chromosome 20. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 64422 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 65 total — 4 pathogenic
• MANE Select transcript: NM_022488

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20962
Approved symbol	ATG3
Name	autophagy related 3
Location	3q13.2
Locus type	gene with protein product
Status	Approved
Aliases	PC3-96, FLJ22125, MGC15201, DKFZp564M1178
Ensembl gene	ENSG00000144848
Ensembl biotype	protein_coding
OMIM	609606
Entrez	64422

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 7 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000283290, ENST00000402314, ENST00000465980, ENST00000467275, ENST00000488910, ENST00000492886, ENST00000494571, ENST00000495756, ENST00000496423, ENST00000874065, ENST00000874066, ENST00000874067, ENST00000874068

RefSeq mRNA: 2 — MANE Select: NM_022488 NM_001278712, NM_022488

CCDS: CCDS2966, CCDS63721

Canonical transcript exons

ENST00000283290 — 12 exons

Exon	Start	End
ENSE00001076452	112536475	112536602
ENSE00001076453	112534269	112534337
ENSE00001405009	112532510	112532780
ENSE00001901165	112561457	112561962
ENSE00003556922	112537735	112537890
ENSE00003592292	112558376	112558417
ENSE00003610853	112553280	112553329
ENSE00003625404	112550192	112550262
ENSE00003641797	112548533	112548640
ENSE00003673942	112544057	112544106
ENSE00003688016	112541803	112541884
ENSE00003786462	112538146	112538180

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 58.0575 / max 664.7939, expressed in 1821 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
43758	30.7374	1819
43757	25.3587	1809
43756	1.5726	689
202879	0.3888	134

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	98.32	gold quality
mononuclear cell	CL:0000842	98.27	gold quality
sperm	CL:0000019	98.22	gold quality
leukocyte	CL:0000738	98.16	gold quality
adult organism	UBERON:0007023	98.07	gold quality
trabecular bone tissue	UBERON:0002483	97.76	gold quality
male germ cell	CL:0000015	97.74	gold quality
jejunal mucosa	UBERON:0000399	97.73	gold quality
corpus callosum	UBERON:0002336	97.57	gold quality
bone marrow	UBERON:0002371	97.37	gold quality
lateral globus pallidus	UBERON:0002476	97.35	gold quality
inferior vagus X ganglion	UBERON:0005363	97.33	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.29	gold quality
pons	UBERON:0000988	97.26	gold quality
subthalamic nucleus	UBERON:0001906	97.25	gold quality
bone element	UBERON:0001474	97.01	gold quality
calcaneal tendon	UBERON:0003701	96.98	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.80	gold quality
colonic mucosa	UBERON:0000317	96.78	gold quality
penis	UBERON:0000989	96.78	gold quality
spinal cord	UBERON:0002240	96.74	gold quality
left testis	UBERON:0004533	96.68	gold quality
superficial temporal artery	UBERON:0001614	96.56	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.49	gold quality
oral cavity	UBERON:0000167	96.45	gold quality
right testis	UBERON:0004534	96.43	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.41	gold quality
upper leg skin	UBERON:0004262	96.22	gold quality
heart right ventricle	UBERON:0002080	96.18	gold quality
synovial joint	UBERON:0002217	96.16	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	27.48
E-HCAD-1	yes	20.69
E-CURD-88	yes	7.66
E-MTAB-6819	no	2143.52
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting ATG3, 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-548C-3P	99.99	74.01	7587
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-302D-5P	99.50	69.34	1863
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-133A-5P	99.28	69.13	941
HSA-MIR-3925-5P	99.21	67.90	1466
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-5587-5P	99.07	68.58	838
HSA-MIR-5583-3P	99.06	65.68	1018
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-7703	97.64	67.00	965
HSA-MIR-2114-5P	96.00	64.56	617

Literature-anchored findings (GeneRIF, showing 23)

• 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)
• Murine Atg8L/Apg8L modification is mediated by human Atg3. (PMID:16704426)
• These results unveil a role for ATG12-ATG3 in mitochondrial homeostasis and implicate the ATG12 conjugation system in cellular functions distinct from the early steps of autophagosome formation. (PMID:20723759)
• caspase-8 overexpression led to Atg3 degradation and this event depended on caspase-8 enzymatic activity (PMID:22644571)
• Hidden Markov models were used to detect protein homology among the flexible regions of Atg3 homologs and importance of conserved regions evaluated by performing affinity capture experiments with human Atg3 deletion constructs; binding studies and competition experiments demonstrate that overlapping sites in the Atg3FR are important for E3 binding and E1 binding. (PMID:24186333)
• 13 residues of the ATG3 fragment form a short beta-strand followed by an alpha-helix on a surface area that is an exclusive binding site for ATG12. (PMID:24191030)
• ATG3 gene and its gene family may play an important role in transformation of myelodysplastic syndrome. (PMID:24420857)
• Lipidation of the LC3/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3. (PMID:24747438)
• The region of human ATG3 that interacts with ATG7 is precisely identified using nuclear magnetic resonance. (PMID:26043688)
• ATG3 upregulation contributes to autophagy induced by the detachment of intestinal epithelial cells from the extracellular matrix, but promotes autophagy-independent apoptosis of the attached cells (PMID:26061804)
• Our data demonstrate that HOTAIR promotes the activation of autophagy in HCC cells by upregulating the expression of the autophagy-related genes ATG3 and ATG7. (PMID:27301338)
• PTK2 inhibition-induced sustained levels of ATG3 were able to sensitize cancer cells to DNA-damaging agents. (PMID:28103122)
• Results revealed that miR-16 was significantly downregulated, and ATG3 was significantly upregulated in non-small cell lung carcinoma (NSCLC) patient tissue samples. ATG3 was found to be a direct target of miR-16. (PMID:29138833)
• We have also observed membrane aggregation induced by ATG3 in vitro, which could point to a more complex function of this protein in AP biogenesis. Moreover, in vitro GABARAP lipidation assays suggest that ATG3-membrane interaction could facilitate the lipidation of ATG8 homologues. (PMID:29142222)
• miR-155 silencing rescued autophagosome number in Mycobacterium tuberculosis infected dendritic cells and enhanced autolysosome fusion, thereby supporting a previously unidentified role of the miR-155 as inhibitor of ATG3 expression. (PMID:29300789)
• this study identified an amino acid motif in ATG3 causing eIF5A dependency for its efficient translation (PMID:29712776)
• Study validated that miR-1 overexpression improved DDP sensitivity of NSCLC cells by inhibiting ATG3-mediated autophagy. (PMID:29851226)
• Authors confirmed that the effect of PVT1 promoting autophagy was dependent on regulating ATG3 expression. Further investigations revealed that PVT1 could upregulate autophagy-related gene 3 (ATG3) expression by acting as an endogenous sponge of miR-365, which was an inhibitor gene on ATG3 protein by targeting 3’UTR of ATG3 mRNA. (PMID:30794914)
• LncRNA NEAT1 promotes autophagy via regulating miR-204/ATG3 and enhanced cell resistance to sorafenib in hepatocellular carcinoma. (PMID:31549407)
• Let-7c-3p Regulates Autophagy under Oxidative Stress by Targeting ATG3 in Lens Epithelial Cells. (PMID:32258130)
• Overexpression of miR-431 attenuates hypoxia/reoxygenation-induced myocardial damage via autophagy-related 3. (PMID:33382073)
• An N-terminal conserved region in human Atg3 couples membrane curvature sensitivity to conjugase activity during autophagy. (PMID:33446636)
• Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function. (PMID:34555423)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	atg3	ENSDARG00000009350
mus_musculus	Atg3	ENSMUSG00000022663
rattus_norvegicus	Atg3	ENSRNOG00000002094
drosophila_melanogaster	Atg3	FBGN0036813
caenorhabditis_elegans		WBGENE00021922

Protein

Protein identifiers

Ubiquitin-like-conjugating enzyme ATG3 — Q9NT62 (reviewed: Q9NT62)

Alternative names: Autophagy-related protein 3, Protein PC3-96

All UniProt accessions (3): Q9NT62, A0AAA9XEB5, F8WDI0

UniProt curated annotations — full annotation on UniProt →

Function. E2 conjugating enzyme that catalyzes the covalent conjugation of the C-terminal Gly of ATG8-like proteins (GABARAP, GABARAPL1, GABARAPL2 or MAP1LC3A) to the amino group of phosphatidylethanolamine (PE)-containing lipids in the membrane resulting in membrane-bound ATG8-like proteins which is one of the key steps in the development of autophagic isolation membranes during autophagosome formation. Cycles back and forth between binding to ATG7 for loading with the ATG8-like proteins and binding to E3 enzyme, composed of ATG12, ATG5 and ATG16L1 to promote ATG8-like proteins lipidation. Also plays a role as a membrane curvature sensor that facilitates LC3/GABARAP lipidation by sensing local membrane stress associated with lipid-packing defects as occurs with high molar proportions of conical lipids or strident membrane curvature. Interacts with negatively-charged membranes promoting membrane tethering and enhancing LC3/GABARAP lipidation. Also acts as an autocatalytic E2-like enzyme by catalyzing the conjugation of ATG12 to itself in an ATG7-dependent manner, this complex thus formed, plays a role in mitochondrial homeostasis but not in autophagy. ATG12-ATG3 conjugation promotes late endosome to lysosome trafficking and basal autophagosome maturation via its interaction with PDCD6IP. ATG12-ATG3 conjugate is also formed upon viccina virus infection, leading to the disruption the cellular autophagy which is not necessary for vaccinia survival and proliferation. Promotes primary ciliogenesis by removing OFD1 from centriolar satellites via the autophagic pathway.

Subunit / interactions. Homdimer. Interacts with ATG7; this interaction forms an E1-E2 complex that is essential for the transfer of GABARAP thioester from ATG7 to ATG3 and disrupts interaction with the E3 enzyme complex. Interacts with ATG12; this interaction is ATG7-dependent, essential for phosphatidylethanolamine (PE)-conjugated ATG8-like proteins formation and also mediates the autoconjugation of ATG12 on ATG3. Interacts with FNBP1L. Interacts with the E3 enzyme complex composed of 4 sets of ATG12-ATG5 and ATG16L1 (400 kDa); this interaction disrupts interaction with ATG7 and promotes ATG8-like proteins lipidation. Interacts with GABARAP and MAP1LC3A. Interacts with the ATG12-ATG5 conjugate; this interaction inhibits ATG8-like proteins lipidation. Interacts (ATG12-ATG3 conjugate form) with PDCD6IP (via the BRO1 domain); this interaction is bridged by ATG12 and promotes multiple PDCD6IP-mediated functions such as endolysosomal trafficking, macroautophagy and exosome biogenesis.

Subcellular location. Cytoplasm.

Tissue specificity. Widely expressed, with a highest expression in heart, skeletal muscle, kidney, liver and placenta.

Post-translational modifications. Cleaved by CASP8 upon death ligand binding such as tumor necrosis factor-alpha. CASP8 cleavage blocks survival-related autophagy and favors apoptosis. Conjugated to ATG12 at Lys-243. ATG12-conjugation plays a role in regulation of mitochondrial homeostasis and cell death, while it is not involved in phosphatidylethanolamine-conjugation to ATG8-like proteins and autophagy.

Domain organisation. The N-terminal region works in concert with its geometry-selective amphipathic helix (AH) to promote LC3-PE conjugation activity only on the target membrane. The LC3 interacting regions (LIR) motif mediates interaction with GABARAP and MAP1LC3A in a beta-sheet conformation-dependent manner. The LIR motif is required for LC3 lipidation and ATG3~LC3 thioester formation. The membrane-curvature-sensing motif targets curved membranes.

Similarity. Belongs to the ATG3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NT62-1	1	yes
Q9NT62-2	2

RefSeq proteins (2): NP_001265641, NP_071933* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007135	Atg3/Atg10	Family

Pfam: PF03987

UniProt features (57 total): mutagenesis site 23, strand 10, helix 9, short sequence motif 4, turn 3, region of interest 2, chain 1, cross-link 1, splice variant 1, active site 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4NAW	X-RAY DIFFRACTION	2.19
8AFI	X-RAY DIFFRACTION	2.66
9E8P	X-RAY DIFFRACTION	2.7
8FKM	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NT62-F1	74.02	0.31

Functional residue map

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

Catalytic / active sites (2): 264 (glycyl thioester intermediate); 169–170 (cleavage; by casp8)

Post-translational modifications (2): 243, 1

Mutagenesis-validated functional residues (23):

Position	Phenotype
8	significantly reduces atg8-family conjugating enzyme activity; when associated with k-15. decreases protein membrane int
9	slightly decreases interaction with lipid monolayers; when associated with d-11. slightly decreases insertion into lipid
11	slightly decreases interaction with lipid monolayers; when associated with d-9. slightly decreases insertion into lipid
15	significantly reduces atg8-family conjugating enzyme activity; when associated with d-8. decreases protein membrane inte
21	impairs atg8-family conjugating enzyme activity. does not affect protein membrane interactions. does not affect formatio
23	severely reduces atg8-family conjugating enzyme activity. reduces of about 40% protein membrane interactions. does not a
25	increases of about 30% more atg8-family conjugating enzyme activity. does not affect protein membrane interactions. does
95	severely diminish gabarap:atg3 conjugation.
97	severely diminish gabarap:atg3 conjugation.
107	almost completely abrogates gabarap:atg3 conjugation.
108	significantly reduces gabarap:atg3 conjugation.
144–151	strongly decreases affinity for the complex atg12:atg5:atg16l1. severely decreases phosphatidylethanolamine (pe)-conjuga
156	strongly decreases affinity for the complex atg12:atg5:atg16l1. impairs interaction with the complex atg12:atg5:atg16l1;
157	strongly decreases affinity for the complex atg12:atg5:atg16l1. impairs interaction with the complex atg12:atg5:atg16l1;
160	strongly decreases affinity for the complex atg12:atg5:atg16l1. affects modestly the atg3-atg7 interaction. reduces the
161	strongly decreases affinity for the complex atg12:atg5:atg16l1.
167	weakens the atg3-atg7 interaction. reduces the thioester-linkage formation with gabarap.
169	weakens the atg3-atg7 interaction. severely reduces the thioester-linkage formation with gabarap.
171	weakens the atg3-atg7 interaction. reduces the thioester-linkage formation with gabarap.
172	weakens the atg3-atg7 interaction. significantly reduces the thioester-linkage formation with gabarap.
173	weakens the atg3-atg7 interaction. significantly reduces the thioester-linkage formation with gabarap.
264	does not affect interaction with atg12:atg5. impairs map1lc3a lipidation. impairs map1lc3b lipidation. impairs atg3:atg8
264	instead of the formation of an intermediate complex with a thiol ester bond between atg3 (e2-like enzyme) and gabarapl1/

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy
R-HSA-9612973	Autophagy

MSigDB gene sets: 223 (showing top): GOBP_VACUOLE_ORGANIZATION, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_MACROAUTOPHAGY, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_POLYSACCHARIDE_CATABOLIC_PROCESS, GOBP_PROTEIN_TARGETING_TO_MEMBRANE

GO Biological Process (12): autophagosome assembly (GO:0000045), autophagy of mitochondrion (GO:0000422), protein targeting to membrane (GO:0006612), protein transport (GO:0015031), protein ubiquitination (GO:0016567), mitochondrial fragmentation involved in apoptotic process (GO:0043653), nucleophagy (GO:0044804), negative regulation of phagocytosis (GO:0050765), glycophagy (GO:0061723), regulation of cilium assembly (GO:1902017), autophagy (GO:0006914), macroautophagy (GO:0016236)

GO Molecular Function (7): Atg8-family ligase activity (GO:0019776), Atg12 transferase activity (GO:0019777), ubiquitin-like protein transferase activity (GO:0019787), enzyme binding (GO:0019899), Atg8-family conjugating enzyme activity (GO:0141046), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (4): phagophore assembly site (GO:0000407), cytoplasm (GO:0005737), cytosol (GO:0005829), Atg12-Atg5-Atg16 complex (GO:0034274)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Autophagy	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular anatomical structure	3
autophagy	2
macroautophagy	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
protein targeting	1
establishment of protein localization to membrane	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
protein modification by small protein conjugation	1
apoptotic mitochondrial changes	1
phagocytosis	1
negative regulation of endocytosis	1
regulation of phagocytosis	1
glycogen catabolic process	1
cilium assembly	1
regulation of plasma membrane bounded cell projection assembly	1
regulation of organelle assembly	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
autophagosome assembly	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
aminoacyltransferase activity	1
catalytic activity, acting on a protein	1
protein binding	1
ubiquitin-like protein conjugating enzyme activity	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
transferase complex	1

Protein interactions and networks

STRING

1916 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATG3	GABARAPL2	P60520	999
ATG3	F5GZY7	F5GZY7	999
ATG3	ATG12	O94817	999
ATG3	ATG7	O95352	999
ATG3	ATG5	Q9H1Y0	996
ATG3	GABARAP	O95166	982
ATG3	ATG16L1	Q676U5	970
ATG3	BECN1	Q14457	967
ATG3	ULK1	O75385	964
ATG3	MAP1LC3B	Q9GZQ8	956
ATG3	ATG4B	Q9Y4P1	955
ATG3	MAP1LC3A	Q9H492	954
ATG3	ATG10	Q9H0Y0	947
ATG3	CFLAR	O15519	942
ATG3	RB1CC1	Q8TDY2	934

IntAct

87 interactions, top by confidence:

A	B	Type	Score
ATG12	ATG3	psi-mi:“MI:0407”(direct interaction)	0.890
ATG12	ATG3	psi-mi:“MI:0915”(physical association)	0.890
GABARAPL2	ATG3	psi-mi:“MI:0407”(direct interaction)	0.850
ATG3	GABARAPL2	psi-mi:“MI:0407”(direct interaction)	0.850
MAP1LC3B	ATG3	psi-mi:“MI:0407”(direct interaction)	0.800
ATG3	MAP1LC3B	psi-mi:“MI:0407”(direct interaction)	0.800
MAP1LC3B	ATG7	psi-mi:“MI:0914”(association)	0.740
MAP1LC3B	MAP1B	psi-mi:“MI:0914”(association)	0.730
GABARAPL2	IPO5	psi-mi:“MI:0914”(association)	0.690
GABARAP	ATG3	psi-mi:“MI:0407”(direct interaction)	0.670
ATG7	GABARAP	psi-mi:“MI:0914”(association)	0.670
GABARAPL1	IPO5	psi-mi:“MI:0914”(association)	0.590
GABARAP	IPO5	psi-mi:“MI:0914”(association)	0.590
MOB2	ATG3	psi-mi:“MI:0915”(physical association)	0.560
ATG3	GNB2	psi-mi:“MI:0915”(physical association)	0.560
ATG3	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.530
GPR141	STXBP3	psi-mi:“MI:0914”(association)	0.530
ATG7	GFER	psi-mi:“MI:0914”(association)	0.530
ATG3	GABARAPL1	psi-mi:“MI:0407”(direct interaction)	0.520
MAP1LC3B	NIPSNAP2	psi-mi:“MI:0914”(association)	0.520
ATG3	TECPR1	psi-mi:“MI:0915”(physical association)	0.500
ATG3	SPTAN1	psi-mi:“MI:0915”(physical association)	0.400
ATG3	Atg12	psi-mi:“MI:0915”(physical association)	0.400
Prkcz	GOLIM4	psi-mi:“MI:0914”(association)	0.350
Tubg1	ZC3H18	psi-mi:“MI:0914”(association)	0.350

BioGRID (350): ATG3 (Affinity Capture-MS), MAP1LC3A (Reconstituted Complex), GABARAPL2 (Biochemical Activity), GABARAPL2 (Reconstituted Complex), GABARAP (Reconstituted Complex), GABARAP (Biochemical Activity), MAP1LC3A (Biochemical Activity), ATG3 (Affinity Capture-MS), ATG3 (Affinity Capture-MS), ATG3 (Affinity Capture-MS), ATG3 (Affinity Capture-MS), MAP1LC3A (Affinity Capture-Western), CLU (Affinity Capture-Western), ATG3 (Affinity Capture-Western), ATG3 (Affinity Capture-MS)

ESM2 similar proteins: O14737, O43752, O82197, P50502, P50503, P56812, Q05AY2, Q0VCL3, Q0WTY4, Q2HJH9, Q3ZBJ0, Q4QQV8, Q5FW29, Q5R6Q2, Q5RBR3, Q5RBT0, Q5RBW6, Q5RF31, Q5SRX1, Q5XGW6, Q5ZHP5, Q5ZLF0, Q63635, Q68FS2, Q6AZ50, Q6DD52, Q6GL11, Q6GNN8, Q6IQ73, Q6PEC1, Q6ZVM7, Q7T339, Q7ZVC4, Q8K396, Q8NFI4, Q91WV0, Q941D5, Q99L47, Q9CPX6, Q9D7S9

Diamond homologs: A1CAN8, A1DF15, A3LX85, A5DN42, A5DVH6, A6S8P6, A6ZS81, A7F172, A7KAI2, A7KAL4, A7TK16, C8VDI2, F7VSU2, G2XNY3, I1RX50, M7UQV4, O43035, P0CM34, P0CM35, P40344, Q0U388, Q0VCL3, Q0WWQ1, Q2H427, Q2U7R4, Q4WUE5, Q51LD2, Q550A8, Q5ABQ7, Q5I0S6, Q6AZ50, Q6BSC4, Q6C4Q9, Q6CL19, Q6FQJ2, Q6GQE7, Q6PFS7, Q755K1, Q7SDY2, Q9CPX6

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
MAP1LC3A	up-regulates	ATG3	binding
MAP1LC3B	up-regulates	ATG3	binding
MAP1LC3C	“up-regulates activity”	ATG3	binding
ATG3	“up-regulates activity”	GABARAP	binding
ATG3	“up-regulates activity”	GABARAPL2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 74 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	11	25.4×	1e-10
Autophagy	8	23.7×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
mitophagy	12	65.8×	5e-17
autophagosome maturation	9	54.5×	7e-12
autophagosome assembly	12	46.5×	3e-15
macroautophagy	7	29.1×	4e-07
cellular response to starvation	6	20.0×	4e-05
autophagy	7	13.3×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	35
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
154065	GRCh38/hg38 3q13.2-13.31(chr3:112425234-115795585)x1	Pathogenic
3391881	GRCh37/hg19 3q13.2-13.31(chr3:112144082-115514432)x1	Pathogenic
57805	GRCh38/hg38 3q13.2-13.31(chr3:112479482-115774102)x1	Pathogenic
666447	GRCh37/hg19 3q13.2-13.31(chr3:112183943-115492949)x1	Pathogenic

SpliceAI

1480 predictions. Top by Δscore:

Variant	Effect	Δscore
3:112534333:CATGC:C	acceptor_gain	1.0000
3:112534335:TGC:T	acceptor_gain	1.0000
3:112534338:C:CC	acceptor_gain	1.0000
3:112534339:T:G	acceptor_loss	1.0000
3:112534346:C:CT	acceptor_gain	1.0000
3:112534346:C:T	acceptor_gain	1.0000
3:112535231:T:C	acceptor_gain	1.0000
3:112536471:AGAC:A	donor_loss	1.0000
3:112536472:GACC:G	donor_loss	1.0000
3:112536473:ACCT:A	donor_loss	1.0000
3:112536474:CCTGC:C	donor_loss	1.0000
3:112536598:CGTTG:C	acceptor_gain	1.0000
3:112536600:TTG:T	acceptor_gain	1.0000
3:112536601:TG:T	acceptor_gain	1.0000
3:112536601:TGCTG:T	acceptor_loss	1.0000
3:112536603:C:A	acceptor_loss	1.0000
3:112536603:C:CC	acceptor_gain	1.0000
3:112536604:T:C	acceptor_loss	1.0000
3:112537730:TTTA:T	donor_loss	1.0000
3:112537731:TTAC:T	donor_loss	1.0000
3:112537732:TA:T	donor_loss	1.0000
3:112537886:GTAGC:G	acceptor_gain	1.0000
3:112537887:TAGC:T	acceptor_gain	1.0000
3:112537888:AGC:A	acceptor_gain	1.0000
3:112537889:GC:G	acceptor_gain	1.0000
3:112537890:CC:C	acceptor_gain	1.0000
3:112537891:C:CC	acceptor_gain	1.0000
3:112537891:C:T	acceptor_gain	1.0000
3:112537897:A:AC	acceptor_gain	1.0000
3:112537897:A:C	acceptor_gain	1.0000

AlphaMissense

2072 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:112532718:G:A	T309I	1.000
3:112532724:T:A	D307V	1.000
3:112532724:T:G	D307A	1.000
3:112532725:C:A	D307Y	1.000
3:112532725:C:G	D307H	1.000
3:112532728:A:G	Y306H	1.000
3:112532733:A:C	I304R	1.000
3:112532733:A:T	I304K	1.000
3:112532736:G:A	T303I	1.000
3:112532739:G:T	P302Q	1.000
3:112532740:G:A	P302S	1.000
3:112532740:G:T	P302T	1.000
3:112532742:A:T	I301N	1.000
3:112532745:A:T	V300D	1.000
3:112532749:C:G	A299P	1.000
3:112532756:A:C	F296L	1.000
3:112532756:A:T	F296L	1.000
3:112532757:A:C	F296C	1.000
3:112532757:A:G	F296S	1.000
3:112532758:A:G	F296L	1.000
3:112532759:T:A	K295N	1.000
3:112532759:T:G	K295N	1.000
3:112532761:T:C	K295E	1.000
3:112532763:A:C	L294W	1.000
3:112532763:A:G	L294S	1.000
3:112532765:G:C	F293L	1.000
3:112532765:G:T	F293L	1.000
3:112532766:A:G	F293S	1.000
3:112532767:A:G	F293L	1.000
3:112532779:A:G	Y289H	1.000

dbSNP variants (sampled 300 via entrez): RS1000058179 (3:112550255 C>T), RS1000184299 (3:112539317 C>G), RS1000242591 (3:112546185 C>T), RS1000378189 (3:112537740 C>G), RS1000598261 (3:112560717 A>G), RS1000616295 (3:112532959 TAAGACTACCTG>T), RS1000635385 (3:112533108 A>G), RS1000687611 (3:112532820 G>T), RS1000799114 (3:112552476 T>C), RS1001007016 (3:112554541 A>G), RS1001060404 (3:112549178 A>G), RS1001110728 (3:112548808 C>A,G), RS1001133439 (3:112554712 A>T), RS1001196254 (3:112539718 A>G), RS1001247168 (3:112544776 T>A,C)

Disease associations

OMIM: gene MIM:609606 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002088_10	Asthma (childhood onset)	2.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	6
Cisplatin	decreases expression, decreases response to substance, increases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
Rotenone	increases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, decreases expression	2
7-hydroxydehydronuciferine	increases expression	1
syringic acid	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
4-biphenylamine	affects expression, affects reaction	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	increases expression	1
cypermethrin	increases expression	1
tetrabromobisphenol A	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
perfluorooctanoic acid	increases expression	1
perfluorobutyric acid	increases expression	1
cadmium sulfide	increases expression	1
galangin	decreases reaction, affects cotreatment, decreases activity, increases expression	1
di-n-butylphosphoric acid	affects expression	1
glycidamide	increases expression	1
4-phenylbutyric acid	decreases reaction, increases expression	1
trovafloxacin	affects cotreatment, increases expression	1
deguelin	increases expression	1
platycodin D	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
pachastrissamine	affects expression	1
bisphenol B	increases expression	1

Cellosaurus cell lines

17 cell lines: 16 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2SA	Abcam HEK293T ATG3 KO	Transformed cell line	Female
CVCL_B7W3	Abcam Raji ATG3 KO	Cancer cell line	Male
CVCL_B9WL	Abcam THP-1 ATG3 KO	Cancer cell line	Male
CVCL_C6YM	Abcam PC-3 ATG3 KO	Cancer cell line	Male
CVCL_C7IT	HeLa S3 ATG3 KO	Cancer cell line	Female
CVCL_C8QC	HeLa HaloTag-LC3	Cancer cell line	Female
CVCL_C8QD	HeLa HaloTag-LC3/ATG3-mCherry	Cancer cell line	Female
CVCL_C8QE	HeLa HaloTag-LC3/ATG3-C264A-mCherry	Cancer cell line	Female
CVCL_C8QF	HeLa HaloTag-LC3/ATG3-Y209A-mCherry	Cancer cell line	Female
CVCL_C8QG	HeLa HaloTag-LC3/ATG3-Y210A-mCherry	Cancer cell line	Female

Clinical trials (associated diseases)

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