ATG12

Summary

ATG12 (autophagy related 12, HGNC:588) is a protein-coding gene on chromosome 5q22.3, encoding Ubiquitin-like protein ATG12 (O94817). Ubiquitin-like protein involved in autophagy vesicles formation.

Autophagy is a process of bulk protein degradation in which cytoplasmic components, including organelles, are enclosed in double-membrane structures called autophagosomes and delivered to lysosomes or vacuoles for degradation. ATG12 is the human homolog of a yeast protein involved in autophagy (Mizushima et al., 1998 [PubMed 9852036]).

Source: NCBI Gene 9140 — RefSeq curated summary.

At a glance

• Gene–disease (curated): colorectal cancer (Limited, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 46 total — 4 likely-pathogenic
• MANE Select transcript: NM_004707

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:588
Approved symbol	ATG12
Name	autophagy related 12
Location	5q22.3
Locus type	gene with protein product
Status	Approved
Aliases	APG12
Ensembl gene	ENSG00000145782
Ensembl biotype	protein_coding
OMIM	609608
Entrez	9140

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 4 nonsense_mediated_decay, 4 retained_intron, 3 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000379594, ENST00000500945, ENST00000505252, ENST00000505993, ENST00000507793, ENST00000508464, ENST00000509598, ENST00000509910, ENST00000511984, ENST00000513167, ENST00000513292, ENST00000513322, ENST00000514775, ENST00000914944

RefSeq mRNA: 2 — MANE Select: NM_004707 NM_001277783, NM_004707

CCDS: CCDS4122, CCDS64222

Canonical transcript exons

ENST00000509910 — 4 exons

Exon	Start	End
ENSE00001318973	115828200	115831863
ENSE00003596368	115832602	115832664
ENSE00003605775	115837628	115837764
ENSE00003646988	115841390	115841565

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 96.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.8786 / max 288.0773, expressed in 1824 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63027	40.7022	1820
63028	5.1765	1701

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	96.82	gold quality
pericardium	UBERON:0002407	96.12	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.84	gold quality
pons	UBERON:0000988	95.73	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.66	gold quality
substantia nigra pars compacta	UBERON:0001965	95.61	gold quality
corpus callosum	UBERON:0002336	95.61	gold quality
lateral globus pallidus	UBERON:0002476	95.57	gold quality
subthalamic nucleus	UBERON:0001906	95.41	gold quality
visceral pleura	UBERON:0002401	95.17	gold quality
inferior vagus X ganglion	UBERON:0005363	95.11	gold quality
synovial joint	UBERON:0002217	94.93	gold quality
nipple	UBERON:0002030	94.81	gold quality
superficial temporal artery	UBERON:0001614	94.79	gold quality
tibia	UBERON:0000979	94.71	gold quality
pylorus	UBERON:0001166	94.69	gold quality
parietal pleura	UBERON:0002400	94.66	gold quality
trigeminal ganglion	UBERON:0001675	94.60	gold quality
corpus epididymis	UBERON:0004359	94.51	gold quality
stromal cell of endometrium	CL:0002255	94.50	gold quality
seminal vesicle	UBERON:0000998	94.49	gold quality
jejunal mucosa	UBERON:0000399	94.45	gold quality
urethra	UBERON:0000057	94.42	gold quality
superior vestibular nucleus	UBERON:0007227	94.26	gold quality
cranial nerve II	UBERON:0000941	94.22	gold quality
vena cava	UBERON:0004087	94.17	gold quality
cardia of stomach	UBERON:0001162	94.09	gold quality
lymph node	UBERON:0000029	94.06	gold quality
blood vessel layer	UBERON:0004797	94.05	gold quality
monocyte	CL:0000576	94.01	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, GLI1

miRNA regulators (miRDB)

153 targeting ATG12, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-7-1-3P	99.91	71.53	4384

Literature-anchored findings (GeneRIF, showing 37)

• 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)
• Apg12p, but not the Apg12p.Apg5p conjugate, facilitates LC3 processing (PMID:12207896)
• Mitochondrial DNA deletions and chloramphenicol treatment stimulate APG12. (PMID:17457038)
• Knockdown of p300 reduces acetylation of Atg5, Atg7, Atg8, and Atg12, although overexpressed p300 increases the acetylation of these same proteins. (PMID:19124466)
• 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 Atg12 is as a positive mediator of mitochondrial apoptosis and show that Atg12 directly regulates the apoptotic pathway by binding and inactivating prosurvival Bcl-2 family members, including Bcl-2 and Mcl-1. (PMID:22152474)
• These data relate LC3B, ATG5 and ATG12 to mitochondrial quality control after oxidative damage, and to cellular longevity. (PMID:22170153)
• 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)
• ATG12 is a novel determinant of breast cancer primary resistance to HER1/2-targeted therapeutics. (PMID:23307622)
• Cav-1 competitively interacts with the ATG12-ATG5 system to suppress the formation and function of the latter in lung epithelial cells. (PMID:24727585)
• The results revealed that the expression of Atg12 and LC3 II/LC3 I in the chondrocytes treated with TXC increased, compared to that in the untreated chondrocytes (PMID:24899049)
• Analysis of hepatitis B virus capsid maturation steps revealed that Rab33B and Atg5/12/16L1 are required for proper particle assembly and/or stability. (PMID:25439980)
• reveal a novel interconnection between autophagy, proteasome activity, and cell death mediated by the ubiquitin-like properties of ATG12 (PMID:25629932)
• ATG5-ATG12 is increased in hepatitis B virus-associated hepatocellular carcinoma and has a role in apoptosis (PMID:27729742)
• the role of the autophagy elongation complex (ATG5-12/16L1) in Hepatitis C virus replication and membranous web formation, was examined. (PMID:28067309)
• above findings suggest that ATG5-ATG12 positively regulate anti-viral NF-kappaB and IRF3 signaling during FMDV infection, thereby limiting FMDV proliferation. FMDV has evolved mechanisms to counteract the antiviral function of ATG5-ATG12, via degradation of them by viral protein 3C(pro). (PMID:28102839)
• STAT3 and ATG12 are targets of miR-454-3p. (PMID:28182000)
• transcriptional activity of ATG12 gene promoter was not significantly affected by other two DNA sequence variants identified in Parkinson’s disease patient (PMID:28229934)
• rs26538 was relevant to the lower risk of coal workers’ pneumoconiosis and conferred to reduce the transcription activity of ATG12’s promoter. (PMID:28844669)
• this study identified a novel mechanism by which oncogenic RAS promotes survival of malignant intestinal epithelial cells. This mechanism is driven by RAS-dependent loss of ATG12 in these cells. (PMID:28933585)
• Results show that ATG12 is a downstream effector in MALAT1-mediated autophagy in gastric cancer cells. (PMID:29162158)
• HBV gained access to Atg5-12/16L1 via interaction of its core protein with the Atg12 moiety of the complex. In contrast, subsequent autophagosome maturation and closure events were unnecessary for HBV replication, as evidenced by inhibition of Atg8/LC3 conjugation. Interfering with the HBV/Atg12 cross talk may be a tool for virus control. (PMID:29367244)
• The finding that miR378 targets ATG12 indicated that miR378 may have a potential role in autophagy. These findings may provide novel insights into the mechanism of metastasis in cervical cancer and a novel therapeutic target for the treatment of cervical cancer. (PMID:29488616)
• These results suggested that ATG12 expression quantitative trait loci SNP rs26537 might contribute to an allele-specific effect on the expression of host gene ATG12 and explain a fraction of head and neck squamous cell carcinoma genetic susceptibility. (PMID:29637616)
• miR-23a downregulation modulates the inflammatory response by targeting ATG12-mediated autophagy. (PMID:29845275)
• Ambra1 plays an important role in regulating the sensitivity of breast cancer cells to epirubicin. Regulatory effect of Ambra1 on epirubicin sensitivity is achieved through the regulation of autophagy by targeting ATG12. (PMID:30027574)
• Results show that ATG12 levels were consistently higher in glioma tissues. In addition, ATG12 is found as a target gene of miR-454 by bioinformatic analysis. (PMID:30413650)
• BIRC5/Survivin is a novel ATG12-ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells. (PMID:31612776)
• ATG12 deficiency leads to tumor cell oncosis owing to diminished mitochondrial biogenesis and reduced cellular bioenergetics. (PMID:31844253)
• PTBP3 promotes malignancy and hypoxia-induced chemoresistance in pancreatic cancer cells by ATG12 up-regulation. (PMID:31989778)
• WASF3 silencing promotes proliferation, migration and invasiveness of gastric cancer cells; its knockdown depended on the inhibition of Atg12-mediated autophagy (PMID:32359534)
• LncRNA KCNQ1OT1 as a miR-26a-5p sponge regulates ATG12-mediated cardiomyocyte autophagy and aggravates myocardial infarction. (PMID:34089766)
• Toxoplasma gondii profilin and tachyzoites RH strain may manipulate autophagy via downregulating Atg5 and Atg12 and upregulating Atg7. (PMID:34453672)
• LncRNA OIP5-AS1 Promotes the Autophagy-Related Imatinib Resistance in Chronic Myeloid Leukemia Cells by Regulating miR-30e-5p/ATG12 Axis. (PMID:34723728)
• Adaptor SH3BGRL drives autophagy-mediated chemoresistance through promoting PIK3C3 translation and ATG12 stability in breast cancers. (PMID:34870550)
• ATG12 deficiency results in intracellular glutamine depletion, abrogation of tumor hypoxia and a favorable prognosis in cancer. (PMID:34904929)
• circ_SIRT1 upregulates ATG12 to facilitate Imatinib resistance in CML through interacting with EIF4A3. (PMID:37866664)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	atg12	ENSDARG00000069545
mus_musculus	Atg12	ENSMUSG00000032905
rattus_norvegicus	Atg12	ENSRNOG00000000157
drosophila_melanogaster	Atg12	FBGN0036255
caenorhabditis_elegans		WBGENE00002982

Protein

Protein identifiers

Ubiquitin-like protein ATG12 — O94817 (reviewed: O94817)

Alternative names: Autophagy-related protein 12

All UniProt accessions (5): D6RB14, H0Y9W4, H0YA29, H7BYD7, O94817

UniProt curated annotations — full annotation on UniProt →

Function. Ubiquitin-like protein involved in autophagy vesicles formation. Conjugation with ATG5 through a ubiquitin-like conjugating system involving also 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. As part of the ATG8 conjugation system with ATG5 and ATG16L1, required for recruitment of LRRK2 to stressed lysosomes and induction of LRRK2 kinase activity in response to lysosomal stress. (Microbial infection) May act as a proviral factor. In association with ATG5, 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 the initiation of HCV replication, but not required once infection is established.

Subunit / interactions. Forms a conjugate with ATG5. 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. Interacts with DHX58/RIG-1, IFIH1/MDA5 and MAVS/IPS-1 in monomeric form as well as in ATG12-ATG5 conjugate. The interaction with MAVS is further enhanced upon vesicular stomatitis virus (VSV) infection. Interacts with ATG3; this interaction is essential for phosphatidylethanolamine (PE)-conjugated ATG8-like proteins formation. Interacts with ATG7. Interacts with ATG10. 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. Interacts with SH3BGRL. The ATG12-ATG5 conjugate interacts 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. Preautophagosomal structure membrane.

Tissue specificity. Ubiquitous.

Post-translational modifications. Acetylated by EP300.

Domain organisation. Shares weak sequence similarity with ubiquitin family, but contains an ‘ubiquitin superfold’ and the C-terminal Gly is required for isopeptide linkage.

Induction. Expression is induced by mitochondrial DNA deletions, chloramphenicol and nicotinamide.

Miscellaneous. Small amount of ATG5-ATG12 conjugate is enough to perform normal autophagy.

Similarity. Belongs to the ATG12 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O94817-1	1	yes
O94817-4	2

RefSeq proteins (2): NP_001264712, NP_004698* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007242	Atg12	Family
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily

Pfam: PF04110

UniProt features (26 total): mutagenesis site 11, strand 6, helix 2, splice variant 2, chain 1, region of interest 1, compositionally biased region 1, turn 1, cross-link 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4NAW	X-RAY DIFFRACTION	2.19
4GDK	X-RAY DIFFRACTION	2.7
4GDL	X-RAY DIFFRACTION	2.88

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94817-F1	80.31	0.58

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 (1): 140

Mutagenesis-validated functional residues (11):

Position	Phenotype
73	impairs e3 activity of the atg12-atg5 conjugate.
108	impairs atg12 stability.
113	impairs e3 activity of the atg12-atg5 conjugate.
122	impairs e3 activity of the atg12-atg5 conjugate.
123	impairs atg12 stability.
138	impairs e3 activity of the atg12-atg5 conjugate.
139	impairs e3 activity of the atg12-atg5 conjugate.
54	impairs e3 activity of the atg12-atg5 conjugate.
62	impairs e3 activity of the atg12-atg5 conjugate.
63	impairs e3 activity of the atg12-atg5 conjugate.
72	impairs e3 activity of the atg12-atg5 conjugate.

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: 273 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, MORF_MTA1, RNGTGGGC_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_VACUOLE_ORGANIZATION, GNF2_BNIP2, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, GOCC_VACUOLAR_MEMBRANE, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, MORF_HDAC2

GO Biological Process (12): autophagosome assembly (GO:0000045), autophagy of mitochondrion (GO:0000422), macroautophagy (GO:0016236), negative regulation of type I interferon production (GO:0032480), piecemeal microautophagy of the nucleus (GO:0034727), negative regulation of innate immune response (GO:0045824), negative regulation of defense response to virus (GO:0050687), glycophagy (GO:0061723), autophagosome maturation (GO:0097352), regulation of autophagosome maturation (GO:1901096), positive regulation of viral translation (GO:1904973), autophagy (GO:0006914)

GO Molecular Function (3): protein tag activity (GO:0031386), protein binding (GO:0005515), Atg8-family ligase activity (GO:0019776)

GO Cellular Component (11): autophagosome membrane (GO:0000421), nucleoplasm (GO:0005654), autophagosome (GO:0005776), cytosol (GO:0005829), phagocytic vesicle membrane (GO:0030670), protein-containing complex (GO:0032991), phagophore assembly site membrane (GO:0034045), Atg12-Atg5-Atg16 complex (GO:0034274), transferase complex (GO:1990234), cytoplasm (GO:0005737), membrane (GO:0016020)

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	4
autophagy	2
negative regulation of response to biotic stimulus	2
negative regulation of defense response	2
negative regulation of response to external stimulus	2
macroautophagy	2
cytoplasm	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
autophagosome assembly	1
negative regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
microautophagy	1
nucleophagy	1
nucleus disassembly	1
innate immune response	1
regulation of innate immune response	1
negative regulation of immune response	1
regulation of defense response to virus	1
defense response to virus	1
glycogen catabolic process	1
protein-containing complex disassembly	1
regulation of macroautophagy	1
regulation of organelle organization	1
regulation of protein-containing complex disassembly	1
autophagosome maturation	1
viral translation	1
positive regulation of viral process	1
regulation of viral translation	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
molecular tag activity	1
binding	1

Protein interactions and networks

STRING

2364 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATG12	ATG10	Q9H0Y0	999
ATG12	ATG3	Q9NT62	999
ATG12	ATG7	O95352	999
ATG12	ATG5	Q9H1Y0	999
ATG12	ATG16L1	Q676U5	999
ATG12	GABARAPL2	P60520	998
ATG12	F5GZY7	F5GZY7	996
ATG12	RIGI	O95786	990
ATG12	WIPI2	Q9Y4P8	988
ATG12	BCL2	P10415	986
ATG12	MAVS	Q7Z434	986
ATG12	MCL1	Q07820	985
ATG12	RB1CC1	Q8TDY2	979
ATG12	TECPR1	Q7Z6L1	979
ATG12	IFIH1	Q9BYX4	978

IntAct

106 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
ATG5	ATG12	psi-mi:“MI:0914”(association)	0.800
ATG10	ATG12	psi-mi:“MI:0914”(association)	0.670
CRX	ATG12	psi-mi:“MI:0915”(physical association)	0.560
ATG12	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
ATG12	SERTAD1	psi-mi:“MI:0915”(physical association)	0.560
ATG12	SERTAD2	psi-mi:“MI:0915”(physical association)	0.560
ATG12	IER2	psi-mi:“MI:0915”(physical association)	0.560
ATG3	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.530
KXD1	TRAK2	psi-mi:“MI:0914”(association)	0.530
ATG12	Atg3	psi-mi:“MI:0915”(physical association)	0.400
ATG12	ECE1	psi-mi:“MI:0915”(physical association)	0.370
PLSCR1	ATG12	psi-mi:“MI:0915”(physical association)	0.370
ATG12	KRTAP4-12	psi-mi:“MI:0915”(physical association)	0.370
MDFI	ATG12	psi-mi:“MI:0915”(physical association)	0.370
Atg16l1	ATG12	psi-mi:“MI:0914”(association)	0.350
Atg5	ATG12	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
RIGI	ATG12	psi-mi:“MI:0914”(association)	0.350
IFIH1	ATG12	psi-mi:“MI:0914”(association)	0.350
MAVS	ATG12	psi-mi:“MI:0914”(association)	0.350

BioGRID (146): ATG12 (Affinity Capture-Western), ATG12 (Affinity Capture-Western), ATG12 (Two-hybrid), Atg3 (Reconstituted Complex), Atg3 (Affinity Capture-Western), ATG12 (Affinity Capture-Western), ATG12 (Affinity Capture-MS), ATG12 (Two-hybrid), KRTAP4-12 (Two-hybrid), ATG12 (Two-hybrid), ATG12 (Two-hybrid), ATG12 (Affinity Capture-MS), ATG12 (Affinity Capture-MS), ATG12 (Affinity Capture-MS), DHX36 (Affinity Capture-MS)

ESM2 similar proteins: A0A0E0SC50, A1CTJ1, A1D4X8, A1DMW6, A2X052, A4D9P4, A4RN19, A6RA46, A7EAE5, A7EGK5, A7KAM3, B4FTR7, B8AK78, F7W503, O35954, O94817, P0CM28, P0CM29, P49842, P62869, P62870, Q01317, Q0JCC3, Q0UNW1, Q10CI8, Q13367, Q15370, Q1DY54, Q1E8C2, Q2GSG9, Q2TBJ5, Q2UMW6, Q2URI8, Q3T0W7, Q42713, Q43307, Q4WKD7, Q51P78, Q5BCH0, Q5R7W1

Diamond homologs: A0A0E0SC50, A1CTJ1, A1DMW6, A2YAG8, A3GI31, A4D9P4, A5DK05, A5E1F1, A6RA46, A6ZLF7, A7EAE5, A7KAJ7, A7KAM3, A7TJM4, F7W503, O94817, P0CM28, P0CM29, P38316, Q0UNW1, Q10931, Q1E8C2, Q1SF86, Q2GSG9, Q2TBJ5, Q2UMW6, Q3T0W7, Q51P78, Q5AKU4, Q5BCH0, Q5R7W1, Q69NP0, Q6BU30, Q6BZZ1, Q6CUD5, Q7S083, Q86CR6, Q8S924, Q9CQY1, Q9LVK3

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ATG10	up-regulates	ATG12	binding
ATG7	up-regulates	ATG12	binding
ATG12	“form complex”	ATG12/5/16L1	binding
ATG12	up-regulates	Autophagosome_formation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 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	9	18.2×	4e-07
Autophagy	6	15.6×	4e-04
mRNA Splicing	6	11.6×	8e-04
Processing of Capped Intron-Containing Pre-mRNA	6	8.7×	2e-03
Dengue Virus-Host Interactions	9	7.2×	4e-04
Metabolism of RNA	9	6.6×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome assembly	13	41.1×	2e-15
mitophagy	6	26.9×	1e-05
macroautophagy	5	16.9×	6e-04
autophagy	7	10.9×	2e-04
defense response to virus	11	10.7×	9e-07

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	4
Uncertain significance	23
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
4310089	NM_004707.4(ATG12):c.363+3A>T	Likely pathogenic
4755388	NM_004707.4(ATG12):c.413C>T (p.Ala138Val)	Likely pathogenic
4755389	NM_004707.4(ATG12):c.235C>T (p.Arg79Ter)	Likely pathogenic
4755390	NM_004707.4(ATG12):c.324T>G (p.Phe108Leu)	Likely pathogenic

SpliceAI

960 predictions. Top by Δscore:

Variant	Effect	Δscore
5:115831692:A:AC	donor_gain	1.0000
5:115831693:C:CC	donor_gain	1.0000
5:115831756:T:TA	donor_gain	1.0000
5:115832665:C:CC	acceptor_gain	1.0000
5:115837627:CCAA:C	donor_gain	1.0000
5:115837630:A:AC	donor_gain	1.0000
5:115837631:C:CC	donor_gain	1.0000
5:115837762:CAA:C	acceptor_gain	1.0000
5:115837765:C:CC	acceptor_gain	1.0000
5:115841253:T:TA	donor_gain	1.0000
5:115841388:A:AC	donor_gain	1.0000
5:115841389:C:CC	donor_gain	1.0000
5:115831701:A:AC	donor_gain	0.9900
5:115831705:CAT:C	donor_gain	0.9900
5:115831707:T:C	donor_gain	0.9900
5:115831722:G:A	donor_gain	0.9900
5:115831862:CA:C	acceptor_gain	0.9900
5:115831864:C:CC	acceptor_gain	0.9900
5:115832661:TAAA:T	acceptor_gain	0.9900
5:115837631:CTGTT:C	donor_gain	0.9900
5:115837679:T:TA	donor_gain	0.9900
5:115837761:TCAA:T	acceptor_gain	0.9900
5:115837762:CAAC:C	acceptor_gain	0.9900
5:115837763:AA:A	acceptor_gain	0.9900
5:115841225:AAAGG:A	donor_gain	0.9900
5:115841249:CA:C	donor_gain	0.9900
5:115841249:CACTT:C	donor_gain	0.9900
5:115834160:T:TA	donor_gain	0.9800
5:115834160:TC:T	donor_gain	0.9800
5:115837760:GTCAA:G	acceptor_gain	0.9800

AlphaMissense

891 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:115831808:C:T	G140E	1.000
5:115831809:C:G	G140R	1.000
5:115831809:C:T	G140R	1.000
5:115831810:C:A	W139C	1.000
5:115831810:C:G	W139C	1.000
5:115831812:A:G	W139R	1.000
5:115831812:A:T	W139R	1.000
5:115831825:G:C	C134W	1.000
5:115831826:C:T	C134Y	1.000
5:115831830:A:C	Y133D	1.000
5:115831830:A:G	Y133H	1.000
5:115831841:A:G	L129P	1.000
5:115831841:A:T	L129Q	1.000
5:115831858:A:C	F123L	1.000
5:115831858:A:T	F123L	1.000
5:115831860:A:G	F123L	1.000
5:115832636:G:T	P110H	1.000
5:115832639:G:T	A109D	1.000
5:115832641:A:C	F108L	1.000
5:115832641:A:T	F108L	1.000
5:115832642:A:G	F108S	1.000
5:115832643:A:G	F108L	1.000
5:115832654:A:T	V104E	1.000
5:115832658:A:C	Y103D	1.000
5:115837667:G:C	F87L	1.000
5:115837667:G:T	F87L	1.000
5:115837669:A:G	F87L	1.000
5:115837711:A:G	W73R	1.000
5:115837711:A:T	W73R	1.000
5:115837740:C:T	G63E	1.000

dbSNP variants (sampled 300 via entrez): RS1000265343 (5:115829670 G>C), RS1000599299 (5:115830696 T>A,G), RS1000631910 (5:115831037 T>G), RS1000755428 (5:115840789 T>C), RS1001312374 (5:115841000 C>A,T), RS1001329317 (5:115843415 A>C,G), RS1001416683 (5:115839703 T>C,G), RS1001430675 (5:115836640 C>T), RS1001483941 (5:115831481 T>C), RS1001529903 (5:115828955 G>C), RS1001727863 (5:115829263 C>T), RS1001863424 (5:115830095 C>T), RS1001935181 (5:115835955 G>T), RS1002003074 (5:115834749 T>C), RS1002257113 (5:115840593 C>G,T)

Disease associations

OMIM: gene MIM:609608 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
colorectal cancer	Limited	Autosomal dominant

Mondo (2): mitochondrial disease (MONDO:0044970), colorectal cancer (MONDO:0005575)

Orphanet (1): Mitochondrial disease (Orphanet:68380)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90011900_98	Serum alkaline phosphatase levels	4.000000e-11
GCST90013406_221	Liver enzyme levels (alkaline phosphatase)	2.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetylcysteine	increases expression, affects binding, increases reaction, decreases reaction	5
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Paraquat	decreases expression, decreases reaction, affects binding, affects reaction, increases expression	3
Cadmium Chloride	increases expression	3
Particulate Matter	increases expression, decreases expression, increases abundance	3
cobaltous chloride	affects cotreatment, increases expression	2
Arsenic Trioxide	increases reaction, affects reaction, decreases reaction, increases expression, affects binding	2
Vehicle Emissions	decreases expression, increases abundance, increases expression	2
Doxorubicin	affects expression, increases expression, decreases reaction	2
YW3-56	increases expression	1
7-hydroxydehydronuciferine	increases expression	1
dicrotophos	decreases expression	1
thymoquinone	decreases expression	1
astaxanthine	increases expression, decreases reaction	1
4-biphenylamine	affects expression, affects reaction	1
bisphenol A	increases expression, decreases reaction	1
geraniol	decreases expression, decreases reaction	1
tetrandrine	increases expression	1
Nonidet P-40	increases expression	1
embelin	affects binding, increases cleavage	1
arsenite	increases reaction, affects binding	1
methylparaben	increases expression	1
cypermethrin	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
3-methyladenine	decreases expression, decreases reaction	1
hydroquinone	increases expression	1
galangin	affects cotreatment, decreases activity, increases expression, decreases reaction	1
epigallocatechin gallate	increases expression, affects reaction	1
justicidins	affects binding, decreases reaction	1

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 1 embryonic stem cell, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B1A2	Abcam THP-1 ATG12 KO	Cancer cell line	Male
CVCL_C4EL	H9 AAVS1-TRE3G-NGN2 ATG12-/-	Embryonic stem cell	Female
CVCL_D1KS	KOLF2.1J AAVS1-TREG3-NGN2 ATG12-/-	Induced pluripotent stem cell	Male
CVCL_SD90	HAP1 ATG12 (-) 1	Cancer cell line	Male
CVCL_SD91	HAP1 ATG12 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00114829	PHASE4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	PHASE4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	PHASE4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	PHASE4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00129870	PHASE4	TERMINATED	CONCEPT: Comparison of Oxaliplatin vs Conventional Methods With Calcium/Magnesium in First-Line Metastatic Colorectal Cancer
NCT00138060	PHASE4	COMPLETED	Toxicity/Benefit Ratio Optimization of Chemotherapy in Colorectal Cancer (CRC) Patients by Determination of Individual Genotypic Determinants
NCT00216424	PHASE4	TERMINATED	Capecitabine (Xeloda) and Radiation for Patients With Rectosigmoid Carcinoma
NCT00327093	PHASE4	TERMINATED	Elaboration of a Model for Predicting Efficacy of Monoclonal Antibodies (Cetuximab and Bevacizumab) in Patients With Colorectal Cancer and Liver Metastases
NCT00332943	PHASE4	COMPLETED	MR Colonography With Fecal Tagging. Barium vs. BariumFerumoxsil
NCT00441311	PHASE4	COMPLETED	Dissemination of Colorectal Cancer Screening to Primary Care Physicians
NCT00460837	PHASE4	WITHDRAWN	Comparison of Bowel Preparation in Virtual Colonoscopy (VC) - Patient Experience
NCT00473980	PHASE4	COMPLETED	Preoperative Non-steroidal Anti-inflammatory Drugs(NSAID) to Colorectal Cancer Patients
NCT00488904	PHASE4	COMPLETED	Omega-3 Fatty Acids and Postoperative Complications After Colorectal Surgery
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00502671	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) as Adjuvant Monotherapy in Patients With Colon Cancer.
NCT00559676	PHASE4	COMPLETED	Study of Biomarkers in Patients Undergoing Chemotherapy for Metastatic Colorectal Cancer
NCT00577031	PHASE4	COMPLETED	OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.
NCT00626054	PHASE4	COMPLETED	Comparison of Two Methods of Administration of a PEG Solution
NCT00812864	PHASE4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00868569	PHASE4	UNKNOWN	Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer
NCT00868816	PHASE4	COMPLETED	Oxaliplatine Based Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: 8 Cycles Versus 12 Cycles
NCT00874406	PHASE4	UNKNOWN	Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer
NCT00928928	PHASE4	COMPLETED	Oxidative Stress Markers in Open and Laparoscopic Colectomy for Cancer
NCT00942461	PHASE4	COMPLETED	Inflammatory Response in Laparoscopic and Open Colectomy
NCT01023633	PHASE4	UNKNOWN	OPTIMOX1 in Chinese mCRC Patients
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01315990	PHASE4	UNKNOWN	FOLFIRI in Combination With Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer Including a Regular Dermal Prophylaxis to Prevent Acneiforme Follicular Exanthema
NCT01493713	PHASE4	COMPLETED	Correlation Between RECIST, Morphologic Response by CT- Histopathologic Response in Hepatic Metastasis Secondary to Colorectal Cancer
NCT01609660	PHASE4	COMPLETED	Impact of Probiotics on the Intestinal Microbiota
NCT01641458	PHASE4	COMPLETED	Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
NCT01689792	PHASE4	COMPLETED	A Multi-centre Study Comparing the Polyp Detection Rate of Two Different Types of Bowel Preparation: a 2-litre Solution (MOVIPREP®) Versus a Hyperosmotic and Stimulant Combined Low Volume Bowel Preparation (Sodium Picosulfate and Magnesium Citrate)
NCT01695772	PHASE4	COMPLETED	A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer
NCT01695863	PHASE4	COMPLETED	Efficacy and Patient Satisfaction of Miralax and Gatorade Versus Movi Prep
NCT01706822	PHASE4	TERMINATED	Radial Reload Laparoscopic LAR Case Series
NCT01740947	PHASE4	TERMINATED	Does Administration of Antibiotics in Patients Undergoing Surgery for Colorectal Cancer Result in Less Complications and Better Prognosis?
NCT01831310	PHASE4	COMPLETED	Nutrition for Colorectal Cancer Patients and Neutrophil Functions
NCT01841294	PHASE4	UNKNOWN	NK Activity Modulation Induced by Intravenous Lidocaine During Colorectal Laparoscopic Surgery
NCT01959061	PHASE4	UNKNOWN	Efficacy and Safety of Raltitrexed-based Transarterial Chemoembolisation(TACE)for Colorectal Cancer Liver Metastases
NCT02032953	PHASE4	UNKNOWN	Enhancing the Anabolic Effect of Perioperative Nutrition With Insulin While Maintaining Normoglycemia
NCT02567331	PHASE4	COMPLETED	A Study of Capecitabine (Xeloda) in Patients With Metastatic Colorectal Cancer