ATG9A

Summary

ATG9A (autophagy related 9A, HGNC:22408) is a protein-coding gene on chromosome 2q35, encoding Autophagy-related protein 9A (Q7Z3C6). Phospholipid scramblase involved in autophagy by mediating autophagosomal membrane expansion. It is a selective cancer dependency (DepMap: 11.2% of cell lines).

Enables phospholipid scramblase activity. Involved in autophagosome assembly. Located in several cellular components, including Golgi apparatus; endosome; and phagophore assembly site.

Source: NCBI Gene 79065 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency disease (Limited, GenCC)
• Clinical variants (ClinVar): 110 total
• Cancer dependency (DepMap): dependent in 11.2% of screened cell lines
• MANE Select transcript: NM_001077198

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22408
Approved symbol	ATG9A
Name	autophagy related 9A
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22169
Ensembl gene	ENSG00000198925
Ensembl biotype	protein_coding
OMIM	612204
Entrez	79065

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 38 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000361242, ENST00000396761, ENST00000409033, ENST00000409422, ENST00000409618, ENST00000412355, ENST00000428226, ENST00000429920, ENST00000431715, ENST00000432520, ENST00000434939, ENST00000436856, ENST00000439812, ENST00000443140, ENST00000455079, ENST00000456708, ENST00000457841, ENST00000466217, ENST00000475339, ENST00000486766, ENST00000488833, ENST00000901769, ENST00000901770, ENST00000901771, ENST00000901772, ENST00000901773, ENST00000901774, ENST00000901775, ENST00000901776, ENST00000901777, ENST00000901778, ENST00000901779, ENST00000901780, ENST00000901781, ENST00000901782, ENST00000901783, ENST00000901784, ENST00000915618, ENST00000915619, ENST00000915620, ENST00000944421, ENST00000944422, ENST00000944423, ENST00000944424, ENST00000944425, ENST00000944426

RefSeq mRNA: 2 — MANE Select: NM_001077198 NM_001077198, NM_024085

CCDS: CCDS42820

Canonical transcript exons

ENST00000361242 — 16 exons

Exon	Start	End
ENSE00001075567	219224106	219224854
ENSE00001075575	219223869	219224022
ENSE00001526207	219229535	219229636
ENSE00001702941	219228434	219228485
ENSE00003492969	219223585	219223764
ENSE00003523519	219225411	219225572
ENSE00003636157	219227770	219227813
ENSE00003669467	219222645	219222893
ENSE00003681983	219226869	219226933
ENSE00003689031	219219380	219220452
ENSE00003689341	219227922	219228053
ENSE00003784945	219225071	219225212
ENSE00003818669	219222050	219222167
ENSE00003821973	219222272	219222450
ENSE00003822814	219221080	219221302
ENSE00003827710	219220747	219220892

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 97.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.0582 / max 214.2654, expressed in 1811 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34040	22.0106	1806
34038	6.2054	1693
34039	0.8422	561

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	97.09	gold quality
muscle of leg	UBERON:0001383	96.49	gold quality
skeletal muscle tissue	UBERON:0001134	95.99	gold quality
apex of heart	UBERON:0002098	95.83	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.71	gold quality
left testis	UBERON:0004533	95.46	gold quality
right testis	UBERON:0004534	95.18	gold quality
blood	UBERON:0000178	94.79	gold quality
muscle tissue	UBERON:0002385	94.79	gold quality
stromal cell of endometrium	CL:0002255	94.65	gold quality
testis	UBERON:0000473	94.62	gold quality
heart left ventricle	UBERON:0002084	94.57	gold quality
prefrontal cortex	UBERON:0000451	94.26	gold quality
frontal cortex	UBERON:0001870	93.94	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.90	gold quality
right frontal lobe	UBERON:0002810	93.68	gold quality
cerebellum	UBERON:0002037	93.50	gold quality
islet of Langerhans	UBERON:0000006	93.49	gold quality
cerebellar cortex	UBERON:0002129	93.45	gold quality
cerebellar hemisphere	UBERON:0002245	93.45	gold quality
superior frontal gyrus	UBERON:0002661	93.40	gold quality
heart	UBERON:0000948	93.28	gold quality
lower esophagus mucosa	UBERON:0035834	93.08	gold quality
mucosa of stomach	UBERON:0001199	93.05	gold quality
right atrium auricular region	UBERON:0006631	92.96	gold quality
primary visual cortex	UBERON:0002436	92.84	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.67	gold quality
cerebral cortex	UBERON:0000956	92.61	gold quality
skin of leg	UBERON:0001511	92.60	gold quality
duodenum	UBERON:0002114	92.52	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	327.43
E-ANND-3	yes	2.85

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

74 targeting ATG9A, 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-8485	100.00	77.57	4731
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-6852-5P	99.17	66.69	2073

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 11.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• In human adult tissues APG9L1 is ubiquitously expressed. (PMID:15755735)
• First demonstration that mammalian Atg9A, originally called mAtg9, is required for starvation-induced autophagy, and localizes to Golgi and endosomes. (PMID:16940348)
• ATG9A was found by co-immunoprecipitation to interact with FAM48A/p38IP/q8NEM7.2. (PMID:19893488)
• Manipulation of p38IP and p38alpha alters mAtg9 localization, suggesting p38alpha regulates, through p38IP, the starvation-induced mAtg9 trafficking to forming autophagosomes. (PMID:19893488)
• These findings suggest that Bif-1 acts as a critical regulator of Atg9 puncta formation presumably by mediating Golgi fission for autophagosome biogenesis during starvation. (PMID:21068542)
• mAtg9 trafficking through multiple organelles, including recycling endosomes, is essential for the initiation and progression of autophagy (PMID:22456507)
• the presence of ATG9A in the cytoplasm of tumor cells may be an independent biomarker for disease recurrence and survival in patients with oral squamous cell carcinoma (PMID:24085552)
• TBC1D5 and the AP2 complex are important novel regulators of the rerouting of ATG9-containing vesicular carriers toward sites of autophagosome formation. (PMID:24603492)
• miR-29b mRNA, MAPK10 protein expression, and ATG9A protein expression are closely related to chemosensitivity of ovarian carcinoma. (PMID:24767251)
• D620N mutation in VPS35 restricts WASH complex recruitment to endosomes, inhibiting autophagy. The autophagy defects can be explained, at least in part, by abnormal trafficking of the autophagy protein ATG9A. (PMID:24819384)
• Data found that the interaction between 14-3-3 zeta and Atg9A is mediated by phosphorylation at Ser761. (PMID:25266655)
• These two steps are essential for the maturation of small single-membrane autophagic precursors containing ATG16L1 and mATG9 proteins into double-membrane autophagosomes (PMID:25461811)
• Importantly, TBC1D14 and TRAPPIII regulate ATG9 trafficking independently of ULK1. (PMID:26711178)
• Findings show for this first time that ATG9A loss in trastuzumab resistant cells allowed Her2 to escape from lysosomal targeted degradation through K63 poly-ubiquitination via c-Cbl. (PMID:27050377)
• Contrary to its normal trafficking between plasma membrane, intracellular organelles and autophagic membranes, ATG9A concentrates in transferrin receptor-positive juxtanuclear recycling endosomes in SMPD1-deficient cells. (PMID:27070082)
• Results suggest that quinocetone stimulates the MRLC-mediated mAtg9 trafficking, which is critical for autophagosome formation, via the ATF6 upregulated expression of DAPK1. (PMID:27085326)
• This study highlights the transcriptional inactivation mechanisms of ATG2B, ATG4D, ATG9A and ATG9B promoter methylation status and the possible origin of autophagy signal pathway repression in invasive ductal carcinomas. (PMID:27265029)
• these findings provide new insights into the intracellular pathways followed by ATG9A to reach different subcellular compartments, and into the intramolecular determinants that drive the sorting of this protein. (PMID:27316455)
• the nucleation of autophagosomes occurs in endoplasmic reticulum ubulovesicular regions, where the ULK1 complex coalesces with ER and the ATG9 compartment (PMID:27510922)
• the C-terminal glycine of human ATG9A is required for its transport from the endoplasmic reticulum to the Golgi apparatus (PMID:27663665)
• we focus on the contributions of the plasma membrane to autophagosome biogenesis governed by ATG16L1 and ATG9A trafficking, and summarize the physiological and pathological implications of this macroautophagy route, from development and stem cell fate to neurodegeneration and cancer. (PMID:27758042)
• phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex. (PMID:27934868)
• In these Rab1B-depleted cells, ATG9A accumulated in intermediate membrane structures at autophagosome formation sites. These results indicate that Rab1B is involved in regulating the proper development of autophagosomes. (PMID:28522593)
• In the inner ear HEI-OC1 cell line, miR-34a overexpression resulted in an accumulation of phagophores and impaired autophagosome-lysosome fusion, and led to cell death subsequently. Notably, autophagy-related protein 9A (ATG9A), an autophagy protein, was significantly decreased after miR-34a overexpression. Knockdown of ATG9A inhibited autophagy flux, which is similar to the effects of miR-34a overexpression (PMID:28981097)
• TMEM74 promotes tumor cell survival by inducing autophagy via interactions with ATG16L1 and ATG9A. (PMID:29048433)
• the identification of ATG9A as a specific AP-4 cargo (PMID:29180427)
• We propose a model where upon autophagy induction, SNX18 recruits Dynamin-2 to induce budding of ATG9A and ATG16L1 containing membranes from recycling endosomes that traffic to sites of autophagosome formation. (PMID:29437695)
• ATG9A upregulation after long-term 5-ARI treatment constitutes a possible mechanism of BPH progression. Inhibition of autophagy via targeting ATG9A, may become an effective method to reduce the risk of BPH progression. (PMID:29568063)
• We venture a functional link between ATG7 and ATG9A variants and Primary ovarian insufficiency (POI). We demonstrated that variant ATG7 and ATG9A led to a decrease in autophagosome biosynthesis and consequently to an impairment of autophagy, a key biological process implicated in the preservation of the primordial follicles forming the ovarian reserve (PMID:30224786)
• AP-4 deficiency causes missorting of ATG9A in diverse cell types, including patient-derived cells, as well as dysregulation of autophagy. (PMID:30262884)
• ATG9A promotes HIV-1 infectivity in an Env-dependent manner. The interaction of Nef with ATG9A, however, is not required for Nef to enhance HIV-1 infectivity. (PMID:31269971)
• The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear distribution of AP-4 and its cargo ATG9A. (PMID:32073997)
• Critical role of mitochondrial ubiquitination and the OPTN-ATG9A axis in mitophagy. (PMID:32556086)
• Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery. (PMID:32610138)
• The HIF target ATG9A is essential for epithelial barrier function and tight junction biogenesis. (PMID:32726170)
• Atg9 is a lipid scramblase that mediates autophagosomal membrane expansion. (PMID:33106658)
• Structure, lipid scrambling activity and role in autophagosome formation of ATG9A. (PMID:33106659)
• The phosphatidylinositol 3-phosphate-binding protein SNX4 controls ATG9A recycling and autophagy. (PMID:33468622)
• RUSC2 and WDR47 oppositely regulate kinesin-1-dependent distribution of ATG9A to the cell periphery. (PMID:34432492)
• The autophagy protein ATG9A enables lipid mobilization from lipid droplets. (PMID:34799570)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	atg9a	ENSDARG00000044551
mus_musculus	Atg9a	ENSMUSG00000033124
rattus_norvegicus	Atg9a	ENSRNOG00000018975
drosophila_melanogaster	Atg9	FBGN0034110
caenorhabditis_elegans		WBGENE00020706

Paralogs (1): ATG9B (ENSG00000181652)

Protein

Protein identifiers

Autophagy-related protein 9A — Q7Z3C6 (reviewed: Q7Z3C6)

Alternative names: APG9-like 1, mATG9

All UniProt accessions (11): Q7Z3C6, C9IYZ9, C9JD65, C9JDK4, C9JFV2, C9JKV7, C9JS65, C9JX27, C9JXG2, F2Z3I6, H7C1G6

UniProt curated annotations — full annotation on UniProt →

Function. Phospholipid scramblase involved in autophagy by mediating autophagosomal membrane expansion. Cycles between the preautophagosomal structure/phagophore assembly site (PAS) and the cytoplasmic vesicle pool and supplies membrane for the growing autophagosome. Lipid scramblase activity plays a key role in preautophagosomal structure/phagophore assembly by distributing the phospholipids that arrive through ATG2 (ATG2A or ATG2B) from the cytoplasmic to the luminal leaflet of the bilayer, thereby driving autophagosomal membrane expansion. Also required to supply phosphatidylinositol 4-phosphate to the autophagosome initiation site by recruiting the phosphatidylinositol 4-kinase beta (PI4KB) in a process dependent on ARFIP2, but not ARFIP1. In addition to autophagy, also plays a role in necrotic cell death.

Subunit / interactions. Homotrimer; forms a homotrimer with a central pore that forms a path between the two membrane leaflets. Interacts (via cytoplasmic its C-terminus) with ATG2A. Interacts with SUPT20H. Interacts (via the tyrosine-based sorting signal motif) with AP4M1; promoting association with the AP-4 complex. Interacts with ARFIP1 and ARFIP2. Interacts with PI4K2A and PI4KB. Interacts with ATG4A; the interaction is direct and promotes ATG9A trafficking.

Subcellular location. Preautophagosomal structure membrane. Cytoplasmic vesicle. Autophagosome membrane. Golgi apparatus. trans-Golgi network membrane. Late endosome membrane. Recycling endosome membrane. Endoplasmic reticulum membrane. Mitochondrion membrane.

Post-translational modifications. Ufmylated in a DDRGK1 dependent manner.

Domain organisation. Forms a homotrimer with a solvated central pore, which is connected laterally to the cytosol through the cavity within each protomer. Acts as a lipid scramblase that uses its central pore to function: the central pore opens laterally to accommodate lipid headgroups, thereby enabling lipid flipping and redistribution of lipids added to the outer leaflet of ATG9A-containing vesicles, thereby enabling growth into autophagosomes. The tyrosine-based sorting signal motif, also named YXX-psi motif, promotes interaction with the AP-4 complex.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the ATG9 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q7Z3C6-1	1	yes
Q7Z3C6-2	2
Q7Z3C6-3	3

RefSeq proteins (2): NP_001070666, NP_076990 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007241	Autophagy-rel_prot_9	Family

Pfam: PF04109

Catalyzed reactions (Rhea), 3 shown:

• a 1,2-diacyl-sn-glycero-3-phosphocholine(in) = a 1,2-diacyl-sn-glycero-3-phosphocholine(out) (RHEA:38571)
• a 1,2-diacyl-sn-glycero-3-phospho-L-serine(in) = a 1,2-diacyl-sn-glycero-3-phospho-L-serine(out) (RHEA:38663)
• a 1,2-diacyl-sn-glycero-3-phosphoethanolamine(in) = a 1,2-diacyl-sn-glycero-3-phosphoethanolamine(out) (RHEA:38895)

UniProt features (104 total): helix 29, mutagenesis site 14, strand 10, topological domain 9, modified residue 9, sequence conflict 7, transmembrane region 4, intramembrane region 4, turn 3, region of interest 3, compositionally biased region 3, splice variant 3, sequence variant 2, initiator methionine 1, chain 1, short sequence motif 1, glycosylation site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6WQZ	ELECTRON MICROSCOPY	2.8
6WR4	ELECTRON MICROSCOPY	2.9
7JLO	ELECTRON MICROSCOPY	3.4
7JLP	ELECTRON MICROSCOPY	3.4
8KBZ	ELECTRON MICROSCOPY	3.97
7JLQ	ELECTRON MICROSCOPY	4
8KC3	ELECTRON MICROSCOPY	7
8Y1L	ELECTRON MICROSCOPY	7.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z3C6-F1	74.84	0.50

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 (9): 2, 14, 16, 18, 656, 735, 738, 741, 828

Glycosylation sites (1): 99

Mutagenesis-validated functional residues (14):

Position	Phenotype
8	abolished interaction with the ap-4 complex.
9	abolished interaction with the ap-4 complex.
10	does not affect interaction with the ap-4 complex.
11	abolished interaction with the ap-4 complex.
12	abolished interaction with the ap-4 complex.
15	does not affect interaction with the ap-4 complex.
99	abolished n-glycosylation.
265	impaired autophagy.
321–323	reduced lipid scramblase activity and autophagy. strongly reduced autophagy; when associated with w-412. strongly reduce
412	does not affect lipid scramblase activity. strongly reduced autophagy; when associated with l-321–l-323.
419	strongly reduced lipid scramblase activity and autophagy; when associated with l-321–l-323.
422	impaired autophagy.
516–519	impaired transport from the endoplasmic reticulum to the golgi apparatus without affecting homooligomerization.
711–713	impaired transport through the golgi apparatus.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy
R-HSA-5205685	PINK1-PRKN Mediated Mitophagy
R-HSA-5205647	Mitophagy
R-HSA-9612973	Autophagy
R-HSA-9663891	Selective autophagy

MSigDB gene sets: 209 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, HORIUCHI_WTAP_TARGETS_DN, GOBP_VACUOLE_ORGANIZATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOCC_VACUOLAR_MEMBRANE, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, AP2_Q3, CAGCTG_AP4_Q5, GOBP_REGULATION_OF_MEMBRANE_LIPID_DISTRIBUTION, GOBP_MACROAUTOPHAGY, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, CATRRAGC_UNKNOWN, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_BONE_DEVELOPMENT

GO Biological Process (14): autophagosome assembly (GO:0000045), mitophagy (GO:0000423), negative regulation of macrophage cytokine production (GO:0010936), negative regulation of interferon-beta production (GO:0032688), protein localization to Golgi apparatus (GO:0034067), protein localization to phagophore assembly site (GO:0034497), piecemeal microautophagy of the nucleus (GO:0034727), innate immune response (GO:0045087), bone morphogenesis (GO:0060349), reticulophagy (GO:0061709), programmed necrotic cell death (GO:0097300), lipid transport (GO:0006869), autophagy (GO:0006914), plasma membrane phospholipid scrambling (GO:0017121)

GO Molecular Function (2): phospholipid scramblase activity (GO:0017128), protein binding (GO:0005515)

GO Cellular Component (20): Golgi membrane (GO:0000139), phagophore assembly site (GO:0000407), mitochondrion (GO:0005739), endosome (GO:0005768), late endosome (GO:0005770), autophagosome (GO:0005776), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), membrane (GO:0016020), late endosome membrane (GO:0031902), mitochondrial membrane (GO:0031966), phagophore assembly site membrane (GO:0034045), recycling endosome (GO:0055037), recycling endosome membrane (GO:0055038), synaptic membrane (GO:0097060), autophagosome membrane (GO:0000421), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Autophagy	1
Mitophagy	1
Selective autophagy	1
Macroautophagy	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	5
cellular anatomical structure	3
intracellular membrane-bounded organelle	3
endomembrane system	3
macroautophagy	2
endosome	2
organelle membrane	2
endosome membrane	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
negative regulation of cytokine production involved in immune response	1
macrophage cytokine production	1
regulation of macrophage cytokine production	1
negative regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
protein localization to organelle	1
autophagosome assembly	1
intracellular protein localization	1
microautophagy	1
nucleophagy	1
nucleus disassembly	1
immune response	1
defense response to symbiont	1
animal organ morphogenesis	1
skeletal system morphogenesis	1
bone development	1
programmed cell death	1
transport	1
lipid localization	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
plasma membrane organization	1

Protein interactions and networks

STRING

1960 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATG9A	SUPT20H	Q8NEM7	949
ATG9A	ATG2A	Q2TAZ0	868
ATG9A	MAP1LC3A	Q9H492	864
ATG9A	ATG16L1	Q676U5	850
ATG9A	ATG7	O95352	831
ATG9A	RB1CC1	Q8TDY2	823
ATG9A	ATG101	Q9BSB4	822
ATG9A	ATG13	O75143	819
ATG9A	ATG14	Q6ZNE5	816
ATG9A	WIPI1	Q5MNZ9	814
ATG9A	GABARAPL2	P60520	783
ATG9A	MAP1LC3B	Q9GZQ8	774
ATG9A	ATG5	Q9H1Y0	772
ATG9A	PIK3R4	Q99570	768
ATG9A	BECN1	Q14457	757

IntAct

184 interactions, top by confidence:

A	B	Type	Score
ATG9A	AP2M1	psi-mi:“MI:0407”(direct interaction)	0.890
AP2M1	ATG9A	psi-mi:“MI:0407”(direct interaction)	0.890
AP2M1	ATG9A	psi-mi:“MI:0915”(physical association)	0.890
TBK1	TBKBP1	psi-mi:“MI:0914”(association)	0.860
AP2M1	EGFR	psi-mi:“MI:0915”(physical association)	0.830
ATG9A	SUPT20H	psi-mi:“MI:0915”(physical association)	0.650
SUPT20H	ATG9A	psi-mi:“MI:0403”(colocalization)	0.650
SUPT20H	ATG9A	psi-mi:“MI:0915”(physical association)	0.650
FAF2	UBB	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
ATG2A	TOMM40	psi-mi:“MI:0914”(association)	0.610
ATG9A	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	ATG9A	psi-mi:“MI:0915”(physical association)	0.560
REL	ATG9A	psi-mi:“MI:0915”(physical association)	0.560
ATG9A	UBE3A	psi-mi:“MI:0915”(physical association)	0.560
ATG9A	KRT31	psi-mi:“MI:0915”(physical association)	0.560
LONRF1	ATG9A	psi-mi:“MI:0915”(physical association)	0.560
ATG9A	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.560
ATG9A	KRTAP4-2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-9	ATG9A	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (550): ATG9A (Two-hybrid), ATG9A (Two-hybrid), ATG9A (Two-hybrid), ATG9A (Two-hybrid), KRTAP4-2 (Two-hybrid), LONRF1 (Two-hybrid), KRTAP10-8 (Two-hybrid), NOTCH2NL (Two-hybrid), SUPT20H (Two-hybrid), ATG9A (Affinity Capture-Western), SUPT20H (Co-fractionation), SUPT20H (Affinity Capture-Western), MYH9 (Affinity Capture-Western), ATG9A (Affinity Capture-MS), ATG9A (Affinity Capture-MS)

ESM2 similar proteins: A3KN95, A4IFG4, A7E2I7, E2RDP2, J3QMI4, O94810, O95382, P0C5W1, P23677, P82350, Q15628, Q16586, Q1RMX3, Q24JP5, Q28686, Q29RH2, Q3T904, Q3U0S6, Q45T69, Q49LS1, Q5FWU3, Q5RCS0, Q5U651, Q64255, Q674R7, Q684M2, Q68FE2, Q68FE7, Q6EBV9, Q6GQT5, Q6NY19, Q6P9Q4, Q6PEY1, Q7Z3C6, Q80WF4, Q80XF7, Q86TL0, Q86XJ0, Q8C052, Q8C152

Diamond homologs: A1CU77, A1DNW0, A2QLJ9, A3LZS3, A5DEX5, A6ZXH8, A7ERK1, A7KAI7, A7KAM0, A7TR50, I1S9X9, O74312, P0CM40, P0CM41, Q0UYL2, Q12142, Q1E6Q3, Q2UUT6, Q3T904, Q4P683, Q4WLT9, Q51WZ9, Q54NA3, Q5ANC9, Q5B6U6, Q5FWU3, Q5RCS0, Q68FE2, Q6BW58, Q6C2F5, Q6CT08, Q6FQT7, Q6TGJ4, Q75A48, Q7S4D7, Q7Z3C6, Q875A7, Q876N4, Q8RUS5, W0TIW1

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
AMPK	“up-regulates activity”	ATG9A	phosphorylation
ULK1	“up-regulates activity”	ATG9A	phosphorylation
SRC	“up-regulates activity”	ATG9A	phosphorylation
ATG9A	“up-regulates activity”	YWHAE	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 178 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
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	34.5×	3e-06
Activation of BAD and translocation to mitochondria	5	32.5×	4e-05
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	28.7×	7e-05
Activation of BH3-only proteins	5	21.2×	2e-04
RHO GTPases activate PKNs	7	19.0×	1e-05
Translocation of SLC2A4 (GLUT4) to the plasma membrane	10	13.2×	1e-06
Intrinsic Pathway for Apoptosis	5	12.5×	2e-03
SARS-CoV-1-host interactions	7	10.5×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
macroautophagy	7	11.3×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	90
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2285 predictions. Top by Δscore:

Variant	Effect	Δscore
2:219220745:A:AT	donor_loss	1.0000
2:219220889:GGAT:G	acceptor_gain	1.0000
2:219220890:GAT:G	acceptor_gain	1.0000
2:219220891:AT:A	acceptor_gain	1.0000
2:219220893:C:CA	acceptor_loss	1.0000
2:219220893:C:CC	acceptor_gain	1.0000
2:219220894:T:A	acceptor_loss	1.0000
2:219221076:ATAC:A	donor_loss	1.0000
2:219221077:TACC:T	donor_loss	1.0000
2:219221078:AC:A	donor_loss	1.0000
2:219221079:C:G	donor_loss	1.0000
2:219221303:C:CC	acceptor_gain	1.0000
2:219222045:CTCA:C	donor_loss	1.0000
2:219222046:TCAC:T	donor_loss	1.0000
2:219222047:CAC:C	donor_loss	1.0000
2:219222048:A:T	donor_loss	1.0000
2:219222178:C:CT	acceptor_gain	1.0000
2:219222178:C:T	acceptor_gain	1.0000
2:219222179:A:T	acceptor_gain	1.0000
2:219223581:GTA:G	donor_loss	1.0000
2:219223583:ACCT:A	donor_loss	1.0000
2:219223584:CC:C	donor_loss	1.0000
2:219223762:CAC:C	acceptor_gain	1.0000
2:219223763:ACC:A	acceptor_loss	1.0000
2:219223765:C:CA	acceptor_loss	1.0000
2:219223867:A:AC	donor_gain	1.0000
2:219223868:C:CC	donor_gain	1.0000
2:219223868:CTG:C	donor_gain	1.0000
2:219224851:CAGA:C	acceptor_gain	1.0000
2:219225065:TCTTA:T	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000435791 (2:219227702 C>T), RS1000755904 (2:219226435 G>A), RS1000763126 (2:219231106 T>A), RS1000903640 (2:219227005 A>C), RS1000917600 (2:219220667 C>G,T), RS1001656227 (2:219221966 G>A), RS1001936888 (2:219224777 G>A,T), RS1002446579 (2:219230273 G>C), RS1002862766 (2:219229473 G>A), RS1002928475 (2:219223323 C>T), RS1002961245 (2:219225809 GCCA>G), RS1003199723 (2:219230641 T>A,C), RS1003375773 (2:219219246 A>G), RS1003429566 (2:219219460 C>A,G,T), RS1003473296 (2:219231468 C>T)

Disease associations

OMIM: gene MIM:612204 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency disease	Limited	Autosomal recessive

Mondo (1): immunodeficiency disease (MONDO:0021094)

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3731885	ABCB6, ATG9A		0.00	0
rs3755047	ABCB6, ATG9A		0.00	0

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
FR900359	affects phosphorylation	1
urushiol	decreases expression	1
1,12-benzoperylene	decreases expression	1
bisphenol A	decreases expression	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	decreases expression	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
eprenetapopt	affects expression, affects reaction	1
Acetylcysteine	affects cotreatment, decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Ethanol	decreases expression	1
Benzo(a)pyrene	increases expression	1
Caffeine	affects phosphorylation	1
Chloroquine	affects cotreatment, decreases expression	1
Cisplatin	decreases response to substance, increases expression	1
Dieldrin	increases response to substance	1
Ivermectin	decreases expression	1
Oxygen	affects binding, increases reaction	1
Ozone	affects expression, increases abundance	1
Ribonucleotides	affects binding	1
Selenium	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1

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_B7W4	Abcam Raji ATG9A KO	Cancer cell line	Male
CVCL_B9WM	Abcam THP-1 ATG9A KO	Cancer cell line	Male
CVCL_C6YN	Abcam PC-3 ATG9A KO	Cancer cell line	Male
CVCL_E0ZH	Ubigene NCI-H1299 ATG9A KO	Cancer cell line	Male
CVCL_F0LG	HeLa S3 ATG9A KO clone 3	Cancer cell line	Female
CVCL_SE05	HAP1 ATG9A (-) 1	Cancer cell line	Male
CVCL_SE06	HAP1 ATG9A (-) 2	Cancer cell line	Male
CVCL_SE07	HAP1 ATG9A (-) 3	Cancer cell line	Male
CVCL_W349	HEK293A mRFP-ATG9	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001542	PHASE4	COMPLETED	Fluconazole Prophylaxis of Thrush in AIDS
NCT00144157	PHASE4	COMPLETED	Open Label Study of NVP+CBV Treatment in Women Who Have Received sdNVP for the pMTCT of HIV
NCT00162643	PHASE4	UNKNOWN	PI Vs. NNRTI Based Therapy for HIV Advanced Disease
NCT00273988	PHASE4	COMPLETED	Pharmacokinetic Study of Interaction Between Nevirapine and Methadone in HIV-1 Infected, Opioid-dependent Adults
NCT00981318	PHASE4	TERMINATED	Pilot Assessment of Lopinavir/Ritonavir and Maraviroc
NCT01086878	PHASE4	COMPLETED	Safety of Cotrimoxazole in HIV- and HAART-exposed Infants
NCT01090102	PHASE4	COMPLETED	Mesalamine to Reduce T Cell Activation in HIV Infection
NCT01147042	PHASE4	TERMINATED	Biochemical Response to Interferon-Gamma in Subjects With Specific Gene Mutation in Chronic Granulomatous Disease
NCT01230580	PHASE4	UNKNOWN	Protease Inhibitor Monotherapy Versus Ongoing Triple-therapy in the Long Term Management of HIV Infection (PIVOT)
NCT01465958	PHASE4	COMPLETED	Pharmacokinetics, Safety, and Tolerability of Subcutaneous GAMUNEX-C in Pediatric Subjects With Primary Immunodeficiency
NCT02274662	PHASE4	COMPLETED	Expanded Access Protocol Thymus Transplantation
NCT02348177	PHASE4	COMPLETED	Pharmacokinetics of Lopinavir/Ritonavir Superboosting in Infants and Young Children Co-infected With HIV and TB
NCT02396979	PHASE4	COMPLETED	Intervention of HIV, Drug Use and the Criminal Justice System in Malaysia
NCT02490956	PHASE4	UNKNOWN	Diagnostic Immunization With Rabies Vaccine in Patients With PID
NCT02503293	PHASE4	COMPLETED	A Study to Compare Quality of Life and Satisfaction in Primary Immunodeficient Patients Treated With Subcutaneous Injections of Gammanorm® 165 mg/mL Administered With Two Different Delivery Devices: Injections Using Pump or Rapid Push
NCT02881437	PHASE4	COMPLETED	IgG Level in Primary Immunodeficiency Switching From Standard SCIG to Every Other Week HyQvia
NCT03033745	PHASE4	COMPLETED	Safety and Tolerability of Higher Infusion Parameters of IgPro20 (Hizentra) in Subjects With Primary Immunodeficiency (PID)
NCT03677557	PHASE4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT04192487	PHASE4	COMPLETED	Effects of Crofelemer on the Gut Microbiome in Healthy Volunteers and in HIV+ Patients With Non-Infectious Diarrhea
NCT04566692	PHASE4	COMPLETED	A Study to Evaluate IGSC 20% Biweekly Dosing in Treatment-Experienced Participants and Loading/Maintenance Dosing in Treatment-Naïve Participants With Primary Immunodeficiency
NCT05493969	PHASE4	NOT_YET_RECRUITING	Efficacy and Tolerability of DTG Plus 3TC in HIV Infected Adults With Virologically Suppression and TDF Toxicity
NCT06576024	PHASE4	COMPLETED	Immunogenicity and Safety of Inactivated Hepatitis A Vaccine in HIV-infected People
NCT06634641	PHASE4	RECRUITING	Clozapine-related Immunodeficiency in Parkinsons Disease
NCT07076446	PHASE4	ACTIVE_NOT_RECRUITING	An Open-label, Multicenter Study to Assess the Pharmacokinetics (PK), Safety, and Tolerability of Subcutaneous IgPro20 in Immunoglobulin (IG) Treatment-naïve Participants With Primary Immunodeficiency (PID)
NCT00000118	PHASE3	COMPLETED	Ganciclovir Implant Study for Cytomegalovirus Retinitis
NCT00000134	PHASE3	COMPLETED	Studies of the Ocular Complications of AIDS (SOCA)–Cytomegalovirus Retinitis Retreatment Trial (CRRT)
NCT00000590	PHASE3	COMPLETED	Anti-HIV Immunoglobulin (HIVIG) in Prevention of Maternal-Fetal HIV Transmission (Pediatric ACTG Protocol 185)
NCT00001267	PHASE3	COMPLETED	A Randomized Pilot Study for the Treatment of AIDS or AIDS Related Complex With an Alternating or Simultaneous Combination Regimen of AZT and 2’,3’-Dideoxyinosine
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00144183	PHASE3	COMPLETED	A Study of Single Dose Nevirapine (NVP) Combined With Combivir® for the Prevention of Mother to Child Transmission (pMTCT) - Treatment Options Preservation Study (TOPS)
NCT00243568	PHASE3	WITHDRAWN	Vicriviroc, a CCR5 Inhibitor, Added to an Optimized Antiretroviral Therapy for Previously Treated HIV (VICTOR-E2) (Study P04285
NCT00278954	PHASE3	COMPLETED	Efficacy, Safety and Pharmacokinetics of Gammaplex in Primary Immunodeficiency Diseases.
NCT00474370	PHASE3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04889AM8)(COMPLETED)
NCT00478231	PHASE3	COMPLETED	Multicenter, Safety Study Of Maraviroc
NCT00523211	PHASE3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04405AM5)
NCT00698334	PHASE3	COMPLETED	Efficacy of Thrice Weekly Directly Observed Treatment, Short-course (DOTS) in HIV-associated Tuberculosis
NCT00966160	PHASE3	COMPLETED	CD4 Cell Recovery in HIV-1 Patients Comparing 2 Treatment Regimes
NCT01363011	PHASE3	COMPLETED	Cobicistat-containing Highly Active Antiretroviral Regimens in HIV-1 Infected Patients With Mild to Moderate Renal Impairment
NCT01440569	PHASE3	COMPLETED	Safety and Efficacy of Cobicistat-boosted Darunavir in HIV Infected Adults
NCT01475838	PHASE3	COMPLETED	Study to Evaluate Switching From Regimens Consisting of a Ritonavir-boosted Protease Inhibitor Plus Emtricitabine/Tenofovir Fixed-Dose Combination to the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Single-Tablet Regimen in Virologically Suppressed, HIV-1 Infected Patients