ATG16L1

Summary

ATG16L1 (autophagy related 16 like 1, HGNC:21498) is a protein-coding gene on chromosome 2q37.1, encoding Autophagy-related protein 16-1 (Q676U5). Plays an essential role in both canonical and non-canonical autophagy: interacts with ATG12-ATG5 to mediate the lipidation to ATG8 family proteins (MAP1LC3A, MAP1LC3B, MAP1LC3C, GABARAPL1, GABARAPL2 and GABARAP).

The protein encoded by this gene is part of a large protein complex that is necessary for autophagy, the major process by which intracellular components are targeted to lysosomes for degradation. Defects in this gene are a cause of susceptibility to inflammatory bowel disease type 10 (IBD10). Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 55054 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 92 total
• MANE Select transcript: NM_030803

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21498
Approved symbol	ATG16L1
Name	autophagy related 16 like 1
Location	2q37.1
Locus type	gene with protein product
Status	Approved
Aliases	WDR30, FLJ10035, ATG16A
Ensembl gene	ENSG00000085978
Ensembl biotype	protein_coding
OMIM	610767
Entrez	55054

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 20 protein_coding, 6 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000347464, ENST00000373525, ENST00000392017, ENST00000392018, ENST00000392020, ENST00000392021, ENST00000417017, ENST00000419681, ENST00000431917, ENST00000444735, ENST00000464645, ENST00000472242, ENST00000473865, ENST00000474148, ENST00000479942, ENST00000485623, ENST00000492298, ENST00000498620, ENST00000905939, ENST00000905940, ENST00000905941, ENST00000962354, ENST00000962355, ENST00000962356, ENST00000962357, ENST00000962358, ENST00000962359, ENST00000962360, ENST00000962361

RefSeq mRNA: 6 — MANE Select: NM_030803 NM_001190266, NM_001190267, NM_001363742, NM_017974, NM_030803, NM_198890

CCDS: CCDS2502, CCDS2503, CCDS54438, CCDS86927

Canonical transcript exons

ENST00000392017 — 18 exons

Exon	Start	End
ENSE00003459327	233263130	233263235
ENSE00003485463	233281105	233281175
ENSE00003492168	233274676	233274778
ENSE00003499532	233277568	233277673
ENSE00003547188	233270002	233270067
ENSE00003567083	233256102	233256195
ENSE00003567906	233292387	233292434
ENSE00003571343	233272966	233273052
ENSE00003582036	233273721	233273777
ENSE00003586736	233292128	233292277
ENSE00003618505	233263992	233264065
ENSE00003622416	233290248	233290353
ENSE00003671138	233289854	233289974
ENSE00003672127	233293256	233293357
ENSE00003676263	233264892	233265143
ENSE00003690881	233282682	233282753
ENSE00003842911	233294257	233295669
ENSE00003846761	233251673	233251942

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 93.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.5029 / max 217.7955, expressed in 1804 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
26036	14.4409	1802
26037	2.5955	1024
26038	0.4666	273

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	93.57	gold quality
cerebellar hemisphere	UBERON:0002245	93.37	gold quality
cerebellar cortex	UBERON:0002129	93.22	gold quality
cerebellum	UBERON:0002037	91.31	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.25	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.79	gold quality
granulocyte	CL:0000094	89.72	gold quality
right frontal lobe	UBERON:0002810	89.54	gold quality
right lobe of thyroid gland	UBERON:0001119	88.57	gold quality
cortical plate	UBERON:0005343	88.21	gold quality
left lobe of thyroid gland	UBERON:0001120	88.13	gold quality
skin of leg	UBERON:0001511	88.08	gold quality
gastrocnemius	UBERON:0001388	87.95	gold quality
skin of abdomen	UBERON:0001416	87.50	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.49	gold quality
muscle of leg	UBERON:0001383	87.30	gold quality
mucosa of transverse colon	UBERON:0004991	86.98	gold quality
prefrontal cortex	UBERON:0000451	86.89	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.76	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.74	gold quality
lower esophagus	UBERON:0013473	86.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.71	gold quality
transverse colon	UBERON:0001157	86.69	gold quality
calcaneal tendon	UBERON:0003701	86.56	gold quality
sural nerve	UBERON:0015488	86.50	gold quality
thyroid gland	UBERON:0002046	86.29	gold quality
body of stomach	UBERON:0001161	86.28	gold quality
lower esophagus mucosa	UBERON:0035834	86.28	gold quality
minor salivary gland	UBERON:0001830	86.16	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	86.11	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.76

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

103 targeting ATG16L1, 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-4795-3P	100.00	74.62	4024
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606

Literature-anchored findings (GeneRIF, showing 40)

• Contains a coiled-coil domain and a motif with seven WD repeats, which are also shared by mouse Apg16L. (PMID:15620219)
• A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. (PMID:17200669)
• The association of ATG16L1 with Crohn’s disease and possibly with ulcerative colitis supports a role for autophagy in the pathogenesis of inflammatory bowel disease. (PMID:17484864)
• No evidence of positive association of ATG16L1 with Crohn’s disease was found in the Japanese population. (PMID:17534574)
• we have replicated the association of allele G of rs2241880 in the ATG16L1 gene with Crohn’s disease by demonstrating its effect in the childhood form of the disorder (PMID:17625155)
• ATG16L1 T300A is strongly associated with Crohn’s disease in New Zealand Caucasians with inflammatory bowel disease. (PMID:17894849)
• ATG16L1 is significantly associated with Crohn disease. (PMID:17921695)
• confirmed the association of IL23R and ATG16L1 with CD susceptibility and also the association of IL23R with UC. We found IL23R and ATG16L1 were not associated with celiac disease susceptibility. (PMID:18047540)
• The ATG16L1 variant is associated with susceptibility to adult CD in Scotland, but not early-onset disease. (PMID:18088053)
• ATG16L1 is a CD susceptibility gene without epistatic interaction (PMID:18162085)
• No genotype-phenotype correlations were found among the Brazilian CD population with with ATG16L1. (PMID:18200510)
• review of recent advances in genome-wide association studies of inflammatory bowel disease, with specific focus on growing evidence of the ATG16L1 gene’s role in Crohn’s disease [review] (PMID:18366306)
• Rab33 modulates autophagosome formation through interaction with Atg16L (PMID:18448665)
• ATG16L1 gene is asscociated with Crohn disease susceptibility in Hungarian patients. (PMID:18499543)
• ATG16L1, IBD5, and IL23R SNPs were significantly associated with Crohn’s Disease (PMID:18521914)
• A greater than seven-fold increased CD risk was observed for current smokers with a GG genotype (vs nonsmoking AA genotype). A significant inverse association was found between T300A and UC. This was strongest for patients with extensive, severe disease. (PMID:18671817)
• There is an association of IL23R polymorphisms with inflammatory bowel disease, and ATG16L1 with Crohn’s disease, in both adult- and pediatric-onset subsets in our italian study population. (PMID:18698678)
• ATG16L1 deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway (PMID:18849966)
• the association of ATG16L1*300A with increased risk of Crohn’s disease is due to impaired bacterial handling and lowered rates of bacterial capture by autophagy. (PMID:18852889)
• We have confirmed associations between Crohn disease and ATG16L1 in a pediatric cohort of Canadian children (PMID:18985712)
• associated with predisposition to Crohn’s disease (PMID:19120485)
• One role for the autophagy pathway in Crohn disease pathogenesis is through selective effects on the biology and specialized properties of Paneth cells. (PMID:19139628)
• genetic associations for CD with IL23R, ATG16L1, IRGM, NKX2-3, 1q24, 10q21, 5p13, and PTPN2 and report evidence for associations with HERC2 and CCNY. (PMID:19174780)
• gene polymorphism is associated with Crohn’s disease (PMID:19269148)
• Genetic variants in IL-23R and ATG16L1 independently predispose to increased susceptibility to Crohn’s disease in a Canadian population. (PMID:19276991)
• The G allele of ATG16L1 T300A is a low-penetrant gene for Crohn’s disease in Caucasians. (PMID:19337756)
• the ATG16L1 rs2241880 and IRGM rs13361189 and rs4958847 polymorphisms are important markers for Crohn’s disease susceptibility and indicate that these variants are also associated with ulcerative colitis. (PMID:19491842)
• The Thr300Ala polymorphism is associated with Crohn’s disease, but not with ulcerative colitis (PMID:19575361)
• ATG16L1 p.197Ala allele conferred increased risk of CD (allelic frequency 60% in patients vs 51% in controls; OR 1.25, 95% CI 1.02-1.52, P=0.03). (PMID:19590455)
• We confirmed the association of Crohn’s disease with ATG16L1 rs2241880 variant in early-onset CD. (PMID:19659808)
• no evidence of association with celiac disease has been reported for the Crohn’s disease susceptibility polymorphisms studied in the NKX2-3, ATG16L1, and IRGM genes. (PMID:19683022)
• Atg16L1 T300A is differentially involved in Crohn disease and canonical autophagy (PMID:19783656)
• Results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1. (PMID:19898471)
• Logistic regression analysis of pairwise interaction of the inflammatory bowel disease (IBD) loci indicated that IL23R, ATG16L1, and CARD15 contribute independently to disease risk. (PMID:20066736)
• The ATG16L1 T300A polymorphism contributes to susceptibility to Crohn’s disease and ulcerative colitis in adults. (PMID:20222171)
• the frequency of G allele of the rs2241880 ATG16L1 polymorphism was increased in both paediatric and adult Crohn’s disease patients compared to controls (PMID:20380008)
• The association of the ATG16L1 variant and IRGM variants with Crohn’s disease was confirmed. No evidence for gene-gene interaction between ATG16L1 and IRGM and granuloma formation was found. (PMID:20395867)
• ATG16L1 is relevant to inflammatory bowel disease in the Asian population. (PMID:20485703)
• ATG16L1 and NOD2 are components of an autophagy-mediated antibacterial pathway that is altered in a cell- and function-specific manner by CD-associated mutations. (PMID:20637199)
• Data show in mammalian cells that the heavy chain of clathrin interacts with Atg16L1 and is involved in the formation of Atg16L1-positive early autophagosome precursors. (PMID:20639872)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	atg16l1	ENSDARG00000099430
mus_musculus	Atg16l1	ENSMUSG00000026289
rattus_norvegicus	Atg16l1	ENSRNOG00000017913
drosophila_melanogaster	Atg16	FBGN0039705
caenorhabditis_elegans		WBGENE00017178
caenorhabditis_elegans		WBGENE00019427

Paralogs (1): ATG16L2 (ENSG00000168010)

Protein

Protein identifiers

Autophagy-related protein 16-1 — Q676U5 (reviewed: Q676U5)

Alternative names: APG16-like 1

All UniProt accessions (7): Q676U5, C9J1B2, C9J8C6, C9JAY7, C9JK97, E7EVC7, F8WAF9

UniProt curated annotations — full annotation on UniProt →

Function. Plays an essential role in both canonical and non-canonical autophagy: interacts with ATG12-ATG5 to mediate the lipidation to ATG8 family proteins (MAP1LC3A, MAP1LC3B, MAP1LC3C, GABARAPL1, GABARAPL2 and GABARAP). Acts as a molecular hub, coordinating autophagy pathways via distinct domains that support either canonical or non-canonical signaling. During canonical autophagy, interacts with ATG12-ATG5 to mediate the conjugation of phosphatidylethanolamine (PE) to ATG8 proteins, to produce a membrane-bound activated form of ATG8. Thereby, controls the elongation of the nascent autophagosomal membrane. As part of the ATG8 conjugation system with ATG5 and ATG12, required for recruitment of LRRK2 to stressed lysosomes and induction of LRRK2 kinase activity in response to lysosomal stress. Also involved in non-canonical autophagy, a parallel pathway involving conjugation of ATG8 proteins to single membranes at endolysosomal compartments, probably by catalyzing conjugation of phosphatidylserine (PS) to ATG8. Non-canonical autophagy plays a key role in epithelial cells to limit lethal infection by influenza A (IAV) virus. Regulates mitochondrial antiviral signaling (MAVS)-dependent type I interferon (IFN-I) production. Negatively regulates NOD1- and NOD2-driven inflammatory cytokine response. Instead, promotes an autophagy-dependent antibacterial pathway together with NOD1 or NOD2. Plays a role in regulating morphology and function of Paneth cell.

Subunit / interactions. Homodimer. Homooligomer. Heterooligomer with ATG16L2. Interacts with WIPI1. Interacts with WIPI2. Interacts with RB1CC1; the interaction is required for ULK1 complex-dependent autophagy. Interacts 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. Part of the major complex composed of 8 sets of ATG12-ATG5 and ATG16L1 (800 kDa). Interacts with RAB33B (GTP- and GDP-bound forms); the complex consists of a tetramer where two RAB33B molecules bind independently one molecule of the ATG16L1 homodimer; the interaction promotes ATG12-ATG5-ATG16L1 complex recruitment to phagophores. Interacts (via WD repeats) with TMEM59; the interaction mediates unconventional autophagic activity of TMEM59. Interacts with TLR2. Interacts (via WD repeats) with MEFV. Interacts with PPP1CA; the interaction dephosphorylates ATG16L1 causing dissociation of ATG12-ATG5-ATG16L1 complex. Interacts (via N-terminal) with CLTC. Interacts with NOD1. Interacts with NOD2. Interacts with TUFM. Interacts with TRIM16. Interacts (via WD repeats) with SPATA33. Interacts with IRGM.

Subcellular location. Cytoplasm. Preautophagosomal structure membrane. Endosome membrane. Lysosome membrane.

Post-translational modifications. Proteolytic cleavage by activated CASP3 leads to degradation and may regulate autophagy upon cellular stress and apoptotic stimuli. Phosphorylation at Ser-139 promotes association with the ATG12-ATG5 conjugate to form the ATG12-ATG5-ATG16L1 complex.

Disease relevance. Inflammatory bowel disease 10 (IBD10) [MIM:611081] A chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology. It is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Domain organisation. The WD repeats are required for non-canonical autophagy but not for canonical autophagy. The WD repeats are required for the recruitment of LRRK2 to stressed lysosomes.

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 WD repeat ATG16 family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q676U5-1	1, APG16L beta	yes
Q676U5-2	2
Q676U5-3	3
Q676U5-4	4
Q676U5-5	5

RefSeq proteins (6): NP_001177195, NP_001177196, NP_001350671, NP_060444, NP_110430, NP_942593 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR013923	Autophagy-rel_prot_16_dom	Domain
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR020472	WD40_PAC1	Repeat
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR045160	ATG16	Family

Pfam: PF00400, PF08614

UniProt features (81 total): strand 29, mutagenesis site 16, repeat 7, turn 6, splice variant 5, helix 4, region of interest 3, modified residue 3, sequence conflict 3, sequence variant 2, chain 1, coiled-coil region 1, short sequence motif 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
7F69	X-RAY DIFFRACTION	1.5
5NUV	X-RAY DIFFRACTION	1.55
9J54	X-RAY DIFFRACTION	1.61
7XFR	X-RAY DIFFRACTION	1.76
9JF2	X-RAY DIFFRACTION	1.76
4NAW	X-RAY DIFFRACTION	2.19
4TQ0	X-RAY DIFFRACTION	2.7
4GDK	X-RAY DIFFRACTION	2.7
8ZQG	X-RAY DIFFRACTION	2.77
4GDL	X-RAY DIFFRACTION	2.88
5D7G	X-RAY DIFFRACTION	3
7W36	X-RAY DIFFRACTION	3
5NPV	X-RAY DIFFRACTION	3.1
5NPW	X-RAY DIFFRACTION	3.1
9H2Q	ELECTRON MICROSCOPY	3.8
5ZYX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q676U5-F1	84.15	0.70

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 (3): 139, 269, 287

Mutagenesis-validated functional residues (16):

Position	Phenotype
17	abolishes interaction with atg5.
21	abolishes interaction with atg5.
24	abolishes interaction with atg5.
32–36	in fii mutant; abolished binding to membranes and lipidation to atg8 family proteins.
36	reduces interaction with atg5.
139	abolishes phosphorylation. impairs interaction with atg12-atg5 complex.
206	decreased binding affinity by 36-fold with rab33b. decreased binding affinity by 254-fold with rab33b and colocalization
209	decreased binding affinity by 9-fold with rab33b. decreased binding affinity by 254-fold with rab33b and colocalization
226	impairs interaction with wipi2.
230	impairs interaction with wipi2.
299	prevents cleavage by activated casp3.
308–310	in vrv mutant; abolished binding to membranes and lipidation to atg8 family proteins.
467	abolished non-canonical autophagy without affecting canonical autophagy.
490	abolished non-canonical autophagy without affecting canonical autophagy. impaired conjugation of phosphatidylserine (ps)
540	impairs interaction with ppp1ca; when associated with a-542.
542	impairs interaction with ppp1ca; when associated with a-540.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

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

MSigDB gene sets: 258 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, GOBP_AXO_DENDRITIC_TRANSPORT, PAX4_01, GOBP_VACUOLE_ORGANIZATION, MODULE_255, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOCC_VACUOLAR_MEMBRANE, TGCACTT_MIR519C_MIR519B_MIR519A, ATACCTC_MIR202, MODULE_317, GOBP_XENOPHAGY, GOMF_GTPASE_BINDING, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_MACROAUTOPHAGY, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM

GO Biological Process (16): autophagosome assembly (GO:0000045), C-terminal protein lipidation (GO:0006501), positive regulation of autophagy (GO:0010508), protein transport (GO:0015031), macroautophagy (GO:0016236), microautophagy (GO:0016237), hippocampus development (GO:0021766), corpus callosum development (GO:0022038), protein localization to phagophore assembly site (GO:0034497), negative stranded viral RNA replication (GO:0039689), defense response to virus (GO:0051607), xenophagy (GO:0098792), axonal transport (GO:0098930), dendrite arborization (GO:0140059), negative regulation of dendrite extension (GO:1903860), autophagy (GO:0006914)

GO Molecular Function (5): ubiquitin-like protein transferase activity (GO:0019787), identical protein binding (GO:0042802), protein-membrane adaptor activity (GO:0043495), GTPase binding (GO:0051020), protein binding (GO:0005515)

GO Cellular Component (18): autophagosome membrane (GO:0000421), autophagosome (GO:0005776), cytosol (GO:0005829), axoneme (GO:0005930), axon (GO:0030424), phagophore assembly site membrane (GO:0034045), Atg12-Atg5-Atg16 complex (GO:0034274), endolysosome membrane (GO:0036020), sperm midpiece (GO:0097225), glutamatergic synapse (GO:0098978), vacuole-isolation membrane contact site (GO:0120095), cytoplasm (GO:0005737), lysosome (GO:0005764), lysosomal membrane (GO:0005765), endosome (GO:0005768), endosome membrane (GO:0010008), membrane (GO:0016020), synapse (GO:0045202)

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
cellular anatomical structure	5
autophagy	3
intracellular protein localization	2
autophagosome assembly	2
anatomical structure development	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
protein lipidation	1
C-terminal protein amino acid modification	1
positive regulation of catabolic process	1
regulation of autophagy	1
transport	1
establishment of protein localization	1
pallium development	1
limbic system development	1
telencephalon development	1
viral RNA genome replication	1
RNA-templated viral transcription	1
defense response	1
response to virus	1
macroautophagy	1
defense response to other organism	1
axo-dendritic transport	1
axon	1
dendrite morphogenesis	1
neuron projection arborization	1
negative regulation of cell growth	1
negative regulation of developmental growth	1
dendrite extension	1
regulation of dendrite extension	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
aminoacyltransferase activity	1

Protein interactions and networks

STRING

1806 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATG16L1	NOD2	Q9HC29	999
ATG16L1	ATG5	Q9H1Y0	999
ATG16L1	ATG12	O94817	999
ATG16L1	WIPI2	Q9Y4P8	994
ATG16L1	RAB33B	Q9H082	992
ATG16L1	ATG7	O95352	992
ATG16L1	NOD1	Q9Y239	991
ATG16L1	RB1CC1	Q8TDY2	989
ATG16L1	ATG3	Q9NT62	970
ATG16L1	SQSTM1	Q13501	968
ATG16L1	TUFM	P49411	962
ATG16L1	IRGM	A1A4Y4	960
ATG16L1	ATG10	Q9H0Y0	950
ATG16L1	NLRX1	Q86UT6	949
ATG16L1	RAB26	Q9ULW5	935

IntAct

105 interactions, top by confidence:

A	B	Type	Score
ATG101	ATG13	psi-mi:“MI:0914”(association)	0.950
ULK1	ATG13	psi-mi:“MI:0914”(association)	0.940
ATG13	ULK1	psi-mi:“MI:0914”(association)	0.940
ATG5	ATG16L1	psi-mi:“MI:0407”(direct interaction)	0.850
RB1CC1	ATG13	psi-mi:“MI:0914”(association)	0.820
RB1CC1	ATG16L1	psi-mi:“MI:0915”(physical association)	0.800
ATG5	ATG12	psi-mi:“MI:0914”(association)	0.800
ATG16L1	RB1CC1	psi-mi:“MI:0914”(association)	0.800
ATG16L1	RAB33B	psi-mi:“MI:0915”(physical association)	0.740
RAB33A	ATG16L1	psi-mi:“MI:0915”(physical association)	0.670
WIPI2	BNIP3L	psi-mi:“MI:0914”(association)	0.640
ATG16L1	ATG16L1	psi-mi:“MI:0915”(physical association)	0.560
TMEM59	ATG16L1	psi-mi:“MI:0915”(physical association)	0.540
ATG16L1	TMEM59	psi-mi:“MI:0915”(physical association)	0.540
TMEM59	ATG16L1	psi-mi:“MI:0407”(direct interaction)	0.540
ATG3	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.530
KXD1	HIP1	psi-mi:“MI:0914”(association)	0.530

BioGRID (1932): ATG16L1 (Affinity Capture-Western), RB1CC1 (Affinity Capture-Western), ATG16L1 (Affinity Capture-RNA), ATG16L1 (Affinity Capture-RNA), ATG16L1 (Co-fractionation), ATG16L1 (Co-purification), NOD1 (Affinity Capture-Western), NOD2 (Affinity Capture-Western), ATG16L1 (Affinity Capture-Western), ATG16L1 (Affinity Capture-Western), ATG16L1 (Reconstituted Complex), ATG16L1 (Reconstituted Complex), ATG16L1 (Co-crystal Structure), ATG16L1 (Affinity Capture-MS), ATG16L1 (Affinity Capture-MS)

ESM2 similar proteins: A2AWA9, A4IIX9, A5D7H2, A6QL63, O88506, P54198, P58405, P79987, Q13033, Q17QU5, Q3MHH0, Q3ZBE1, Q4R3J7, Q504Q3, Q5F3R7, Q5FW06, Q5I0B4, Q5R650, Q5R8I6, Q5RAN1, Q5T6F0, Q5ZMQ0, Q61666, Q676U5, Q6AY57, Q6DDF0, Q6GQW0, Q6IE70, Q6P9R2, Q6PA72, Q6TGU2, Q7ZWU5, Q803V5, Q80W47, Q863I2, Q8BGF7, Q8BGZ3, Q8BH44, Q8CBE3, Q8K0F1

Diamond homologs: A0AUS0, A1CJY4, A1D7I5, A2ZLU6, B0XAF3, B0XYC8, B8M0Q1, C6L7U1, D1FP53, D1FP57, D3ZUM2, E4NKF8, G1SJB4, G4MQX3, I3L5V6, O22193, O23225, O42248, O48700, O48847, O74653, O80742, O81902, P0C6E7, P38129, P63243, P63244, P63245, P63246, P63247, P68040, Q058P4, Q09715, Q0DR28, Q0IMG9, Q0WUF6, Q10FT0, Q10PI9, Q3E9F5, Q3E9F7

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
ATG16L1	up-regulates	CLTC	binding
ATG16L1	up-regulates	CLTCL1	binding
RAB33B	up-regulates	ATG16L1	binding
ATG16L1	“form complex”	ATG12/5/16L1	binding
NOD2	“up-regulates activity”	ATG16L1	binding
NOD1	“up-regulates activity”	ATG16L1	binding
WIPI1	“up-regulates quantity”	ATG16L1	binding
WIPI2	“up-regulates quantity”	ATG16L1	binding
ATG16L1	“down-regulates activity”	RIPK2	binding
hsa-miR-106a	“down-regulates quantity by destabilization”	ATG16L1	“post transcriptional regulation”
GAN	“down-regulates quantity”	ATG16L1	ubiquitination
TFE3	“up-regulates quantity by expression”	ATG16L1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 84 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	16	28.0×	6e-17
TBC/RABGAPs	6	23.6×	2e-05
Autophagy	10	22.5×	3e-09

GO biological processes:

GO term	Partners	Fold	FDR
piecemeal microautophagy of the nucleus	7	89.8×	8e-11
autophagosome assembly	20	61.6×	1e-28
mitophagy	13	56.6×	1e-17
autophagosome maturation	9	43.3×	7e-11
macroautophagy	7	23.1×	2e-06
positive regulation of autophagy	7	19.9×	4e-06
autophagy	9	13.6×	2e-06
epithelial cell differentiation	5	12.0×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	54
Likely benign	10
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2850 predictions. Top by Δscore:

Variant	Effect	Δscore
2:233251938:GCAGT:G	donor_gain	1.0000
2:233251941:GT:G	donor_gain	1.0000
2:233256191:A:G	donor_gain	1.0000
2:233256191:ATAAG:A	donor_loss	1.0000
2:233256193:AAGGT:A	donor_loss	1.0000
2:233256194:AGG:A	donor_loss	1.0000
2:233256195:GGTA:G	donor_loss	1.0000
2:233256196:G:GA	donor_loss	1.0000
2:233256197:T:A	donor_loss	1.0000
2:233263096:A:AG	acceptor_gain	1.0000
2:233263098:A:AG	acceptor_gain	1.0000
2:233263990:A:AG	acceptor_gain	1.0000
2:233263991:G:GG	acceptor_gain	1.0000
2:233263991:GTT:G	acceptor_gain	1.0000
2:233263991:GTTA:G	acceptor_gain	1.0000
2:233264061:GCAAA:G	donor_gain	1.0000
2:233264066:G:GG	donor_gain	1.0000
2:233265103:G:GT	donor_gain	1.0000
2:233270063:GAACA:G	donor_gain	1.0000
2:233270064:AACA:A	donor_gain	1.0000
2:233270065:ACA:A	donor_gain	1.0000
2:233270066:CA:C	donor_gain	1.0000
2:233270066:CAGTA:C	donor_loss	1.0000
2:233270067:AG:A	donor_loss	1.0000
2:233270068:G:GG	donor_gain	1.0000
2:233270068:GTA:G	donor_loss	1.0000
2:233270069:T:G	donor_loss	1.0000
2:233270072:G:GG	donor_gain	1.0000
2:233272960:TTCCA:T	acceptor_loss	1.0000
2:233272961:TCCA:T	acceptor_loss	1.0000

AlphaMissense

3978 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:233265106:G:C	A202P	1.000
2:233277626:C:A	A338D	1.000
2:233277632:G:A	G340E	1.000
2:233277650:T:A	V346D	1.000
2:233277658:T:A	W349R	1.000
2:233277658:T:C	W349R	1.000
2:233282698:C:A	A383E	1.000
2:233282709:G:C	D387H	1.000
2:233282710:A:T	D387V	1.000
2:233282718:A:C	S390R	1.000
2:233282720:C:A	S390R	1.000
2:233282720:C:G	S390R	1.000
2:233282722:G:C	R391P	1.000
2:233282727:T:A	W393R	1.000
2:233282727:T:C	W393R	1.000
2:233282728:G:C	W393S	1.000
2:233282729:G:C	W393C	1.000
2:233282729:G:T	W393C	1.000
2:233289861:T:C	L404P	1.000
2:233289866:G:A	G406R	1.000
2:233289866:G:C	G406R	1.000
2:233289867:G:A	G406E	1.000
2:233289871:C:A	H407Q	1.000
2:233289871:C:G	H407Q	1.000
2:233289891:C:A	A414D	1.000
2:233289921:T:A	V424D	1.000
2:233289926:G:A	G426R	1.000
2:233289926:G:C	G426R	1.000
2:233289927:G:A	G426E	1.000
2:233289929:A:C	S427R	1.000

dbSNP variants (sampled 300 via entrez): RS1000079513 (2:233289812 C>G), RS1000146200 (2:233296161 G>A), RS1000155515 (2:233284177 T>C), RS1000339386 (2:233271259 A>C), RS1000485704 (2:233281357 C>G,T), RS1000563098 (2:233288329 T>C), RS1000789760 (2:233279223 T>G), RS1000814412 (2:233275575 T>C), RS1000851482 (2:233258736 G>A), RS1000881910 (2:233276757 G>A,T), RS1000960293 (2:233273179 G>A), RS1000972223 (2:233260675 T>C), RS1001074202 (2:233253337 T>G), RS1001099583 (2:233275203 G>A), RS1001288511 (2:233258788 C>T)

Disease associations

OMIM: gene MIM:610767 | disease phenotypes: MIM:611081

GenCC curated gene-disease

Mondo (1): inflammatory bowel disease 10 (MONDO:0012610)

Orphanet (0):

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000023_4	Crohn’s disease	1.000000e-13
GCST000042_2	Crohn’s disease	5.000000e-14
GCST000207_28	Crohn’s disease	2.000000e-32
GCST000705_1	Crohn’s disease	3.000000e-06
GCST000879_62	Crohn’s disease	7.000000e-41
GCST001438_2	Crohn’s disease	1.000000e-12
GCST001652_6	Crohn’s disease	5.000000e-09
GCST001729_11	Crohn’s disease	4.000000e-70
GCST003097_7	Pediatric autoimmune diseases	8.000000e-11
GCST004131_31	Inflammatory bowel disease	3.000000e-28
GCST004132_8	Crohn’s disease	2.000000e-61
GCST005537_7	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	5.000000e-67
GCST008817_3	Bilirubin levels	5.000000e-37
GCST010048_1	Bilirubin levels	3.000000e-08
GCST010117_2	Bilirubin levels	5.000000e-08
GCST90011900_176	Serum alkaline phosphatase levels	3.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004570	bilirubin measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567021	Inflammatory Bowel Disease 10 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10210302	Efficacy	3	adalimumab	Crohn Disease

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10210302	ATG16L1	3	2.75	1	adalimumab
rs2241880	ATG16L1, SCARNA5		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	increases expression, increases reaction, decreases reaction, affects binding	3
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
sodium arsenite	increases expression, decreases reaction, increases phosphorylation, affects cotreatment, increases abundance	2
Doxorubicin	decreases expression, increases expression, decreases reaction	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	affects phosphorylation	1
sodium arsenate	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
coumarin	affects phosphorylation	1
galangin	affects cotreatment, decreases activity, increases expression, decreases reaction	1
beta-methylcholine	affects expression	1
polyhexamethyleneguanidine	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
trovafloxacin	affects cotreatment, increases expression	1
2-palmitoylglycerol	increases expression	1
abrine	increases expression	1
dorsomorphin	decreases reaction, increases phosphorylation	1
LY2109761	decreases reaction, increases expression	1
BML-275	decreases reaction, increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Acetylcysteine	decreases reaction, increases expression	1
Acrolein	decreases reaction, increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Diethylhexyl Phthalate	decreases methylation, increases abundance	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Melphalan	increases expression	1
Methotrexate	increases expression	1

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1A4	Abcam THP-1 ATG16L1 KO	Cancer cell line	Male
CVCL_B1KE	Abcam HeLa ATG16L1 KO 1	Cancer cell line	Female
CVCL_B1KF	Abcam HeLa ATG16L1 KO 2	Cancer cell line	Female
CVCL_B1KG	Abcam HeLa ATG16L1 KO 3	Cancer cell line	Female
CVCL_SD96	HAP1 ATG16L1 (-) 1	Cancer cell line	Male
CVCL_SD97	HAP1 ATG16L1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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