ATG16L2

Summary

ATG16L2 (autophagy related 16 like 2, HGNC:25464) is a protein-coding gene on chromosome 11q13.4, encoding Protein Atg16l2 (Q8NAA4). May play a role in regulating epithelial homeostasis in an ATG16L1-dependent manner.

Predicted to be involved in autophagosome assembly. Predicted to act upstream of or within negative stranded viral RNA replication. Located in nucleoplasm. Part of Atg12-Atg5-Atg16 complex.

Source: NCBI Gene 89849 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 152 total
• MANE Select transcript: NM_033388

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25464
Approved symbol	ATG16L2
Name	autophagy related 16 like 2
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	FLJ00012, WDR80, ATG16B
Ensembl gene	ENSG00000168010
Ensembl biotype	protein_coding
OMIM	618716
Entrez	89849

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 16 protein_coding, 7 retained_intron, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000321297, ENST00000435507, ENST00000439504, ENST00000451353, ENST00000534905, ENST00000535830, ENST00000536995, ENST00000537143, ENST00000537212, ENST00000537837, ENST00000538842, ENST00000538973, ENST00000540222, ENST00000540567, ENST00000541367, ENST00000541554, ENST00000541999, ENST00000542481, ENST00000542908, ENST00000544490, ENST00000545248, ENST00000867652, ENST00000867653, ENST00000914046, ENST00000914047, ENST00000949594, ENST00000949595, ENST00000949596, ENST00000949597

RefSeq mRNA: 2 — MANE Select: NM_033388 NM_001318766, NM_033388

CCDS: CCDS31634

Canonical transcript exons

ENST00000321297 — 18 exons

Exon	Start	End
ENSE00002313954	72814411	72814563
ENSE00003459281	72825302	72825407
ENSE00003474984	72826518	72826589
ENSE00003484984	72826173	72826243
ENSE00003485794	72821668	72821741
ENSE00003495750	72822848	72822961
ENSE00003505388	72824734	72824842
ENSE00003506243	72826703	72826823
ENSE00003541663	72828359	72828508
ENSE00003557387	72827188	72827293
ENSE00003567864	72817756	72817855
ENSE00003600756	72829303	72829635
ENSE00003603211	72828883	72828984
ENSE00003612014	72822478	72822543
ENSE00003631924	72822044	72822295
ENSE00003659874	72824060	72824122
ENSE00003660724	72828729	72828776
ENSE00003684626	72816728	72816827

Expression profiles

Bgee: expression breadth ubiquitous, 216 present calls, max score 99.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.3825 / max 372.9595, expressed in 1550 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115763	8.2225	1542
115762	0.1600	57

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.24	gold quality
spleen	UBERON:0002106	98.36	gold quality
monocyte	CL:0000576	98.24	gold quality
leukocyte	CL:0000738	97.87	gold quality
blood	UBERON:0000178	97.87	gold quality
lower esophagus mucosa	UBERON:0035834	97.40	gold quality
skin of abdomen	UBERON:0001416	97.11	gold quality
vermiform appendix	UBERON:0001154	97.02	gold quality
right lung	UBERON:0002167	96.64	gold quality
skin of leg	UBERON:0001511	96.26	gold quality
bone marrow cell	CL:0002092	96.01	gold quality
mucosa of transverse colon	UBERON:0004991	95.68	gold quality
right uterine tube	UBERON:0001302	95.66	gold quality
upper lobe of left lung	UBERON:0008952	95.45	gold quality
left uterine tube	UBERON:0001303	95.15	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.05	gold quality
right ovary	UBERON:0002118	95.01	gold quality
gall bladder	UBERON:0002110	94.88	gold quality
lymph node	UBERON:0000029	94.74	gold quality
apex of heart	UBERON:0002098	94.68	gold quality
left ovary	UBERON:0002119	94.62	gold quality
upper lobe of lung	UBERON:0008948	94.22	gold quality
endocervix	UBERON:0000458	94.17	gold quality
rectum	UBERON:0001052	94.13	gold quality
transverse colon	UBERON:0001157	94.02	gold quality
sural nerve	UBERON:0015488	94.02	gold quality
zone of skin	UBERON:0000014	93.95	gold quality
ectocervix	UBERON:0012249	93.85	gold quality
esophagus mucosa	UBERON:0002469	93.69	gold quality
right lobe of thyroid gland	UBERON:0001119	93.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

26 targeting ATG16L2, 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-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-887-5P	98.82	65.90	1347
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-605-5P	98.79	68.24	1161
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-30C-1-3P	97.80	66.36	1499
HSA-MIR-30C-2-3P	97.80	66.45	1499
HSA-MIR-6788-5P	97.80	66.41	1532
HSA-MIR-6793-3P	97.66	65.78	1084
HSA-MIR-4689	96.97	65.79	1209
HSA-MIR-3976	96.67	67.79	1187
HSA-MIR-6858-5P	96.05	64.59	1020
HSA-MIR-6888-5P	95.89	63.78	831

Literature-anchored findings (GeneRIF, showing 8)

• Three novel risk loci including ATG16L2 were discovered by genome-wide association study in the Korean Crohn’s disease population, of which two showed patterns of association in the International Inflammatory Bowel Disease Genetics Consortium dataset. (PMID:23850713)
• Atg16L2 may play an important role in autophagy of T cells and serve as a potential biomarker to predict clinical relapse of Multiple sclerosis (PMID:24406150)
• A novel SNP-systemic lupus erythematosus association was identified between FCHSD2 and P2RY2, peaking at rs11235667 on a 33-kb haplotype upstream of ATG16L2. (PMID:26663301)
• ATG16L2 is a susceptibility gene for Crohn’s disease in the Chinese population. The rs11235604 single nucleotide polymorphism is remarkably associated with downregulation of the expression of ATG16L2. (PMID:27611316)
• Patients with the ATG16L2 rs10898880 CC variant genotype had a better LRFS, PFS, and OS (adjusted hazard ratio = 0.59, 0.64, and 0.64; 95% confidence interval: 0.45-0.79, 0.48-0.84, and 0.48-0.86; p = 0.0004, 0.002, and 0.003, respectively), but a greater risk for development of severe RP (adjusted hazard ratio = 1.80, 95% confidence interval: 1.04-3.12, p = 0.037) than did patients with AA/AC genotypes. (PMID:29454863)
• Results found ATG16L2 rs10898880 was significantly associated with the occurrence of grade 3-4 oral mucositis and myelosuppression in nasopharyngeal carcinoma (NPC) patients treated with radiotherapy. (PMID:31692259)
• Identification of a novel differentially methylated region adjacent to ATG16L2 in lung cancer cells using methyl-CpG binding domain protein-enriched genome sequencing. (PMID:33113339)
• The role of ATG16L2 in autophagy and disease. (PMID:35239457)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000109384
mus_musculus	Atg16l2	ENSMUSG00000047767
rattus_norvegicus	Atg16l2	ENSRNOG00000019413
drosophila_melanogaster	Atg16	FBGN0039705
caenorhabditis_elegans		WBGENE00017178
caenorhabditis_elegans		WBGENE00019427

Paralogs (1): ATG16L1 (ENSG00000085978)

Protein

Protein identifiers

Protein Atg16l2 — Q8NAA4 (reviewed: Q8NAA4)

Alternative names: APG16-like 2, Autophagy-related protein 16-2, WD repeat-containing protein 80

All UniProt accessions (12): Q8NAA4, F5GWM4, F5GWZ9, F5H7B6, H0YF72, H0YFC3, H0YFG0, H0YFZ7, H0YG45, H0YG67, H0YGE3, H0YGJ8

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in regulating epithelial homeostasis in an ATG16L1-dependent manner.

Subunit / interactions. Homooligomer. Heterooligomer with ATG16L1. Interacts with ATG5. Self-oligomerizes to form a 800-kDa complex composed of ATG12-ATG5 and ATG16L2. Interacts with RAB33B.

Subcellular location. Cytoplasm. Cytosol.

Miscellaneous. Although ATG16L2 is structurally similar to ATG16L1 and is likewise able to form a complex with the autophagy proteins ATG5 and ATG12, overexpression and knockdown studies in mouse suggest that ATG16L2 is not essential for canonical autophagy.

Similarity. Belongs to the WD repeat ATG16 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NAA4-1	1	yes
Q8NAA4-2	2
Q8NAA4-3	3

RefSeq proteins (2): NP_001305695, NP_203746* (*=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 (19 total): repeat 7, sequence conflict 5, splice variant 2, chain 1, compositionally biased region 1, sequence variant 1, region of interest 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NAA4-F1	80.93	0.58

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy

MSigDB gene sets: 119 (showing top): GOBP_VACUOLE_ORGANIZATION, chr11q13, GOBP_MACROAUTOPHAGY, GOBP_VIRAL_GENOME_REPLICATION, GOBP_ORGANELLE_ASSEMBLY, GOBP_VIRAL_LIFE_CYCLE, WANG_CISPLATIN_RESPONSE_AND_XPC_DN, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GOBP_AUTOPHAGOSOME_ORGANIZATION, GOCC_AUTOPHAGOSOME, GOCC_TRANSFERASE_COMPLEX, SANSOM_APC_TARGETS, MARTENS_BOUND_BY_PML_RARA_FUSION, WANG_RESPONSE_TO_GSK3_INHIBITOR_SB216763_UP, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_A

GO Biological Process (4): autophagosome assembly (GO:0000045), protein transport (GO:0015031), macroautophagy (GO:0016236), negative stranded viral RNA replication (GO:0039689)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): nucleoplasm (GO:0005654), cytosol (GO:0005829), phagophore assembly site membrane (GO:0034045), Atg12-Atg5-Atg16 complex (GO:0034274), cytoplasm (GO:0005737)

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	3
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
transport	1
intracellular protein localization	1
establishment of protein localization	1
autophagosome assembly	1
autophagy	1
viral RNA genome replication	1
RNA-templated viral transcription	1
binding	1
nuclear lumen	1
phagophore assembly site	1
membrane	1
transferase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

894 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATG16L2	ATG5	Q9H1Y0	869
ATG16L2	ATG12	O94817	819
ATG16L2	ATG9B	Q674R7	715
ATG16L2	ATG7	O95352	689
ATG16L2	ATG10	Q9H0Y0	664
ATG16L2	ATG4A	Q8WYN0	664
ATG16L2	ATG4C	Q96DT6	661
ATG16L2	ATG3	Q9NT62	647
ATG16L2	ATG2B	Q96BY7	643
ATG16L2	ATG9A	Q7Z3C6	633
ATG16L2	ATG4D	Q86TL0	627
ATG16L2	ATG2A	Q2TAZ0	608
ATG16L2	RB1CC1	Q8TDY2	599
ATG16L2	FCHSD2	O94868	599
ATG16L2	ULK2	Q8IYT8	593

IntAct

11 interactions, top by confidence:

A	B	Type	Score
ATG5	ATG12	psi-mi:“MI:0914”(association)	0.800
ATG16L2	GABARAP	psi-mi:“MI:0407”(direct interaction)	0.440
MAP1LC3B	ATG16L2	psi-mi:“MI:0407”(direct interaction)	0.440
ATG16L2	IKBIP	psi-mi:“MI:0915”(physical association)	0.400
ATG16L2	TK1	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
ATG5	IGKV1-5	psi-mi:“MI:0914”(association)	0.350
ATG5	PLOD2	psi-mi:“MI:0914”(association)	0.350

BioGRID (21): ATG16L2 (Affinity Capture-MS), ATG16L2 (Affinity Capture-MS), ATG16L2 (Affinity Capture-MS), ATG16L2 (Reconstituted Complex), ATG16L2 (Reconstituted Complex), ATG16L2 (Two-hybrid), ATG16L2 (Two-hybrid), ATG16L2 (Affinity Capture-Western), ATG16L2 (Affinity Capture-Western), ATG16L1 (Affinity Capture-Western), ATG16L2 (Affinity Capture-Western), ATG16L2 (Co-fractionation), ATG5 (Reconstituted Complex), ATG16L2 (Proximity Label-MS), ATG16L2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8HX76, A0JP70, A4IG72, A7E3S5, A7Z052, D3ZW91, E9PY46, P57081, Q05B17, Q0P5H9, Q15061, Q32P44, Q3SZD4, Q3U821, Q499N3, Q4VBE8, Q5BK48, Q5F3K4, Q5RB07, Q5RBH8, Q5RD06, Q5XFW6, Q68EI0, Q6DFC6, Q6KAU8, Q6PFM9, Q6PGF3, Q6ZQL4, Q7ZVF0, Q7ZVR1, Q7ZY78, Q8BH57, Q8C5V5, Q8IWA0, Q8N0Z6, Q8NA23, Q8NAA4, Q8VC03, Q969R8, Q96KV7

Diamond homologs: A4R3M4, A7EKM8, C0S902, C7Z6H2, O14301, O45040, O94620, P0C1J0, P25635, P26308, P54198, P87314, Q0U1B1, Q13112, Q15269, Q2HJH6, Q4P4R3, Q55AR8, Q5GIS3, Q5I0B9, Q5R1S9, Q5RF51, Q5RFQ3, Q61666, Q6PE01, Q8BU03, Q8NAA4, Q96DI7, Q9FN19, Q9LFE2, A4IIX9, B7PY76, O13286, O22212, O74763, O94527, P62881, P62882, Q09855, Q19124

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	112
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

4037 predictions. Top by Δscore:

Variant	Effect	Δscore
11:72814559:GGCCT:G	donor_gain	1.0000
11:72814560:GCCT:G	donor_gain	1.0000
11:72814560:GCCTG:G	donor_gain	1.0000
11:72814564:G:GG	donor_gain	1.0000
11:72822301:G:GT	donor_gain	1.0000
11:72822326:A:T	donor_gain	1.0000
11:72822540:GCGA:G	donor_gain	1.0000
11:72822544:G:GG	donor_gain	1.0000
11:72824123:G:GG	donor_gain	1.0000
11:72825403:GGGAA:G	donor_gain	1.0000
11:72825404:GGAAG:G	donor_gain	1.0000
11:72825405:G:GT	donor_gain	1.0000
11:72825405:G:T	donor_gain	1.0000
11:72825408:G:GG	donor_gain	1.0000
11:72826161:T:TA	acceptor_gain	1.0000
11:72826162:G:A	acceptor_gain	1.0000
11:72826169:CCAGG:C	acceptor_loss	1.0000
11:72826170:CAGGT:C	acceptor_loss	1.0000
11:72826171:A:AG	acceptor_gain	1.0000
11:72826172:G:GG	acceptor_gain	1.0000
11:72826172:GGTC:G	acceptor_gain	1.0000
11:72826241:TCGG:T	donor_loss	1.0000
11:72826242:CGG:C	donor_loss	1.0000
11:72826243:GGT:G	donor_loss	1.0000
11:72826244:G:GA	donor_loss	1.0000
11:72826244:G:GG	donor_gain	1.0000
11:72826245:T:A	donor_loss	1.0000
11:72826249:G:GT	donor_gain	1.0000
11:72828355:TCA:T	acceptor_loss	1.0000
11:72828356:CA:C	acceptor_loss	1.0000

AlphaMissense

3992 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:72826802:T:A	W449R	0.999
11:72826802:T:C	W449R	0.999
11:72827253:A:C	S478R	0.999
11:72827255:T:A	S478R	0.999
11:72827255:T:G	S478R	0.999
11:72826804:G:C	W449C	0.998
11:72826804:G:T	W449C	0.998
11:72828436:T:C	L517P	0.997
11:72826736:G:C	A427P	0.996
11:72826778:A:C	S441R	0.996
11:72826780:C:A	S441R	0.996
11:72826780:C:G	S441R	0.996
11:72827278:G:C	R486P	0.996
11:72827283:T:A	W488R	0.996
11:72827283:T:C	W488R	0.996
11:72828441:A:C	S519R	0.996
11:72828443:C:A	S519R	0.996
11:72828443:C:G	S519R	0.996
11:72829352:A:C	S608R	0.996
11:72829354:C:A	S608R	0.996
11:72829354:C:G	S608R	0.996
11:72826803:G:C	W449S	0.995
11:72826740:C:A	A428D	0.994
11:72828935:T:A	W575R	0.994
11:72828935:T:C	W575R	0.994
11:72826745:T:C	F430L	0.993
11:72826747:C:A	F430L	0.993
11:72826747:C:G	F430L	0.993
11:72828409:T:C	L508P	0.993
11:72826563:T:A	W407R	0.992

dbSNP variants (sampled 300 via entrez): RS1000091446 (11:72839645 G>A), RS1000148970 (11:72843657 A>C), RS1000215235 (11:72844020 CAAAA>C,CAAA), RS1000486286 (11:72818897 C>T), RS1000698528 (11:72838160 C>T), RS1000782573 (11:72813110 C>T), RS1000818529 (11:72817644 C>A), RS1000856149 (11:72831750 C>T), RS1000886364 (11:72834289 A>C), RS1000908534 (11:72832013 G>C), RS1001013590 (11:72823017 G>A), RS1001092119 (11:72825848 A>G), RS1001103256 (11:72828270 G>A,T), RS1001309347 (11:72835076 G>C), RS1001379828 (11:72833989 C>T)

Disease associations

OMIM: gene MIM:618716 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001785_6	Crohn’s disease	4.000000e-07
GCST002094_8	Crohn’s disease	7.000000e-09
GCST003599_3	Systemic lupus erythematosus	7.000000e-11
GCST005990_35	Non-albumin protein levels	1.000000e-21

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, decreases expression, increases abundance, affects expression, increases expression	3
Benzo(a)pyrene	increases expression, increases methylation	3
Tobacco Smoke Pollution	decreases expression, decreases reaction, increases expression, increases reaction	3
Aflatoxin B1	affects expression, increases expression	3
Ozone	affects cotreatment, decreases expression, increases abundance, affects expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression	1
butyraldehyde	decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
trovafloxacin	decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Acetylcysteine	decreases reaction, increases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Methotrexate	increases expression	1
Quercetin	increases expression	1
Smoke	decreases expression	1
Testosterone	decreases expression	1
Tretinoin	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1KH	Abcam HeLa ATG16L2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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