NEIL2

Summary

NEIL2 (nei like DNA glycosylase 2, HGNC:18956) is a protein-coding gene on chromosome 8p23.1, encoding Endonuclease 8-like 2 (Q969S2). Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents.

This gene encodes a member of the Fpg/Nei family of DNA glycosylases. These glycosylases initiate the first step in base excision repair by cleaving oxidatively damaged bases and introducing a DNA strand break via their abasic site lyase activity. This enzyme is primarily associated with DNA repair during transcription and acts prefentially on cytosine-derived lesions, particularly 5-hydroxyuracil and 5-hydroxycytosine. It contains an N-terminal catalytic domain, a hinge region, and a C-terminal DNA-binding domain with helix-two-turn-helix and zinc finger motifs. This enzyme interacts with the X-ray cross complementing factor 1 scaffold protein as part of a multi-protein DNA repair complex. A pseudogene of this gene has been identified.

Source: NCBI Gene 252969 — RefSeq curated summary.

At a glance

• GWAS associations: 22
• Clinical variants (ClinVar): 118 total — 3 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_145043

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18956
Approved symbol	NEIL2
Name	nei like DNA glycosylase 2
Location	8p23.1
Locus type	gene with protein product
Status	Approved
Aliases	NEH2, FLJ31644, MGC2832, MGC4505
Ensembl gene	ENSG00000154328
Ensembl biotype	protein_coding
OMIM	608933
Entrez	252969

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 11 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000284503, ENST00000403422, ENST00000436750, ENST00000455213, ENST00000524741, ENST00000528113, ENST00000528323, ENST00000892124, ENST00000892125, ENST00000941163, ENST00000941164, ENST00000941165, ENST00000941166

RefSeq mRNA: 8 — MANE Select: NM_145043 NM_001135746, NM_001135747, NM_001135748, NM_001349439, NM_001349440, NM_001349441, NM_001349442, NM_145043

CCDS: CCDS47802, CCDS47803, CCDS5984

Canonical transcript exons

ENST00000284503 — 5 exons

Exon	Start	End
ENSE00001086997	11769710	11770335
ENSE00001086998	11785963	11787345
ENSE00001086999	11771446	11771585
ENSE00003622377	11779598	11779950
ENSE00003681489	11783203	11783399

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 97.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.4756 / max 60.1991, expressed in 1714 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87417	7.4756	1714

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	97.26	gold quality
buccal mucosa cell	CL:0002336	96.54	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.92	gold quality
medial globus pallidus	UBERON:0002477	92.35	gold quality
right adrenal gland	UBERON:0001233	91.54	gold quality
right adrenal gland cortex	UBERON:0035827	91.06	gold quality
tendon of biceps brachii	UBERON:0008188	90.81	gold quality
hypothalamus	UBERON:0001898	90.80	gold quality
left adrenal gland	UBERON:0001234	90.79	gold quality
upper arm skin	UBERON:0004263	90.74	silver quality
globus pallidus	UBERON:0001875	90.52	gold quality
left adrenal gland cortex	UBERON:0035825	90.40	gold quality
adrenal cortex	UBERON:0001235	90.26	gold quality
cerebellar vermis	UBERON:0004720	90.07	gold quality
amygdala	UBERON:0001876	89.71	gold quality
testis	UBERON:0000473	89.49	gold quality
adrenal gland	UBERON:0002369	89.36	gold quality
anterior cingulate cortex	UBERON:0009835	89.31	gold quality
nucleus accumbens	UBERON:0001882	89.08	gold quality
right testis	UBERON:0004534	89.04	gold quality
left testis	UBERON:0004533	88.91	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.84	gold quality
substantia nigra	UBERON:0002038	88.69	gold quality
putamen	UBERON:0001874	88.51	gold quality
superior vestibular nucleus	UBERON:0007227	88.46	silver quality
midbrain	UBERON:0001891	88.43	gold quality
right frontal lobe	UBERON:0002810	88.16	gold quality
fallopian tube	UBERON:0003889	88.13	gold quality
adenohypophysis	UBERON:0002196	87.91	gold quality
apex of heart	UBERON:0002098	87.85	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	27.31
E-ANND-3	yes	3.75

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

84 targeting NEIL2, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
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-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 38)

• NEIL2 is involved in global genome repair mainly for removing oxidative products of cytosine. (PMID:12097317)
• NEIL1 and NEIL2 are preferentially involved in repair of lesions in DNA bubbles generated during transcription and/or replication (PMID:14522990)
• hNEIL2 recognized an apurinic/apyrimidinic site exclusively, and the activity for 5-hydroxyuracil and guanine-derived formamidopyrimidine was marginal (PMID:14734554)
• Reversible acetylation of Lys49 could thus regulate the repair activity of NEIL2 in vivo (PMID:15175427)
• the zinc finger motif in NEIL2 is essential for its structural integrity and enzyme activity (PMID:15339932)
• results show that the NEIL2-initiated repair of 5-hydroxyuracil (5-OHU) requires polynucleotide kinase (PNK) (PMID:16982218)
• A novel missense variant C367A and several other mutations were found in familial colorectal cancer DNA suggesting a limited role for this gene in the devlopment of CRC. (PMID:17029639)
• The damage specificity of human homologues of Endo III (hNTHl) and Endo VIII (hNEIL1 and hNEIL2) is compared to elucidate the repair role in cells. (PMID:17150535)
• YB-1 thus appears to have a novel regulatory role in NEIL2-mediated repair under oxidative stress. (PMID:17686777)
• NEIL2, but not NEIL1, polymorphisms may have a role in risk and progression of squamous cell carcinomas of the oral cavity and oropharynx (PMID:18594018)
• in vivo variability in NEIL2 expression in humans identifies SNPs in the NEIL2 promoter region that have functional effects. (PMID:18651651)
• the beta2/beta3 loop where Lys50 is located in NEIL2 is important for DNA binding, presumably lies next to a phosphate-binding site, and may represent a target for regulation of the enzyme activity. (PMID:20175991)
• the critical role of NEIL2 and PNKP in maintenance of the mammalian mitochondrial genome. (PMID:22130663)
• REG4, BIRC5 and NEIL2 genes might have a role in the sensitivity of cancer patients to radiotherapy (PMID:22199273)
• Results suggest that the decreased DNA repair capacity of the DNA glycosylase NEIL2 R257L variant can induce mutations that lead to lung cancer development. (PMID:22497777)
• CSB protein stimulates NEIL2 DNA glycosylase activity (PMID:24406253)
• data strongly suggest that decreased repair of oxidative DNA base lesions due to an impaired NEIL2 expression in non-smokers exposed to SSS would lead to accumulation of mutations in genomic DNA of lung cells over time (PMID:24595271)
• variant alleles in the NEIL2 (rs804270), APE1 (rs2275008), CYP2E1 (rs2031920) and MDM2 (rs2279744) SNPs may independently influence susceptibility to gastric cancer in a Northern Jiangsu Chinese population. (PMID:26373042)
• Studied six SNP loci: (rs2279115 of BCL2 gene, rs804270 of NEIL2 gene, rs909253 of LTA gene, rs2294008 of PSCA gene, rs3765524 and rs10509670 of PLCE1 gene) to evaluate gastric cancer risk using magnetic nanoparticles and universal tagged arrays. (PMID:26554163)
• The variability of potentially important functional polymorphic variants of the IFNG, IFNGR2 and NEIL2 genes was characterized in representatives of four ethnic groups living in the Siberian region. (PMID:26601495)
• NEIL1 and NEIL2 cooperate with TDG during base excision: TDG occupies the abasic site and is displaced by NEILs, which further process the baseless sugar, thereby stimulating TDG-substrate turnover. (PMID:26751644)
• Low NEIL2 expression is associated with neoplasms. (PMID:27004405)
• The abnormal expressions of NEIL1, NEIL2, and NEIL3 are involved in cancer through their association with the somatic mutation load. (PMID:27042257)
• Data indicate that DNA glycosylases MYH, UNG2, MPG, NTH1, NEIL1, 2 and 3 on nascent DNA. (PMID:28575236)
• Correlations between loss of expression of three genes: CETN2 (P < 0.001) and ERCC1 (P = 0.01) from the nucleotide excision repair (NER) and NEIL2 (P = 0.04) from the base excision repair (BER) pathways were associated with endocrine treatment resistance in discovery dataset, and subsequently validated in independent patient cohorts. (PMID:29793947)
• Single-nucleotide polymorphism in a microRNA binding site in NEIL2 3’UTR confers susceptibility to age-related cataracts. (PMID:31253066)
• Requirements for DNA bubble structure for efficient cleavage by helix-two-turn-helix DNA glycosylases. (PMID:31784740)
• Cervical carcinoma risk associate with genetic polymorphisms of NEIL2 gene in Chinese population and its significance as predictive biomarker. (PMID:32198476)
• Helicobacter pylori infection downregulates the DNA glycosylase NEIL2, resulting in increased genome damage and inflammation in gastric epithelial cells. (PMID:32518160)
• Unique Structural Features of Mammalian NEIL2 DNA Glycosylase Prime Its Activity for Diverse DNA Substrates and Environments. (PMID:32846144)
• NEIL1 and NEIL2 Are Recruited as Potential Backup for OGG1 upon OGG1 Depletion or Inhibition by TH5487. (PMID:33925271)
• Genetic variations in 3’UTRs of SMUG1 and NEIL2 genes modulate breast cancer risk, survival and therapy response. (PMID:34097065)
• Mendelian Randomization Analysis Identified Potential Genes Pleiotropically Associated with Polycystic Ovary Syndrome. (PMID:34704236)
• Dynamics and Conformational Changes in Human NEIL2 DNA Glycosylase Analyzed by Hydrogen/Deuterium Exchange Mass Spectrometry. (PMID:34757057)
• A Low-Activity Polymorphic Variant of Human NEIL2 DNA Glycosylase. (PMID:35216329)
• Functional roles and cancer variants of the bifunctional glycosylase NEIL2. (PMID:37310399)
• Structural and biochemical insights into NEIL2’s preference for abasic sites. (PMID:37971311)
• The DNA glycosylase NEIL2 is protective during SARS-CoV-2 infection. (PMID:38071370)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Neil2	ENSMUSG00000035121
rattus_norvegicus	Neil2	ENSRNOG00000010696

Paralogs (2): NEIL3 (ENSG00000109674), NEIL1 (ENSG00000140398)

Protein

Protein identifiers

Endonuclease 8-like 2 — Q969S2 (reviewed: Q969S2)

Alternative names: DNA glycosylase/AP lyase Neil2, DNA-(apurinic or apyrimidinic site) lyase Neil2, Endonuclease VIII-like 2, Nei homolog 2, Nei-like protein 2

All UniProt accessions (2): Q969S2, E9PPL4

UniProt curated annotations — full annotation on UniProt →

Function. Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Has DNA glycosylase activity towards 5-hydroxyuracil and other oxidized derivatives of cytosine with a preference for mismatched double-stranded DNA (DNA bubbles). Has low or no DNA glycosylase activity towards thymine glycol, 2-hydroxyadenine, hypoxanthine and 8-oxoguanine. Has AP (apurinic/apyrimidinic) lyase activity and introduces nicks in the DNA strand. Cleaves the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3’- and 5’-phosphates.

Subunit / interactions. Binds EP300.

Subcellular location. Nucleus.

Tissue specificity. Detected in testis, skeletal muscle, heart, brain, placenta, lung, pancreas, kidney and liver.

Activity regulation. Acetylation of Lys-50 leads to loss of DNA nicking activity. Acetylation of Lys-154 has no effect.

Domain organisation. The zinc-finger domain is important for DNA binding.

Similarity. Belongs to the FPG family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q969S2-1	1	yes
Q969S2-2	2
Q969S2-3	3
Q969S2-4	4

RefSeq proteins (8): NP_001129218, NP_001129219, NP_001129220, NP_001336368, NP_001336369, NP_001336370, NP_001336371, NP_659480* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000214	Znf_DNA_glyclase/AP_lyase	Domain
IPR010979	Ribosomal_uS13-like_H2TH	Homologous_superfamily
IPR012319	FPG_cat	Domain
IPR015886	H2TH_FPG	Domain

Pfam: PF06831

Enzyme classification (BRENDA):

• EC 3.2.2.23 — DNA-formamidopyrimidine glycosylase (BRENDA: 13 organisms, 186 substrates, 18 inhibitors, 108 Km, 87 kcat entries)

Substrate kinetics (BRENDA)

42 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
13MER OLIGONUCLEOTIDE DUPLEX CONTAINING 8-OXOGUA	—	10
8-OXO-7,8-DIHYDROGUANINE:CYT OLIGODEOXYNUCLEOTID	—	9
DNA CONTAINING 8-HYDROXYGUANINE RESIDUES	—	7
DNA CONTAINING 5,6-DIHYDROURACIL	0.0006–0.0096	6
DNA CONTAINING 8-OXO-GUANINE RESIDUES	0.001–0.44	6
23MER OLIGONUCLEOTIDE DUPLEX CONTAINING 8-OXOGUA	—	4
DNA	—	4
DNA CONTAINING 2,6-DIAMINO-4-HYDROXY-5-FORMAMIDO	0.0018–0.0049	4
DNA CONTAINING RING-OPENED N7-METHYLGUANINE RESI	—	4
DNA CONTAINING 7-HYDRO-8-OXOGUANINE RESIDUES	—	3
DNA CONTAINING 7-DEAZA-2’-DEOXYGUANOSINE	0.0001	2
DNA CONTAINING 7-METHYL-8-OXO-2’-DEOXYGUANOSINE	0.0001	2
DNA CONTAINING 8-OXO-GUANINE RESIDUES MISPAIRED	0.022–0.023	2
DNA CONTAINING 8-OXO-GUANINE RESIDUES MISPAIRED	0.0001–0.0051	2
DNA CONTAINING 8-OXO-GUANINE RESIDUES MISPAIRED	0.0002–0.0042	2

Catalyzed reactions (Rhea), 1 shown:

• 2’-deoxyribonucleotide-(2’-deoxyribose 5’-phosphate)-2’-deoxyribonucleotide-DNA = a 3’-end 2’-deoxyribonucleotide-(2,3-dehydro-2,3-deoxyribose 5’-phosphate)-DNA + a 5’-end 5’-phospho-2’-deoxyribonucleoside-DNA + H(+) (RHEA:66592)

UniProt features (29 total): mutagenesis site 7, sequence variant 5, active site 4, modified residue 3, splice variant 3, compositionally biased region 2, initiator methionine 1, chain 1, binding site 1, zinc finger region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q969S2-F1	81.95	0.68

Functional residue map

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

Catalytic / active sites (4): 2 (schiff-base intermediate with dna); 3 (proton donor); 50 (proton donor; for beta-elimination activity); 310 (proton donor; for delta-elimination activity)

Ligand- & substrate-binding residues (1): 231

Post-translational modifications (3): 50, 68, 154

Mutagenesis-validated functional residues (7):

Position	Phenotype
50	loss of glycosylase and ap lyase activity.
154	no effect on glycosylase and ap lyase activity.
291	loss of glycosylase and ap lyase activity.
295	loss of glycosylase and ap lyase activity.
310	strongly reduces strand ap lyase activity.
315	loss of glycosylase and ap lyase activity.
318	loss of glycosylase and ap lyase activity.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-110328	Recognition and association of DNA glycosylase with site containing an affected pyrimidine
R-HSA-110329	Cleavage of the damaged pyrimidine
R-HSA-5649702	APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway
R-HSA-73884	Base Excision Repair
R-HSA-73894	DNA Repair
R-HSA-73928	Depyrimidination
R-HSA-73929	Base-Excision Repair, AP Site Formation
R-HSA-73933	Resolution of Abasic Sites (AP sites)

MSigDB gene sets: 96 (showing top): GOMF_ENDONUCLEASE_ACTIVITY, GOMF_NUCLEASE_ACTIVITY, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, KAUFFMANN_DNA_REPAIR_GENES, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_PYRIMIDINE_CONTAINING_COMPOUND_CATABOLIC_PROCESS, GOBP_PYRIMIDINE_NUCLEOTIDE_METABOLIC_PROCESS, GOBP_DNA_MODIFICATION, GOBP_PYRIMIDINE_NUCLEOTIDE_CATABOLIC_PROCESS, GOBP_DNA_DAMAGE_RESPONSE, GOBP_PYRIMIDINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_CATABOLIC_PROCESS, GCM_SUFU

GO Biological Process (4): depyrimidination (GO:0045008), DNA repair (GO:0006281), base-excision repair (GO:0006284), DNA damage response (GO:0006974)

GO Molecular Function (15): damaged DNA binding (GO:0003684), microtubule binding (GO:0008017), zinc ion binding (GO:0008270), DNA N-glycosylase activity (GO:0019104), class I DNA-(apurinic or apyrimidinic site) endonuclease activity (GO:0140078), nucleic acid binding (GO:0003676), DNA binding (GO:0003677), catalytic activity (GO:0003824), DNA-(apurinic or apyrimidinic site) endonuclease activity (GO:0003906), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798), hydrolase activity, hydrolyzing N-glycosyl compounds (GO:0016799), lyase activity (GO:0016829), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitotic spindle (GO:0072686), microtubule cytoskeleton (GO:0015630)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Depyrimidination	2
Base Excision Repair	2
Resolution of Abasic Sites (AP sites)	1
DNA Repair	1
Base-Excision Repair, AP Site Formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
catalytic activity	2
cellular anatomical structure	2
base-excision repair, AP site formation	1
DNA modification	1
pyrimidine deoxyribonucleotide catabolic process	1
DNA metabolic process	1
DNA damage response	1
DNA repair	1
cellular response to stress	1
DNA binding	1
tubulin binding	1
transition metal ion binding	1
hydrolase activity, hydrolyzing N-glycosyl compounds	1
catalytic activity, acting on DNA	1
DNA-(apurinic or apyrimidinic site) endonuclease activity	1
carbon-oxygen lyase activity	1
nucleic acid binding	1
molecular_function	1
DNA endonuclease activity	1
hydrolase activity	1
hydrolase activity, acting on glycosyl bonds	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
spindle	1
cytoskeleton	1

Protein interactions and networks

STRING

670 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEIL2	KEAP1	Q14145	999
NEIL2	NEIL1	Q96FI4	989
NEIL2	XRCC1	P18887	988
NEIL2	NTHL1	P78549	982
NEIL2	OGG1	P78554	977
NEIL2	YBX1	P16990	814
NEIL2	PNKP	Q96T60	777
NEIL2	FEN1	P39748	752
NEIL2	CUL3	Q13618	732
NEIL2	MUTYH	Q9UIF7	719
NEIL2	APEX1	P27695	714
NEIL2	MPG	P29372	708
NEIL2	SMUG1	Q53HV7	704
NEIL2	UBE2K	P27924	693
NEIL2	BTRC	Q9Y297	671

IntAct

47 interactions, top by confidence:

A	B	Type	Score
NEIL2	TRIM27	psi-mi:“MI:0915”(physical association)	0.720
MEOX1	NEIL2	psi-mi:“MI:0915”(physical association)	0.720
NEIL2	MEOX1	psi-mi:“MI:0915”(physical association)	0.720
TRIM27	NEIL2	psi-mi:“MI:0915”(physical association)	0.720
REL	NEIL2	psi-mi:“MI:0915”(physical association)	0.560
NEIL2	REL	psi-mi:“MI:0915”(physical association)	0.560
CRX	NEIL2	psi-mi:“MI:0915”(physical association)	0.560
	NEIL2	psi-mi:“MI:0915”(physical association)	0.560
PAX5	NEIL2	psi-mi:“MI:0915”(physical association)	0.560
LCN2	NEIL2	psi-mi:“MI:0915”(physical association)	0.560
INCA1	NEIL2	psi-mi:“MI:0915”(physical association)	0.560
CDHR3	NEIL2	psi-mi:“MI:0915”(physical association)	0.560
KCTD17	CBX4	psi-mi:“MI:0914”(association)	0.530
NEIL2	ECE1	psi-mi:“MI:0915”(physical association)	0.370
ECE1	NEIL2	psi-mi:“MI:0915”(physical association)	0.370
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
DCAF4	IGLL5	psi-mi:“MI:0914”(association)	0.350
NPAS1	CIBAR1	psi-mi:“MI:0914”(association)	0.350
EEF1AKMT3	SMCHD1	psi-mi:“MI:0914”(association)	0.350
PLBD1	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
PSG11	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
CIAO2A		psi-mi:“MI:0914”(association)	0.350
NEIL2	CRX	psi-mi:“MI:0915”(physical association)	0.000
NEIL2	REL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (25): NEIL2 (Two-hybrid), NEIL2 (Two-hybrid), NEIL2 (Two-hybrid), EP300 (Affinity Capture-Western), NEIL2 (Affinity Capture-Western), NEIL2 (Biochemical Activity), NEIL2 (Affinity Capture-MS), NEIL2 (Affinity Capture-MS), NEIL2 (Two-hybrid), NEIL2 (Two-hybrid), NEIL2 (Two-hybrid), NEIL2 (Two-hybrid), REL (Two-hybrid), PAX5 (Two-hybrid), INCA1 (Two-hybrid)

ESM2 similar proteins: A6QP75, E1BDF2, E2RD63, P0C242, P22674, P29590, P30282, P41155, P48961, P49593, Q13505, Q14094, Q1LZ97, Q32NJ2, Q32NM1, Q3MHH5, Q3TAA7, Q4FZD7, Q52WX2, Q5F2F2, Q5SRT8, Q60I26, Q60I27, Q69Z89, Q6IN84, Q6UXT9, Q70EL4, Q86UR1, Q8BQX5, Q8BTM9, Q8BUM9, Q8N1F8, Q8N2A8, Q8N9H8, Q8TCX5, Q8TDF6, Q8WXI3, Q91ZT7, Q969S2, Q96DC7

Diamond homologs: A0LV85, A0PQ49, A0QJ66, A0QV21, A1KMR9, A1SLU7, A1T737, A1UED7, A3PXU1, A4J4X3, A4QFD9, A4TE57, A5D0T6, A5U6T0, A5UUN1, A6TFM6, A7NQM8, A8L594, A9B0X2, A9WDC2, B0C5D4, B0TER7, B2HJJ6, B5XTG8, B5XZD9, B8ZRZ2, C0Q1W8, C0ZXQ5, C1AG40, C3PLF5, L0T864, O34403, O69470, O80358, P19210, P55045, P64151, P64152, P64153, P9WNC2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NEIL2	up-regulates	Base-excision_repair

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	83
Likely benign	11
Benign	6

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
686056	GRCh37/hg19 8p23.1(chr8:8093065-11945856)x3	Pathogenic
815085	GRCh37/hg19 8p23.1(chr8:8093065-11881742)x3	Pathogenic
929827	GRCh37/hg19 8p23.1(chr8:7881478-11860845)x1	Pathogenic

SpliceAI

1221 predictions. Top by Δscore:

Variant	Effect	Δscore
8:11769788:GCCG:G	donor_gain	1.0000
8:11769789:CCGG:C	donor_loss	1.0000
8:11769791:GGTG:G	donor_loss	1.0000
8:11769792:G:C	donor_loss	1.0000
8:11769792:G:GG	donor_gain	1.0000
8:11769793:T:G	donor_loss	1.0000
8:11783201:AGGTT:A	acceptor_gain	1.0000
8:11783202:GGTTG:G	acceptor_gain	1.0000
8:11783394:GGC:G	donor_gain	1.0000
8:11783395:GC:G	donor_gain	1.0000
8:11769794:GAGT:G	donor_loss	0.9900
8:11779799:GATTC:G	donor_gain	0.9900
8:11779803:C:CG	donor_gain	0.9900
8:11779803:C:G	donor_gain	0.9900
8:11779843:G:GT	donor_gain	0.9900
8:11779843:G:T	donor_gain	0.9900
8:11783197:TCCCA:T	acceptor_loss	0.9900
8:11783198:CCCAG:C	acceptor_loss	0.9900
8:11783199:CCAGG:C	acceptor_loss	0.9900
8:11783200:CA:C	acceptor_loss	0.9900
8:11783201:A:AC	acceptor_loss	0.9900
8:11783202:GGTT:G	acceptor_gain	0.9900
8:11783261:TGGAG:T	acceptor_gain	0.9900
8:11783262:GGAGC:G	acceptor_gain	0.9900
8:11783396:C:G	donor_gain	0.9900
8:11783397:TAGG:T	donor_loss	0.9900
8:11783398:AGGTA:A	donor_loss	0.9900
8:11783400:GT:G	donor_loss	0.9900
8:11770504:GATT:G	donor_gain	0.9800
8:11781523:C:G	donor_gain	0.9800

AlphaMissense

2165 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:11785976:G:C	K234N	0.996
8:11785976:G:T	K234N	0.996
8:11783312:T:C	F201L	0.993
8:11783314:C:A	F201L	0.993
8:11783314:C:G	F201L	0.993
8:11786076:A:C	S268R	0.987
8:11786078:T:A	S268R	0.987
8:11786078:T:G	S268R	0.987
8:11785967:C:A	N231K	0.985
8:11785967:C:G	N231K	0.985
8:11783358:T:A	V216D	0.984
8:11785963:G:T	G230V	0.984
8:11785979:T:A	N235K	0.982
8:11785979:T:G	N235K	0.982
8:11779605:G:T	G49V	0.981
8:11779875:G:A	G139D	0.981
8:11783388:T:C	F226S	0.980
8:11785963:G:A	G230E	0.979
8:11779626:T:C	F56S	0.978
8:11779881:T:A	V141D	0.978
8:11785974:A:G	K234E	0.976
8:11783251:T:G	C180W	0.975
8:11785981:A:T	E236V	0.975
8:11783295:A:T	D195V	0.974
8:11779875:G:T	G139V	0.973
8:11783313:T:C	F201S	0.972
8:11783231:T:C	F174L	0.971
8:11783233:C:A	F174L	0.971
8:11783233:C:G	F174L	0.971
8:11786073:T:C	F267L	0.971

dbSNP variants (sampled 300 via entrez): RS1000086539 (8:11773968 C>G), RS1000266962 (8:11784479 C>T), RS1000429127 (8:11769687 G>A,T), RS1000485662 (8:11776486 G>C,T), RS1000599875 (8:11776636 A>G), RS1000690643 (8:11773115 C>G,T), RS1000737980 (8:11784707 TG>T), RS1000862526 (8:11769792 G>A,C), RS1000892260 (8:11769928 C>G), RS1001172866 (8:11770353 C>A,G,T), RS1001269153 (8:11783641 C>T), RS1001300297 (8:11783743 G>A,T), RS1001436082 (8:11770227 A>G), RS1001467680 (8:11775774 T>C), RS1001488394 (8:11780054 C>A,G,T)

Disease associations

OMIM: gene MIM:608933 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST001059_17	Neutrophil count	1.000000e-06
GCST002134_2	Alcohol dependence	2.000000e-06
GCST002135_4	Nicotine use	3.000000e-06
GCST005273_3	Polycystic ovary syndrome	8.000000e-10
GCST006148_5	Frontotemporal dementia with GRN mutation	1.000000e-06
GCST006154_2	Frontotemporal dementia	4.000000e-06
GCST007929_57	Medication use (calcium channel blockers)	6.000000e-09
GCST008074_117	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-12
GCST008074_152	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-10
GCST008083_114	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	5.000000e-12
GCST008083_161	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-13
GCST008087_100	Triglyceride levels in current drinkers	4.000000e-07
GCST008087_6	Triglyceride levels in current drinkers	7.000000e-06
GCST010132_11	Processed meat consumption	4.000000e-10
GCST010132_14	Processed meat consumption	2.000000e-15
GCST010132_15	Processed meat consumption	1.000000e-09
GCST010241_16	Apolipoprotein A1 levels	4.000000e-18
GCST010703_306	Brain morphology (MOSTest)	5.000000e-26
GCST011687_5	Systolic blood pressure	8.000000e-08
GCST012228_415	Waist-hip index	1.000000e-09
GCST012230_98	Waist-to-hip ratio adjusted for BMI	2.000000e-09
GCST012231_36	A body shape index	2.000000e-08

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count
EFO:0005430	nicotine use
EFO:0009930	Calcium channel blocker use measurement
EFO:0004530	triglyceride measurement
EFO:0004329	alcohol drinking
EFO:0008111	diet measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004346	neuroimaging measurement
EFO:0006335	systolic blood pressure
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5723575 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
mercuric bromide	decreases expression, affects cotreatment	2
Copper	affects binding, decreases activity, decreases expression	2
Estradiol	affects expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
o,p’-DDT	increases expression	1
afimoxifene	decreases reaction, increases expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
jinfukang	affects cotreatment, increases expression	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	decreases expression	1
NSC 689534	decreases expression, affects binding	1
Resveratrol	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	affects cotreatment, increases expression	1
Diethylstilbestrol	increases expression	1
Estrogens	increases expression, decreases reaction	1

ChEMBL screening assays

1 unique, capped per target: 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5665448	Functional	Inhibition of NEIL2 by quantifying inhibition of NEIL2-mediated cleavage and dissociation of quenched duplex DNA oligonucleotides, measured as fluorescence at 594 nm.	Enzyme Inhibitor Single Concentration assay results for EUbOPEN Chemogenomics Library

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2DJ	HAP1 NEIL2 (-) 3	Cancer cell line	Male
CVCL_E2DK	HAP1 NEIL2 (-) 4	Cancer cell line	Male
CVCL_TA26	HAP1 NEIL2 (-) 1	Cancer cell line	Male
CVCL_TA27	HAP1 NEIL2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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