DNASE1L3

Summary

DNASE1L3 (deoxyribonuclease 1L3, HGNC:2959) is a protein-coding gene on chromosome 3p14.3, encoding Deoxyribonuclease gamma (Q13609). Has DNA hydrolytic activity.

This gene encodes a member of the deoxyribonuclease I family. The encoded protein hydrolyzes DNA, is not inhibited by actin, and mediates the breakdown of DNA during apoptosis. Mutations in this gene are a cause of systemic lupus erythematosus-16. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 1776 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal systemic lupus erythematosus type 16 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 16
• Clinical variants (ClinVar): 294 total — 7 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 57
• Druggable target: yes
• MANE Select transcript: NM_004944

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2959
Approved symbol	DNASE1L3
Name	deoxyribonuclease 1L3
Location	3p14.3
Locus type	gene with protein product
Status	Approved
Aliases	DNAS1L3, LSD, D3
Ensembl gene	ENSG00000163687
Ensembl biotype	protein_coding
OMIM	602244
Entrez	1776

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 13 protein_coding, 1 retained_intron

ENST00000394549, ENST00000460422, ENST00000461914, ENST00000463694, ENST00000477209, ENST00000483681, ENST00000486455, ENST00000907338, ENST00000907339, ENST00000907340, ENST00000907341, ENST00000907342, ENST00000907343, ENST00000907344

RefSeq mRNA: 2 — MANE Select: NM_004944 NM_001256560, NM_004944

CCDS: CCDS2886, CCDS58836

Canonical transcript exons

ENST00000394549 — 8 exons

Exon	Start	End
ENSE00001077324	58208218	58208306
ENSE00001077325	58205471	58205560
ENSE00001077330	58200997	58201109
ENSE00001077332	58197821	58197978
ENSE00001180271	58193343	58193439
ENSE00001891414	58210766	58210972
ENSE00001950107	58192257	58192803
ENSE00002062994	58204769	58204881

Expression profiles

Bgee: expression breadth ubiquitous, 228 present calls, max score 97.35.

FANTOM5 (CAGE): breadth broad, TPM avg 2.9933 / max 734.9993, expressed in 198 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42676	1.8210	118
42674	0.2858	79
42675	0.2730	70
42684	0.2079	26
42682	0.1623	27
42679	0.0570	17
42677	0.0459	13
42683	0.0409	14
42678	0.0309	14
42681	0.0231	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
periodontal ligament	UBERON:0008266	97.35	gold quality
spleen	UBERON:0002106	97.13	gold quality
gingival epithelium	UBERON:0001949	97.01	gold quality
gingiva	UBERON:0001828	96.96	gold quality
trabecular bone tissue	UBERON:0002483	95.47	gold quality
liver	UBERON:0002107	95.20	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.90	gold quality
right lobe of liver	UBERON:0001114	92.63	gold quality
left adrenal gland cortex	UBERON:0035825	92.45	gold quality
right adrenal gland	UBERON:0001233	92.21	gold quality
right adrenal gland cortex	UBERON:0035827	92.13	gold quality
vermiform appendix	UBERON:0001154	92.03	gold quality
adrenal cortex	UBERON:0001235	91.93	gold quality
ileal mucosa	UBERON:0000331	91.68	gold quality
rectum	UBERON:0001052	91.57	gold quality
metanephros cortex	UBERON:0010533	91.55	gold quality
left adrenal gland	UBERON:0001234	91.41	gold quality
adrenal gland	UBERON:0002369	91.03	gold quality
palpebral conjunctiva	UBERON:0001812	90.76	gold quality
synovial joint	UBERON:0002217	90.53	gold quality
lymph node	UBERON:0000029	90.45	gold quality
colonic mucosa	UBERON:0000317	88.37	gold quality
epithelium of nasopharynx	UBERON:0001951	87.56	gold quality
adult mammalian kidney	UBERON:0000082	87.04	gold quality
tongue squamous epithelium	UBERON:0006919	87.02	gold quality
caecum	UBERON:0001153	86.23	gold quality
adenohypophysis	UBERON:0002196	85.66	gold quality
duodenum	UBERON:0002114	85.18	gold quality
jejunal mucosa	UBERON:0000399	85.13	gold quality
adrenal tissue	UBERON:0018303	84.58	gold quality

Single-cell (SCXA)

Detected in 21 experiment(s), a significant marker in 20.

Experiment	Marker?	Max mean expression
E-MTAB-8495	yes	11042.22
E-MTAB-10553	yes	9618.33
E-MTAB-7407	yes	5015.40
E-HCAD-9	yes	4449.88
E-MTAB-8221	yes	4323.19
E-GEOD-130473	yes	3036.52
E-CURD-98	yes	2736.23
E-CURD-79	yes	797.37
E-GEOD-135922	yes	38.02
E-HCAD-1	yes	27.46
E-MTAB-8142	yes	26.54
E-MTAB-6701	yes	25.56
E-HCAD-13	yes	21.83
E-CURD-46	yes	15.90
E-CURD-88	yes	12.06

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 35)

• The Poly(ADP-ribose) polymerase-1-regulated endonuclease DNAS1L3 is required for etoposide-induced internucleosomal DNA fragmentation and increases etoposide cytotoxicity in transfected osteosarcoma cells. (PMID:12154052)
• Identification of two functional nuclear localization signals in DNase gamma that have a role in apoptotic DNA fragmentation. (PMID:12943533)
• DNase gamma is involved in the generation of resected double-strand DNA breaks associated with somatic hypermutation (PMID:15629432)
• DNAS1L3 plays an active role in lymphoma cell sensitization to VP-16 and its deficiency may constitute a novel mechanism of drug resistance in these cells (PMID:16427601)
• A Caucasian-specific allele in SNP R206C produces an inactive form of DNase Il3. (PMID:19559017)
• Results distinguish DNase gamma-dependent and CAD/DFF40-dependent DNA fragmentations, and show that even if DNA fragmentation is initiated by CAD/DFF40, DNase gamma is required for the more complete digestion of the genomic DNA in dying cells. (PMID:19574717)
• investigates the distribution of DNASE1L3 gene SNPs in exons of the gene in eight Asian, three African, and three Caucasian populations worldwide using newly devised genotyping methods. (PMID:21692081)
• We identified a rare autosomal recessive form of systemic lupus erythematosus, in which autozygome analysis revealed a null mutation in the DNASE1L3 gene (PMID:22019780)
• These results suggest a cooperative activity between CAD and DNAS1L3 to accomplish internucleosomal DNA fragmentation . (PMID:23229555)
• DNASE1L3 mutations occur in hypocomplementemic urticarial vasculitis syndrome. (PMID:23666765)
• Single nucleotide polymorphisms in the DNASE1L3 is associated with autoimmune diseases. (PMID:24206041)
• Data indicate a likely functional variant influencing scleroderma susceptibility at deoxyribonuclease I-like 3 protein DNASE1L3 missense polymorphism rs35677470. (PMID:25332064)
• Single nucleotide polymorphisms producing a loss-of-function variant of the enzymes in DNASE1, DNASE1L3, and DNASE2, possibly serving as a genetic risk factor for autoimmune diseases, were confirmed. (PMID:27116004)
• The authors found a significant reduction in serum DNase1l3 level in dermatomyositis/polymyositis and systemic lupus erythematosus, which may associate with clinic features and disease activity. (PMID:28039554)
• Study of the copy number variations (CNVs) for DNASE1L3 and DNASE2 in Japanese and German populations found that only 2 diploid copy numbers for these DNASE CNVs was distributed in both populations; no copy loss or gain was evident for any of the autoimmune-related DNase genes. These human autoimmune-related DNase genes show low genetic diversity of CNVs resulting in alterations of the in vivo levels of DNase activity. (PMID:31022206)
• Serum Deoxyribonuclease 1-like 3 is a potential biomarker for diagnosis of ankylosing spondylitis. (PMID:31794766)
• Six gene and TH2 signature expression in endobronchial biopsies of participants with asthma. (PMID:31903716)
• Homeostatic Milieu Induces Production of Deoxyribonuclease 1-like 3 from Myeloid Cells. (PMID:32188756)
• Plasma DNA Profile Associated with DNASE1L3 Gene Mutations: Clinical Observations, Relationships to Nuclease Substrate Preference, and In Vivo Correction. (PMID:33022220)
• A deoxyribonuclease 1-like 3 genetic variant associates with asthma exacerbations. (PMID:33035569)
• Association of the DNASE1L3 rs35677470 polymorphism with systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis: Structural biological insights. (PMID:33173951)
• Arg206Cys substitution in DNASE1L3 causes a defect in DNASE1L3 protein secretion that confers risk of systemic lupus erythematosus. (PMID:33455918)
• DNase1L3 suppresses hepatocellular carcinoma growth via inhibiting complement autocrine effect. (PMID:33618518)
• DNASE1L3 arrests tumor angiogenesis by impairing the senescence-associated secretory phenotype in response to stress. (PMID:33744849)
• Autoantibody-mediated impairment of DNASE1L3 activity in sporadic systemic lupus erythematosus. (PMID:33783474)
• The Nexus of cfDNA and Nuclease Biology. (PMID:34006390)
• Deoxyribonuclease 1-like 3 may be a potential prognostic biomarker associated with immune infiltration in colon cancer. (PMID:34157681)
• DNASE1L3 deficiency, new phenotypes, and evidence for a transient type I IFN signaling. (PMID:35670985)
• DNASE1L3 inhibits proliferation, invasion and metastasis of hepatocellular carcinoma by interacting with beta-catenin to promote its ubiquitin degradation pathway. (PMID:35748106)
• DNASE1L3 inhibits hepatocellular carcinoma by delaying cell cycle progression through CDK2. (PMID:36327092)
• Reduced digestion of circulating genomic DNA in systemic sclerosis patients with the DNASE1L3 R206C variant. (PMID:36708011)
• Deoxyribonuclease 1-like 3 inhibits colorectal malignancy through antagonizing NEDD4-triggered CDKN1A ubiquitination. (PMID:38108119)
• [Decreased DNase1L3 secretion and associated antibodies induce impaired degradation of NETs in patients with sporadic SLE]. (PMID:38246176)
• Double-negative B cells and DNASE1L3 colocalise with microbiota in gut-associated lymphoid tissue. (PMID:38744839)
• A dual-acting DNASE1/DNASE1L3 biologic prevents autoimmunity and death in genetic and induced lupus models. (PMID:38888971)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dnase1l3	ENSMUSG00000025279
rattus_norvegicus	Dnase1l3	ENSRNOG00000009291

Paralogs (3): DNASE1L1 (ENSG00000013563), DNASE1L2 (ENSG00000167968), DNASE1 (ENSG00000213918)

Protein

Protein identifiers

Deoxyribonuclease gamma — Q13609 (reviewed: Q13609)

Alternative names: DNase I homolog protein DHP2, Deoxyribonuclease I-like 3, Liver and spleen DNase

All UniProt accessions (5): Q13609, A0A0A0MT68, C9J0L2, C9J9N0, H7C4R7

UniProt curated annotations — full annotation on UniProt →

Function. Has DNA hydrolytic activity. Is capable of both single- and double-stranded DNA cleavage, producing DNA fragments with 3’-OH ends. Can cleave chromatin to nucleosomal units and cleaves nucleosomal and liposome-coated DNA. Acts in internucleosomal DNA fragmentation (INDF) during apoptosis and necrosis. The role in apoptosis includes myogenic and neuronal differentiation, and BCR-mediated clonal deletion of self-reactive B cells. Is active on chromatin in apoptotic cell-derived membrane-coated microparticles and thus suppresses anti-DNA autoimmunity. Together with DNASE1, plays a key role in degrading neutrophil extracellular traps (NETs). NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation. Degradation of intravascular NETs by DNASE1 and DNASE1L3 is required to prevent formation of clots that obstruct blood vessels and cause organ damage following inflammation.

Subcellular location. Nucleus. Endoplasmic reticulum. Secreted.

Tissue specificity. Liver and spleen.

Post-translational modifications. Poly-ADP-ribosylated by PARP1. ADP-ribosylation negatively regulates enzymatic activity during apoptosis.

Disease relevance. Systemic lupus erythematosus 16 (SLEB16) [MIM:614420] A rare autosomal recessive form of systemic lupus erythematosus with childhood onset, characterized by high frequency of anti-neutrophil cytoplasmic antibodies and lupus nephritis. Systemic lupus erythematosus is a chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by zinc.

Similarity. Belongs to the DNase I family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13609-1	1	yes
Q13609-2	2

RefSeq proteins (2): NP_001243489, NP_004935* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005135	Endo/exonuclease/phosphatase	Domain
IPR016202	DNase_I	Family
IPR018057	Deoxyribonuclease-1_AS	Active_site
IPR033125	DNASE_I_2	Conserved_site
IPR036691	Endo/exonu/phosph_ase_sf	Homologous_superfamily

Pfam: PF03372

UniProt features (43 total): strand 15, helix 11, sequence variant 6, turn 2, short sequence motif 2, active site 2, signal peptide 1, chain 1, region of interest 1, disulfide bond 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7KIU	X-RAY DIFFRACTION	2.22

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13609-F1	92.08	0.82

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 (2): 100; 155

Disulfide bonds (1): 194–231

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 317 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GOMF_ENDONUCLEASE_ACTIVITY, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_INFLAMMATORY_RESPONSE, JAEGER_METASTASIS_DN, GOMF_NUCLEASE_ACTIVITY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_DNA_CATABOLIC_PROCESS, GOBP_REGULATION_OF_ACUTE_INFLAMMATORY_RESPONSE, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_MYELOID_LEUKOCYTE_ACTIVATION, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4

GO Biological Process (9): neutrophil activation involved in immune response (GO:0002283), regulation of acute inflammatory response (GO:0002673), DNA metabolic process (GO:0006259), apoptotic DNA fragmentation (GO:0006309), programmed cell death involved in cell development (GO:0010623), regulation of neutrophil mediated cytotoxicity (GO:0070948), DNA catabolic process (GO:0006308), apoptotic process (GO:0006915), programmed cell death (GO:0012501)

GO Molecular Function (10): DNA binding (GO:0003677), deoxyribonuclease I activity (GO:0004530), DNA nuclease activity (GO:0004536), calcium ion binding (GO:0005509), catalytic activity (GO:0003824), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), DNA endonuclease activity (GO:0004520), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): extracellular region (GO:0005576), nucleus (GO:0005634), endoplasmic reticulum (GO:0005783)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
programmed cell death	2
DNA nuclease activity	2
nuclease activity	2
intracellular membrane-bounded organelle	2
myeloid cell activation involved in immune response	1
immune response	1
neutrophil activation	1
acute inflammatory response	1
regulation of inflammatory response	1
nucleic acid metabolic process	1
DNA catabolic process	1
apoptotic nuclear changes	1
cell development	1
cellular developmental process	1
regulation of leukocyte mediated cytotoxicity	1
regulation of myeloid leukocyte mediated immunity	1
neutrophil mediated cytotoxicity	1
DNA metabolic process	1
nucleic acid catabolic process	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
signal transduction	1
cell death	1
nucleic acid binding	1
DNA endonuclease activity, producing 5’-phosphomonoesters	1
catalytic activity, acting on DNA	1
metal ion binding	1
molecular_function	1
catalytic activity, acting on a nucleic acid	1
endonuclease activity	1
binding	1
catalytic activity	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1

Protein interactions and networks

STRING

878 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNASE1L3	DNASE2	O00115	684
DNASE1L3	DFFB	O76075	604
DNASE1L3	PXK	Q7Z7A4	509
DNASE1L3	TREX1	Q9NSU2	500
DNASE1L3	RNASEH2A	O75792	446
DNASE1L3	RNASEH2C	Q8TDP1	423
DNASE1L3	CPA3	P15088	398
DNASE1L3	RNASEH2B	Q5TBB1	386
DNASE1L3	CPA4	Q9UI42	378
DNASE1L3	SAMHD1	Q9Y3Z3	377
DNASE1L3	ENDOG	Q14249	375
DNASE1L3	DFFA	O00273	350
DNASE1L3	IRF5	Q13568	339
DNASE1L3	CGAS	Q8N884	324
DNASE1L3	BANK1	Q8NDB2	323

IntAct

10 interactions, top by confidence:

A	B	Type	Score
KRTAP5-9	DNASE1L3	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	DNASE1L3	psi-mi:“MI:0915”(physical association)	0.560
DNASE1L3	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350
CD247	RSL1D1	psi-mi:“MI:0914”(association)	0.350
DNASE1L3	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.000
DNASE1L3	CYSRT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (3): CYSRT1 (Two-hybrid), KRTAP5-9 (Two-hybrid), HIST2H2BE (Proximity Label-MS)

ESM2 similar proteins: O18835, O18998, O42446, O55070, O77588, O77695, O89107, O97524, O97860, P00639, P04066, P08236, P11936, P11937, P12265, P13686, P21704, P22412, P24855, P49183, P49184, P70158, Q01459, Q01460, Q02809, Q13609, Q2QDE6, Q2QDE7, Q2QDE9, Q2QDF0, Q2QDF1, Q4AEE3, Q4FAT7, Q4FZV0, Q5R5N6, Q5R9N3, Q5RFI5, Q63321, Q641Z7, Q6AYS4

Diamond homologs: O18998, O42446, O55070, O89107, P00639, P11936, P11937, P21704, P24855, P49183, P49184, Q13609, Q2QDE6, Q2QDE7, Q2QDE9, Q2QDF0, Q2QDF1, Q4AEE3, Q767J3, Q92874, Q9D1G0, Q9D7J6, Q9YGI5, D3SGB1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	8
Uncertain significance	130
Likely benign	118
Benign	11

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1388626	NM_004944.4(DNASE1L3):c.495del (p.Ile165fs)	Pathogenic
2114624	NM_004944.4(DNASE1L3):c.596del (p.Lys199fs)	Pathogenic
2425243	NC_000003.11:g.(?58193925)(58194053_?)del	Pathogenic
30256	NM_004944.4(DNASE1L3):c.643del (p.Trp215fs)	Pathogenic
3247000	NC_000003.11:g.(?58183528)(58186856_?)del	Pathogenic
3248531	NM_004944.4(DNASE1L3):c.572A>G (p.Asn191Ser)	Pathogenic
4765688	NM_004944.4(DNASE1L3):c.97G>T (p.Glu33Ter)	Pathogenic
1339541	NM_004944.4(DNASE1L3):c.537G>A (p.Trp179Ter)	Likely pathogenic
1513774	NC_000003.11:g.(?58183528)(58194053_?)dup	Likely pathogenic
1516474	NM_004944.4(DNASE1L3):c.230+1G>A	Likely pathogenic
2086752	NM_004944.4(DNASE1L3):c.142-2A>G	Likely pathogenic
3022731	NM_004944.4(DNASE1L3):c.141+2T>C	Likely pathogenic
3589500	NM_004944.4(DNASE1L3):c.805del (p.Leu269fs)	Likely pathogenic
3720518	NM_004944.4(DNASE1L3):c.320+4_320+7del	Likely pathogenic
4771076	NM_004944.4(DNASE1L3):c.320+1G>C	Likely pathogenic

SpliceAI

990 predictions. Top by Δscore:

Variant	Effect	Δscore
3:58193337:CCTTA:C	donor_loss	1.0000
3:58193338:CTTAC:C	donor_loss	1.0000
3:58193339:TTA:T	donor_loss	1.0000
3:58193340:TAC:T	donor_loss	1.0000
3:58193341:A:AC	donor_gain	1.0000
3:58193341:A:C	donor_loss	1.0000
3:58193341:ACCT:A	donor_gain	1.0000
3:58193342:C:A	donor_loss	1.0000
3:58193342:C:CC	donor_gain	1.0000
3:58193342:CCT:C	donor_gain	1.0000
3:58193342:CCTC:C	donor_gain	1.0000
3:58193344:T:TA	donor_gain	1.0000
3:58193435:CAATC:C	acceptor_gain	1.0000
3:58193436:AATC:A	acceptor_gain	1.0000
3:58193437:ATC:A	acceptor_gain	1.0000
3:58193438:TC:T	acceptor_gain	1.0000
3:58193438:TCCTG:T	acceptor_loss	1.0000
3:58193439:CC:C	acceptor_gain	1.0000
3:58193440:C:CC	acceptor_gain	1.0000
3:58193441:T:A	acceptor_loss	1.0000
3:58193446:C:CT	acceptor_gain	1.0000
3:58193785:T:A	donor_gain	1.0000
3:58193786:C:A	donor_gain	1.0000
3:58197974:AAATT:A	acceptor_gain	1.0000
3:58197975:AATT:A	acceptor_gain	1.0000
3:58197977:TT:T	acceptor_gain	1.0000
3:58197979:C:CC	acceptor_gain	1.0000
3:58200991:CCTCA:C	donor_loss	1.0000
3:58200992:CTCA:C	donor_loss	1.0000
3:58200993:TCACC:T	donor_loss	1.0000

AlphaMissense

2044 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:58192789:G:C	S272R	0.995
3:58192789:G:T	S272R	0.995
3:58192791:T:G	S272R	0.995
3:58205521:G:C	S90R	0.995
3:58205521:G:T	S90R	0.995
3:58205523:T:G	S90R	0.995
3:58197882:A:G	W215R	0.993
3:58197882:A:T	W215R	0.993
3:58197958:G:C	D189E	0.993
3:58197958:G:T	D189E	0.993
3:58201080:G:C	H155D	0.993
3:58192783:G:C	H274Q	0.992
3:58192783:G:T	H274Q	0.992
3:58204786:A:G	F139S	0.992
3:58192785:G:C	H274D	0.991
3:58197824:T:A	D234V	0.991
3:58197959:T:A	D189V	0.991
3:58204806:C:A	R132S	0.991
3:58204806:C:G	R132S	0.991
3:58197962:C:A	G188V	0.990
3:58205491:T:A	E100D	0.990
3:58205491:T:G	E100D	0.990
3:58210826:G:C	N27K	0.990
3:58210826:G:T	N27K	0.990
3:58192790:C:A	S272I	0.989
3:58193439:C:A	R235S	0.989
3:58193439:C:G	R235S	0.989
3:58197824:T:G	D234A	0.989
3:58197963:C:G	G188R	0.989
3:58210829:G:C	F26L	0.989

dbSNP variants (sampled 300 via entrez): RS1000143294 (3:58212742 T>C), RS1000201321 (3:58207018 A>C,G), RS1000800489 (3:58203315 A>G), RS1000836694 (3:58198409 C>G,T), RS1000910015 (3:58198622 C>A,T), RS1001015664 (3:58192588 T>C), RS1001118223 (3:58211774 A>C), RS1001437277 (3:58211878 G>C), RS1001643333 (3:58212302 A>C), RS1001710985 (3:58206741 C>T), RS1001724530 (3:58200370 C>A), RS1001850381 (3:58207400 C>A), RS1001867194 (3:58212136 C>T), RS1002469323 (3:58194864 G>A), RS1002493472 (3:58204617 C>G)

Disease associations

OMIM: gene MIM:602244 | disease phenotypes: MIM:614420

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal systemic lupus erythematosus type 16	Strong	Autosomal recessive
hypocomplementemic urticarial vasculitis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autosomal systemic lupus erythematosus type 16	Definitive	AR

Mondo (2): autosomal systemic lupus erythematosus type 16 (MONDO:0013743), hypocomplementemic urticarial vasculitis (MONDO:0018227)

Orphanet (1): Autosomal systemic lupus erythematosus (Orphanet:300345)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000407	Sensorineural hearing impairment
HP:0000509	Conjunctivitis
HP:0000554	Uveitis
HP:0000763	Sensory neuropathy
HP:0000790	Hematuria
HP:0000988	Skin rash
HP:0000989	Pruritus
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001287	Meningitis
HP:0001315	Reduced tendon reflexes
HP:0001369	Arthritis
HP:0001373	Joint dislocation
HP:0001541	Ascites
HP:0001654	Abnormal heart valve morphology
HP:0001698	Pericardial effusion
HP:0001744	Splenomegaly
HP:0002014	Diarrhea
HP:0002017	Nausea and vomiting
HP:0002027	Abdominal pain
HP:0002091	Restrictive ventilatory defect
HP:0002094	Dyspnea
HP:0002097	Emphysema
HP:0002105	Hemoptysis
HP:0002202	Pleural effusion
HP:0002240	Hepatomegaly
HP:0002665	Lymphoma

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST001959_3	Eating disorders (purging via substances)	1.000000e-06
GCST002318_144	Rheumatoid arthritis	5.000000e-08
GCST004202_5	Systemic sclerosis	9.000000e-07
GCST005533_1	Limited cutaneous systemic scleroderma	1.000000e-20
GCST005534_1	Systemic sclerosis	3.000000e-16
GCST005534_8	Systemic sclerosis	4.000000e-31
GCST005568_17	Rheumatoid arthritis (ACPA-positive)	1.000000e-06
GCST005569_40	Rheumatoid arthritis	2.000000e-07
GCST006959_32	Rheumatoid arthritis	5.000000e-08
GCST007278_10	Systemic seropositive rheumatic diseases (Systemic sclerosis or systemic lupus erythematosus or rheumatoid arthritis or idiopathic inflammatory myopathies)	5.000000e-09
GCST008163_62	Height	5.000000e-06
GCST009131_6	Systemic sclerosis	1.000000e-10
GCST009873_34	Autoimmune traits (pleiotropy)	1.000000e-11
GCST009876_1	Systemic sclerosis	1.000000e-12
GCST009877_17	Rheumatoid arthritis	2.000000e-08
GCST010571_18	Autoimmune thyroid disease	9.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:1001017	limited scleroderma

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1649048 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 5 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.50	IC50	3200	nM	CHEMBL222509

PubChem BioAssay actives

2 with measured affinity, of 11 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid	1184413: Inhibition of DNase gamma (unknown origin) transfected in HeLa S3 cells	ic50	3.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
testosterone undecanoate	affects cotreatment, decreases expression	1
sodium arsenite	increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment, affects response to substance	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
monomethylarsonous acid	increases expression	1
Acetaminophen	increases response to substance	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Demecolcine	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Menthol	increases expression	1
Methyl Methanesulfonate	decreases expression	1
Nickel	increases expression	1
Oxygen	increases expression	1
Perfume	increases expression	1
Quercetin	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	increases methylation	1
Vincristine	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Levonorgestrel	affects cotreatment, decreases expression	1
Antirheumatic Agents	decreases expression	1
Copper Sulfate	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1646041	Binding	Inhibition of human recombinant DNase gamma expressed in Rosetta DE3 cells assessed as increase in acid soluble DNA after 30 mins	DR396, an apoptotic DNase γ inhibitor, attenuates high mobility group box 1 release from apoptotic cells. — Bioorg Med Chem

Clinical trials (associated diseases)

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