DNASE1

Summary

DNASE1 (deoxyribonuclease 1, HGNC:2956) is a protein-coding gene on chromosome 16p13.3, encoding Deoxyribonuclease-1 (P24855). Serum endocuclease secreted into body fluids by a wide variety of exocrine and endocrine organs.

This gene encodes a member of the DNase family. This protein is stored in the zymogen granules of the nuclear envelope and functions by cleaving DNA in an endonucleolytic manner. At least six autosomal codominant alleles have been characterized, DNASE11 through DNASE16, and the sequence of DNASE1*2 represented in this record. Mutations in this gene have been associated with systemic lupus erythematosus (SLE), an autoimmune disease. A recombinant form of this protein is used to treat the one of the symptoms of cystic fibrosis by hydrolyzing the extracellular DNA in sputum and reducing its viscosity. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.

Source: NCBI Gene 1773 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal systemic lupus erythematosus type 16 (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 276 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 53
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005223

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2956
Approved symbol	DNASE1
Name	deoxyribonuclease 1
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000213918
Ensembl biotype	protein_coding
OMIM	125505
Entrez	1773

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 6 nonsense_mediated_decay, 5 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000246949, ENST00000407479, ENST00000570376, ENST00000570520, ENST00000570664, ENST00000570761, ENST00000570769, ENST00000570807, ENST00000571460, ENST00000572237, ENST00000573804, ENST00000575479, ENST00000576050, ENST00000576792

RefSeq mRNA: 6 — MANE Select: NM_005223 NM_001351825, NM_001387135, NM_001387139, NM_001387140, NM_001387141, NM_005223

CCDS: CCDS10507

Canonical transcript exons

ENST00000246949 — 9 exons

Exon	Start	End
ENSE00001639309	3655849	3655937
ENSE00002669650	3654691	3655044
ENSE00003470438	3656999	3657111
ENSE00003475620	3656102	3656185
ENSE00003499338	3657906	3658095
ENSE00003539505	3657720	3657816
ENSE00003546794	3655373	3655520
ENSE00003556940	3656638	3656753
ENSE00003612805	3657187	3657341

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 95.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.0615 / max 283.3187, expressed in 1473 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152434	2.4114	1183
152435	1.3298	712
152436	0.2693	143
152442	0.2193	33
152438	0.1686	100
152445	0.1183	24
152439	0.1080	8
207712	0.0993	46
152444	0.0936	28
152433	0.0894	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
duodenum	UBERON:0002114	95.17	gold quality
jejunal mucosa	UBERON:0000399	94.71	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.65	gold quality
tendon of biceps brachii	UBERON:0008188	92.55	gold quality
body of pancreas	UBERON:0001150	92.41	gold quality
small intestine	UBERON:0002108	92.04	gold quality
metanephros cortex	UBERON:0010533	90.84	gold quality
lower esophagus mucosa	UBERON:0035834	90.77	gold quality
buccal mucosa cell	CL:0002336	89.65	gold quality
ileal mucosa	UBERON:0000331	88.09	gold quality
adenohypophysis	UBERON:0002196	87.43	gold quality
body of stomach	UBERON:0001161	87.39	gold quality
pituitary gland	UBERON:0000007	86.65	gold quality
granulocyte	CL:0000094	86.47	gold quality
cortical plate	UBERON:0005343	86.42	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.40	gold quality
cerebellar hemisphere	UBERON:0002245	86.18	gold quality
cerebellar cortex	UBERON:0002129	85.99	gold quality
stomach	UBERON:0000945	85.87	gold quality
adult mammalian kidney	UBERON:0000082	85.69	gold quality
ventricular zone	UBERON:0003053	85.05	gold quality
right testis	UBERON:0004534	84.87	gold quality
left testis	UBERON:0004533	84.80	gold quality
cerebellum	UBERON:0002037	84.02	gold quality
pancreas	UBERON:0001264	83.69	gold quality
fundus of stomach	UBERON:0001160	83.61	gold quality
right uterine tube	UBERON:0001302	83.57	gold quality
jejunum	UBERON:0002115	83.42	gold quality
stromal cell of endometrium	CL:0002255	83.35	gold quality
testis	UBERON:0000473	82.58	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9906	yes	606.45
E-GEOD-125970	yes	74.65
E-CURD-135	no	988.07
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, ESRRG, HIF1A, KLF1, MYOD1, RUNX3, SMARCA1, SP3

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• results show that the chief cells of the stomach produce DNase I (PMID:12005024)
• Deficiencies in this gene may contribute to SLE; gene therapy might be possible (REVIEW) (PMID:12708782)
• The A/T mutation of the DNASE1 gene is absent in both Tunisian systemic lupus erythematosus and in controls. (PMID:14613299)
• The studies of immunological properties and the tissue-distribution patterns of DNase I indicated that the canine enzyme is more closely related to the human DNase I than to other mammalian DNases I (PMID:14688237)
• serum Dnase1 in cooperation with the plasminogen system guarantees a fast and effective breakdown of chromatin during necrosis by the combined cleavage of DNA as well as of DNA binding proteins (PMID:15188364)
• Results describe chromatin disposal during necrosis and the involvement of Deoxyribonuclease 1 in this process with respect to its possible role in the prevention of anti-nuclear auto-immunity. (PMID:16352456)
• human DNASE1 expression is regulated through the use of alternative promoter and alternative splicing (PMID:16771825)
• This study is the first to reveal an extremely high frequency of DNASE1*1 among African populations. Caucasians and Asians had a lower frequency of DNASE1*1 than the African groups. (PMID:17405189)
• Compared to other ethnic populations, Han Chinese had its own unique DNase I gene distribution characteristics (PMID:17588132)
• Han Chinese myocardial infarction (MI) patients, but deoxyribonuclease I gene polymorphisms are not associated with susceptibility to MI in Han Chinese (PMID:18311594)
• In patients with autoimmune thyroid disease (AITD), a novel mutation (1218G>A, exon 5) and multiple polymorphisms were identified in the DNASE1 gene. (PMID:19022625)
• DNASE1 polymorphism appears to affect the specific activity, heat sensitivity, and optimum pH of the DNase I enzyme. (PMID:19055475)
• human recombinant DNase I up-regulates cell surface Fas expression and induces increased susceptibility of T cells to Fas-mediated apoptosis (PMID:19181929)
• DNase1 (deoxyribonuclease I) activity was significantly lower in patients with Systemic lupus erythematosus than in controls. (PMID:19318394)
• Show no particular variant in exon2 sequence of DNASE1 gene among Tunisian patients affected with systemic lupus erythematosus, rheumatoid arthritis and Sjogren syndrome and healthy subjects. (PMID:19360410)
• deficiency is linked to systemic lupus erythematosus (PMID:19362700)
• Low DNase1 activity is associated to the active phase of type III or IV lupus erythromatosus nephropathy. (PMID:19844716)
• A significant association of HumDN1 Variable Number of Tandem Repeats polymorphism in DNASE1 gene with systemic lupus erythematosus, is reported. (PMID:19863681)
• The objectives of this study were to clarify genetic and biochemical aspects of 12 non-synonymous SNPs in the human gene (DNASE1), potentially giving rise to an alteration in the in vivo DNase I activity levels. (PMID:20417303)
• show that serum endonuclease DNase1 is essential for disassembly of neutrophil extracellular traps. (PMID:20439745)
• Reduction in renal Dnase1 expression and activity is limited to mice and SLE patients with signs of membranoproliferative nephritis, and may be a critical event in the development of severe forms of lupus nephritis. (PMID:20856893)
• Modified DNase1 can efficiently eliminate apoptosis-resistant cancer cells through apoptosis. (PMID:21233855)
• The genetic aspects of DNASE1 with regard to all the SNPs in wide-ranging ethnic groups could be first demonstrated. Further, there was no correlation of all the polymorphic SNPs other than nonsynonymous ones with serum DNase I activity levels. (PMID:21235399)
• In thymocyte-selected CD4 T cells (T-CD4 T cells) DNase I hypersensitive sites at the 3’-enhancer region of interleukin-4 play an essential role during the induction of IL-4 expression. (PMID:21282512)
• POU1F1 binds to multiple sites at deoxyribonuclease I hypersensitive site II. (PMID:22094313)
• silencing of renal DNaseI gene expression initiates a cascade of inflammatory signals including activation of Toll like receptors and Clec4e, leading to progression of both murine and human lupus nephritis (PMID:22479529)
• DNase I activity in systemic lupus erythematosus patients was lower than in healthy controls (PMID:23183758)
• The novel structure of rhDNase I presented herein reveals the precise location and coordination sphere of the Mg2+ ion bound at subsite IVb along with the orientation of key side chains in the active site. (PMID:23215638)
• a downregulation of the DNASE1 mRNA expression in patients with autoimmune thyroid disease. This might result in degrading less DNA from dying cells, thereby promoting the development of thyroid autoimmunity. (PMID:23225239)
• Early mesangial nephritis initiates a cascade of inflammatory signals that lead to up-regulation of Trap1 and a consequent down-regulation of renal DNaseI by transcriptional interference. (PMID:23273922)
• DNAse I Q222R polymorphism is a potential genetic risk factor for systemic lupus erythematosus in South Indian Tamils. In addition, the mutant allele confers a significant risk for lupus nephritis. (PMID:23963431)
• Single nucleotide polymorphisms in the DNASE1 is associated with autoimmune diseases. (PMID:24206041)
• Our results indicate that increased DNASE1 expression is common to both SLE and RA, while DNase1 reduction activity is specific to SLE. (PMID:24564745)
• In conclusion, elevated DNase I in diabetes may be related to pancreatic injury and could be one of the causes that induce diabetes. (PMID:24676545)
• Characterization of the nonsynonymous single-nucleotide polymorphism variants of human DNASE1. (PMID:24819173)
• HumDN1 polymorphisms were examined in blood of 11 worldwide populations by polymerase chain reaction. 15 genotypes were found leading to the conclusion that HumDN1 variable no. tandem repeats are ethnic group specific. (PMID:25771153)
• TNF-alpha amplifies DNaseI expression in renal tubular cells while IL-1beta promotes nuclear DNaseI translocation in inactive form in lupus nephritis. (PMID:26065428)
• Val66Met in the BDNF gene and two SNPs, Fokl and Apal, in the VDR gene may potentially be associated with DED. Additionally, the association between DED and Val66Met may vary by depression status. (PMID:26393465)
• in Iranians the 3/6 genotype frequency was significantly higher in systemic lupus erythematosus patients than in healthy controls which implies the possible role of this genotype in SLE susceptibility; the 3/4 and 4/6 genotype frequencies were remarkably high in the control group which indicated the protective role of these genotypes against the disease (PMID:26547219)
• DNase I activity was observed to be increased in type 2 diabetes, and high glucose combined with increased DNase I is suggested to aggravate beta-cell apoptosis. (PMID:27082840)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnase1	ENSDARG00000012539
mus_musculus	Dnase1	ENSMUSG00000005980
rattus_norvegicus	Dnase1	ENSRNOG00000006873

Paralogs (3): DNASE1L1 (ENSG00000013563), DNASE1L3 (ENSG00000163687), DNASE1L2 (ENSG00000167968)

Protein

Protein identifiers

Deoxyribonuclease-1 — P24855 (reviewed: P24855)

Alternative names: Deoxyribonuclease I

All UniProt accessions (8): I3L0Z9, I3L1N2, P24855, I3L298, I3L4B8, I3L4C7, I3L4U3, I3L530

UniProt curated annotations — full annotation on UniProt →

Function. Serum endocuclease secreted into body fluids by a wide variety of exocrine and endocrine organs. Expressed by non-hematopoietic tissues and preferentially cleaves protein-free DNA. Among other functions, seems to be involved in cell death by apoptosis. Binds specifically to G-actin and blocks actin polymerization. Together with DNASE1L3, 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. Secreted. Zymogen granule. Nucleus envelope.

Tissue specificity. Principally in tissues of the digestive system. Highest levels found in urine, but also relatively abundant in semen and saliva.

Disease relevance. Systemic lupus erythematosus (SLE) [MIM:152700] A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. 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. Disease susceptibility is associated with variants affecting the gene represented in this entry. Neutrophil extracellular traps (NETs) are impaired in patients suffering from SLE. NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation.

Cofactor. Divalent metal cations. Prefers Ca(2+) or Mg(2+).

Polymorphism. At least 6 alleles of DNASE1 are known: DNASE11 to DNASE16. The sequence shown is that of DNASE1*2.

Similarity. Belongs to the DNase I family.

Isoforms (2)

UniProt ID	Names	Canonical?
P24855-1	1	yes
P24855-2	2

RefSeq proteins (6): NP_001338754, NP_001374064, NP_001374068, NP_001374069, NP_001374070, NP_005214* (*=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

Enzyme classification (BRENDA):

• EC 3.1.21.1 — deoxyribonuclease I (BRENDA: 51 organisms, 111 substrates, 152 inhibitors, 10 Km, 10 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(PC)10	0.005	1
D(PA)10	0.0042	1
D(PAPCPTPAPCPAPGPTPCPTPAPCPA)	0.0053	1
D(PGPGPCPAPCPTPTPAPC)	0.0072	1
D(PT)10	0.0056	1
D(PTPAPGPAPAPGPAPTPCPAPAPA)	0.0037	1
(25R)-3BETA-HYDROXYCHOLEST-5-EN-27-OATE	—	0
LAMBDA PHAGE DNA	—	0

UniProt features (53 total): strand 13, sequence variant 11, helix 10, turn 4, splice variant 3, site 3, disulfide bond 2, active site 2, glycosylation site 2, signal peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4AWN	X-RAY DIFFRACTION	1.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P24855-F1	94.68	0.89

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 (5): 100; 156; 35 (involved in actin-binding); 87 (nitration by tetranitromethane destroys a ca(2+) binding site and inactivates enzyme); 89 (involved in actin-binding)

Disulfide bonds (2): 195–231, 123–126

Glycosylation sites (2): 40, 128

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 205 (showing top): GOMF_ENDONUCLEASE_ACTIVITY, GOBP_INFLAMMATORY_RESPONSE, GOCC_SECRETORY_GRANULE, GOMF_NUCLEASE_ACTIVITY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, TGACCTY_ERR1_Q2, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_DNA_CATABOLIC_PROCESS, GOBP_REGULATION_OF_ACUTE_INFLAMMATORY_RESPONSE, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, MODULE_118, GOBP_MYELOID_LEUKOCYTE_ACTIVATION, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_MYELOID_LEUKOCYTE_MEDIATED_IMMUNITY

GO Biological Process (5): neutrophil activation involved in immune response (GO:0002283), regulation of acute inflammatory response (GO:0002673), DNA catabolic process (GO:0006308), apoptotic process (GO:0006915), regulation of neutrophil mediated cytotoxicity (GO:0070948)

GO Molecular Function (9): DNA binding (GO:0003677), actin binding (GO:0003779), deoxyribonuclease I activity (GO:0004530), catalytic activity (GO:0003824), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), DNA nuclease activity (GO:0004536), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (6): extracellular region (GO:0005576), nucleus (GO:0005634), nuclear envelope (GO:0005635), zymogen granule (GO:0042588), extracellular exosome (GO:0070062), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclease activity	2
myeloid cell activation involved in immune response	1
immune response	1
neutrophil activation	1
acute inflammatory response	1
regulation of inflammatory response	1
DNA nuclease activity	1
DNA metabolic process	1
nucleic acid catabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
regulation of leukocyte mediated cytotoxicity	1
regulation of myeloid leukocyte mediated immunity	1
neutrophil mediated cytotoxicity	1
nucleic acid binding	1
cytoskeletal protein binding	1
DNA endonuclease activity, producing 5’-phosphomonoesters	1
molecular_function	1
catalytic activity, acting on a nucleic acid	1
catalytic activity, acting on DNA	1
binding	1
catalytic activity	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1
nucleus	1
endomembrane system	1
organelle envelope	1
secretory granule	1
extracellular vesicle	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

1047 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNASE1	DNASE2	O00115	838
DNASE1	RNASE1	P07998	632
DNASE1	TRAP1	Q12931	615
DNASE1	KLF12	Q9Y4X4	547
DNASE1	GSN	P06396	503
DNASE1	ALB	P02768	485
DNASE1	FCGR2A	P12318	465
DNASE1	BANK1	Q8NDB2	465
DNASE1	FCGR2B	P31994	465
DNASE1	EMB	Q6PCB8	454
DNASE1	GAPDH	P00354	452
DNASE1	PFN4	Q8NHR9	450
DNASE1	PFN3	P60673	448
DNASE1	PTPRC	P08575	448
DNASE1	PFN1	P07737	447
DNASE1	CYB5D2	Q8WUJ1	447

IntAct

0 interactions, top by confidence:

BioGRID (4): DNASE1 (Affinity Capture-RNA), DNASE1 (Negative Genetic), DNASE1 (Affinity Capture-RNA), DNASE1 (Co-crystal Structure)

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

1 interactions.

A	Effect	B	Mechanism
RUNX3	“up-regulates quantity by expression”	DNASE1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	181
Likely benign	49
Benign	17

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2506422	NM_016292.3(TRAP1):c.1915C>T (p.Gln639Ter)	Pathogenic
3067943	NM_005223.4(DNASE1):c.91C>T (p.Gln31Ter)	Likely pathogenic

SpliceAI

3956 predictions. Top by Δscore:

Variant	Effect	Δscore
16:3643024:G:T	donor_gain	1.0000
16:3654956:A:G	acceptor_gain	1.0000
16:3655042:CAGGT:C	donor_loss	1.0000
16:3655043:AG:A	donor_loss	1.0000
16:3655044:GG:G	donor_loss	1.0000
16:3655045:GTGA:G	donor_loss	1.0000
16:3655353:T:TA	acceptor_gain	1.0000
16:3655355:T:TA	acceptor_gain	1.0000
16:3655360:T:TA	acceptor_gain	1.0000
16:3655362:T:TA	acceptor_gain	1.0000
16:3655370:CAGGA:C	acceptor_loss	1.0000
16:3655371:A:AG	acceptor_gain	1.0000
16:3655371:A:T	acceptor_loss	1.0000
16:3655371:AG:A	acceptor_gain	1.0000
16:3655371:AGGAT:A	acceptor_gain	1.0000
16:3655372:G:GG	acceptor_gain	1.0000
16:3655372:GG:G	acceptor_gain	1.0000
16:3655372:GGA:G	acceptor_gain	1.0000
16:3655372:GGAT:G	acceptor_gain	1.0000
16:3655372:GGATG:G	acceptor_gain	1.0000
16:3655518:CAGGT:C	donor_loss	1.0000
16:3655519:AGGT:A	donor_loss	1.0000
16:3655520:GGT:G	donor_loss	1.0000
16:3655521:G:A	donor_loss	1.0000
16:3655521:G:GG	donor_gain	1.0000
16:3655522:T:G	donor_loss	1.0000
16:3655938:G:GG	donor_gain	1.0000
16:3655963:G:GT	donor_gain	1.0000
16:3655964:A:T	donor_gain	1.0000
16:3656099:CAG:C	acceptor_loss	1.0000

AlphaMissense

1845 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:3655455:T:C	F28L	0.991
16:3655457:C:A	F28L	0.991
16:3655457:C:G	F28L	0.991
16:3655460:C:A	N29K	0.985
16:3655460:C:G	N29K	0.985
16:3656133:A:C	S90R	0.985
16:3656135:T:A	S90R	0.985
16:3656135:T:G	S90R	0.985
16:3657918:A:C	S272R	0.984
16:3657920:T:A	S272R	0.984
16:3657920:T:G	S272R	0.984
16:3655484:G:C	K37N	0.982
16:3655484:G:T	K37N	0.982
16:3657341:G:T	R235M	0.980
16:3657919:G:T	S272I	0.980
16:3657020:T:A	V153D	0.979
16:3657784:T:C	F257L	0.979
16:3657786:C:A	F257L	0.979
16:3657786:C:G	F257L	0.979
16:3657283:T:A	W216R	0.978
16:3657283:T:C	W216R	0.978
16:3656708:T:C	F131L	0.977
16:3656710:C:A	F131L	0.977
16:3656710:C:G	F131L	0.977
16:3657028:C:G	H156D	0.977
16:3655877:T:A	V59D	0.976
16:3657207:C:A	D190E	0.976
16:3657207:C:G	D190E	0.976
16:3656165:G:C	E100D	0.975
16:3656165:G:T	E100D	0.975

dbSNP variants (sampled 300 via entrez): RS1000014150 (16:3664791 G>A), RS1000061609 (16:3611076 G>C), RS1000066591 (16:3664919 T>C), RS1000073644 (16:3637712 G>A), RS1000103638 (16:3632812 C>T), RS1000131076 (16:3636788 C>G,T), RS1000182139 (16:3636945 G>A), RS1000240496 (16:3621122 G>C), RS1000307874 (16:3652058 C>A), RS1000372752 (16:3615224 C>G), RS1000383226 (16:3661254 T>C), RS1000407146 (16:3637466 C>G,T), RS1000462713 (16:3637951 G>A,T), RS1000471673 (16:3627265 A>G,T), RS1000529924 (16:3641848 G>A)

Disease associations

OMIM: gene MIM:125505 | disease phenotypes: MIM:152700, MIM:601744, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
systemic lupus erythematosus	Supportive	Unknown
autosomal systemic lupus erythematosus type 16	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
systemic lupus erythematosus	Limited	AD

Mondo (5): systemic lupus erythematosus (MONDO:0007915), congenital anomalies of kidney and urinary tract 1 (MONDO:0012561), HER2 positive breast carcinoma (MONDO:0006244), hereditary renal cell carcinoma (MONDO:0003008), autosomal systemic lupus erythematosus type 16 (MONDO:0013743)

Orphanet (1): Systemic lupus erythematosus (Orphanet:536)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000093	Proteinuria
HP:0000123	Nephritis
HP:0000155	Oral ulcer
HP:0000488	Retinopathy
HP:0000709	Psychosis
HP:0000716	Depression
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000992	Cutaneous photosensitivity
HP:0001250	Seizure
HP:0001369	Arthritis
HP:0001596	Alopecia
HP:0001701	Pericarditis
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001878	Hemolytic anemia
HP:0001882	Decreased total leukocyte count
HP:0001945	Fever
HP:0002039	Anorexia
HP:0002072	Chorea
HP:0002102	Pleuritis
HP:0002716	Lymphadenopathy
HP:0002725	Systemic lupus erythematosus
HP:0003453	Antineutrophil antibody positivity
HP:0003493	Antinuclear antibody positivity
HP:0003613	Antiphospholipid antibody positivity
HP:0005421	Decreased circulating complement C3 concentration
HP:0005764	Polyarticular arthritis
HP:0007417	Discoid lupus rash

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008129_82	Body mass index	5.000000e-10
GCST90002394_530	Monocyte percentage of white cells	3.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590
C536851	Familial renal cell carcinoma (supp.)
C563661	Renal Hypodysplasia, Nonsyndromic, 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3351219 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 111,449 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL64894	GENTIAN VIOLET	4	111,449

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 7 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.46	IC50	350	nM	GENTIAN VIOLET

PubChem BioAssay actives

1 with measured affinity, of 73 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
gentian violet	1184412: Inhibition of DNase 1 (unknown origin) using (FAM)-labeled dsDNA as substrate	ic50	0.3500	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, decreases expression	3
Methotrexate	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
afuresertib	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
CGP 52608	increases reaction, affects binding	1
pinostrobin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
trans-10,cis-12-conjugated linoleic acid	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Amiodarone	increases expression	1
Ascorbic Acid	affects cotreatment, decreases expression	1
Ethinyl Estradiol	affects expression	1
Formaldehyde	increases expression	1
Menthol	decreases expression	1
Nickel	decreases expression	1
Quercetin	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Tretinoin	increases expression	1
Urethane	decreases expression	1
Isotretinoin	increases expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	decreases expression	1
Genistein	affects expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3368168	Binding	Inhibition of DNase 1 (unknown origin) using (FAM)-labeled dsDNA as substrate	Deoxyribonuclease inhibitors. — Eur J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9DJ	Ubigene HEK293 DNASE1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120887	PHASE4	COMPLETED	Lupus Atherosclerosis Prevention Study
NCT00125307	PHASE4	COMPLETED	Tacrolimus for the Treatment of Systemic Lupus Erythematosus With Membranous Nephritis
NCT00188188	PHASE4	UNKNOWN	Study of Endothelial Dysfunction in Systemic Lupus and Its Role in Heart Disease
NCT00371501	PHASE4	COMPLETED	Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus
NCT00392093	PHASE4	COMPLETED	Effect of Hormone Replacement Therapy on Lupus Activity
NCT00413361	PHASE4	COMPLETED	The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00668330	PHASE4	COMPLETED	Steroid Induced Osteoporosis in Patients With Systemic Lupus Erythematosus
NCT00739050	PHASE4	TERMINATED	Effect of Simvastatin on Endothelial Function in Premenopausal Women With Systemic Lupus Erythematosus (0733-271)(TERMINATED)
NCT00815282	PHASE4	COMPLETED	Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
NCT00828178	PHASE4	COMPLETED	Efficacy of Fish Oil in Lupus Patients
NCT00866229	PHASE4	UNKNOWN	Efficacy and Adverse Effect of Simvastatin Compare to Rosuvastatin in Systemic Lupus Erythematosus (SLE) Patients With Corticosteroid Therapy and High Low-Density Lipoprotein (LDL) Cholesterol Level
NCT00911521	PHASE4	COMPLETED	Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled Study
NCT01101802	PHASE4	COMPLETED	Mycophenolate Mofetil in Systemic Lupus Erythematosus (MISSILE)
NCT01112215	PHASE4	COMPLETED	Enteric-coated Mycophenolate Sodium Versus Azathioprine for the Extra-renal Lupus Manifestations
NCT01151644	PHASE4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01276782	PHASE4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01322308	PHASE4	COMPLETED	Effect of Pioglitazone on Endothelial Function in Premenopausal Women With Uncomplicated Systemic Lupus Erythematosus
NCT01359826	PHASE4	WITHDRAWN	The Effect of Milnacipran on Fatigue and Quality of Life in Lupus Patients
NCT01597492	PHASE4	COMPLETED	A Study to Evaluate the Effect of Belimumab on Vaccine Responses in Subjects With Systemic Lupus Erythematosus (SLE)
NCT01632241	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
NCT01705977	PHASE4	COMPLETED	Belimumab Assessment of Safety in SLE
NCT01753401	PHASE4	COMPLETED	Acthar for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients With a History of Persistently Active Disease
NCT02270970	PHASE4	UNKNOWN	Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy
NCT02477150	PHASE4	COMPLETED	Safety and Immunogenicity of a Zoster Vaccine in SLE
NCT02741960	PHASE4	COMPLETED	The Effect of Metformin on Reducing Lupus Flares
NCT02779153	PHASE4	WITHDRAWN	Acthar SLE (Systemic Lupus Erythematosus)
NCT02953821	PHASE4	COMPLETED	Acthar Gel for Active Systemic Lupus Erythematosus (SLE)
NCT03042260	PHASE4	UNKNOWN	Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous
NCT03098823	PHASE4	COMPLETED	A Crossover Study to Compare RAYOS to IR Prednisone to Improve Fatigue and Morning Symptoms for SLE
NCT03122431	PHASE4	COMPLETED	Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
NCT03543839	PHASE4	RECRUITING	Trial of Belimumab in Early Lupus
NCT04447053	PHASE4	UNKNOWN	Sequential Belimumab and T-cell Based Therapy in SLE
NCT04515719	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in SLE Patients
NCT04893161	PHASE4	UNKNOWN	A Model About the Response of Belimumab in SLE
NCT04908865	PHASE4	COMPLETED	Open-label Study of Belimumab Plus Standard Therapy in Chinese Pediatric Participants With Active Systemic Lupus Erythematosus (SLE)
NCT04956484	PHASE4	COMPLETED	Belimumab In Early Systemic Lupus Erythematosus
NCT05559671	PHASE4	RECRUITING	Safety of the Herpes Zoster Subunit Vaccine in Lupus
NCT05666336	PHASE4	UNKNOWN	Multi-omics Studies on the Efficacy of Telitacicept in Chinese SLE Patients
NCT05748925	PHASE4	COMPLETED	Cardio Renal Effects of SGLT2 Inhibitors Among Lupus Nephritis Patients