Autosomal systemic lupus erythematosus type 16

Summary

Autosomal systemic lupus erythematosus type 16 (MONDO:0013743) is a disease caused by DNASE1L3 (GenCC Strong), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DNASE1L3 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 73

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal systemic lupus erythematosus type 16
Mondo ID	MONDO:0013743
OMIM	614420
Orphanet	300345
UMLS	C3280742
MedGen	482372
GARD	0017368
Is cancer (heuristic)	no

Also known as: SLEB16 · systemic lupus erythematosus 16 · systemic lupus erythematosus related to DNASE1L3 · systemic lupus erythematosus type 16

Data availability: 73 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › connective tissue disorder › rheumatic disorder › lupus erythematosus › systemic lupus erythematosus › autosomal systemic lupus erythematosus type 16

Related subtypes (11): neonatal lupus erythematosus, pediatric systemic lupus erythematosus, central nervous system lupus, bullous systemic lupus erythematosus, systemic lupus erythematosus related to C4A, systemic lupus erythematosus 17, systemic lupus erythematosus related to C1QA, systemic lupus erythematosus related to C1S, systemic lupus erythematosus 18, systemic lupus erythematosus related to C1QC, systemic lupus erythematosus related to C1QB

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

73 retrieved; paginated sample, class counts are floors:

51 uncertain significance, 9 likely benign, 4 pathogenic/likely pathogenic, 3 benign/likely benign, 2 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1172533	NM_004944.4(DNASE1L3):c.290_291del (p.Thr97fs)	DNASE1L3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2053983	NM_004944.4(DNASE1L3):c.317del (p.Tyr106fs)	DNASE1L3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30256	NM_004944.4(DNASE1L3):c.643del (p.Trp215fs)	DNASE1L3	Pathogenic	criteria provided, multiple submitters, no conflicts
3248531	NM_004944.4(DNASE1L3):c.572A>G (p.Asn191Ser)	DNASE1L3	Pathogenic	criteria provided, single submitter
3589513	NM_004944.4(DNASE1L3):c.159_172del (p.Ile54fs)	DNASE1L3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
641317	NM_004944.4(DNASE1L3):c.441dup (p.Asp148fs)	DNASE1L3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339541	NM_004944.4(DNASE1L3):c.537G>A (p.Trp179Ter)	DNASE1L3	Likely pathogenic	criteria provided, single submitter
3589500	NM_004944.4(DNASE1L3):c.805del (p.Leu269fs)	DNASE1L3	Likely pathogenic	criteria provided, single submitter
1531626	NM_004944.4(DNASE1L3):c.230+15G>T	DNASE1L3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3589504	NM_004944.4(DNASE1L3):c.635G>A (p.Arg212Lys)	DNASE1L3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1005755	NM_004944.4(DNASE1L3):c.577G>A (p.Gly193Ser)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1172534	NM_004944.4(DNASE1L3):c.179T>G (p.Ile60Ser)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1302145	NM_004944.4(DNASE1L3):c.563G>C (p.Gly188Ala)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1355726	NM_004944.4(DNASE1L3):c.854G>A (p.Arg285Lys)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1355837	NM_004944.4(DNASE1L3):c.601G>A (p.Ala201Thr)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1363400	NM_004944.4(DNASE1L3):c.52G>A (p.Ala18Thr)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1367366	NM_004944.4(DNASE1L3):c.151C>T (p.Arg51Cys)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1378335	NM_004944.4(DNASE1L3):c.384T>A (p.Asp128Glu)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1379675	NM_004944.4(DNASE1L3):c.275G>A (p.Arg92Gln)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1380964	NM_004944.4(DNASE1L3):c.392C>A (p.Ser131Tyr)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1388385	NM_004944.4(DNASE1L3):c.730G>A (p.Val244Ile)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1400382	NM_004944.4(DNASE1L3):c.709G>C (p.Val237Leu)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1404334	NM_004944.4(DNASE1L3):c.448G>A (p.Val150Met)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1410671	NM_004944.4(DNASE1L3):c.115A>G (p.Lys39Glu)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1414287	NM_004944.4(DNASE1L3):c.97G>A (p.Glu33Lys)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1424051	NM_004944.4(DNASE1L3):c.437T>C (p.Val146Ala)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1426007	NM_004944.4(DNASE1L3):c.152G>A (p.Arg51His)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1429970	NM_004944.4(DNASE1L3):c.274C>T (p.Arg92Trp)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1430966	NM_004944.4(DNASE1L3):c.112G>A (p.Asp38Asn)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1437952	NM_004944.4(DNASE1L3):c.7C>T (p.Arg3Trp)	DNASE1L3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
DNASE1L3	Strong	Autosomal recessive	autosomal systemic lupus erythematosus type 16	5
C1R	Supportive	Autosomal dominant	autosomal systemic lupus erythematosus type 16	5
DNASE1	Supportive	Autosomal dominant	autosomal systemic lupus erythematosus type 16	4
PRKCD	Supportive	Autosomal dominant	autosomal systemic lupus erythematosus type 16	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNASE1L3	Orphanet:300345	Autosomal systemic lupus erythematosus
DNASE1L3	Orphanet:36412	Hypocomplementemic urticarial vasculitis
C1R	Orphanet:169147	Immunodeficiency due to a classical component pathway complement deficiency
C1R	Orphanet:300345	Autosomal systemic lupus erythematosus
C1R	Orphanet:75392	Periodontal Ehlers-Danlos syndrome
DNASE1	Orphanet:300345	Autosomal systemic lupus erythematosus
DNASE1	Orphanet:536	Systemic lupus erythematosus
PRKCD	Orphanet:664711	EBV-induced lymphoproliferative disease due to PRKCD deficiency

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DNASE1L3	HGNC:2959	ENSG00000163687	Q13609	Deoxyribonuclease gamma	gencc,clinvar
C1R	HGNC:1246	ENSG00000159403	P00736	Complement C1r subcomponent	gencc
DNASE1	HGNC:2956	ENSG00000213918	P24855	Deoxyribonuclease-1	gencc
PRKCD	HGNC:9399	ENSG00000163932	Q05655	Protein kinase C delta type	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNASE1L3	Deoxyribonuclease gamma	Has DNA hydrolytic activity.
C1R	Complement C1r subcomponent	Serine protease component of the complement C1 complex, a multiprotein complex that initiates the classical pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that st…
DNASE1	Deoxyribonuclease-1	Serum endocuclease secreted into body fluids by a wide variety of exocrine and endocrine organs.
PRKCD	Protein kinase C delta type	Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic protein during DNA damage-induced apoptosi…

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Phosphatase	2	42.0×	0.003
Protease	1	9.2×	0.137
Kinase	1	6.9×	0.137

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNASE1L3	Phosphatase	yes		Endo/exonuclease/phosphatase, DNase_I, Deoxyribonuclease-1_AS
C1R	Protease	yes	3.4.21.41	Sushi_SCR_CCP_dom, EGF, CUB_dom
DNASE1	Phosphatase	yes	3.1.21.1	Endo/exonuclease/phosphatase, DNase_I, Deoxyribonuclease-1_AS
PRKCD	Kinase	yes	2.7.11.13	C2_dom, Prot_kinase_dom, AGC-kinase_C

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingival epithelium	1
periodontal ligament	1
spleen	1
liver	1
right lobe of liver	1
right ovary	1
duodenum	1
jejunal mucosa	1
small intestine Peyer’s patch	1
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNASE1L3	228	broad	marker	periodontal ligament, spleen, gingival epithelium
C1R	134	ubiquitous	marker	right lobe of liver, liver, right ovary
DNASE1	226	ubiquitous	marker	duodenum, jejunal mucosa, small intestine Peyer’s patch
PRKCD	229	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKCD	3,286
C1R	2,153
DNASE1	1,051
DNASE1L3	891

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C1R	P00736	12
PRKCD	Q05655	2
DNASE1L3	Q13609	1
DNASE1	P24855	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 51. Enrichment computed across 4 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Classical antibody-mediated complement activation	1	951.7×	0.019	C1R
HuR (ELAVL1) binds and stabilizes mRNA	1	634.4×	0.019	PRKCD
Regulation of mRNA stability by proteins that bind AU-rich elements	1	380.7×	0.019	PRKCD
Initial triggering of complement	1	300.5×	0.019	C1R
VEGFR2 mediated cell proliferation	1	285.5×	0.019	PRKCD
Apoptotic cleavage of cellular proteins	1	237.9×	0.019	PRKCD
SHC1 events in ERBB2 signaling	1	237.9×	0.019	PRKCD
Apoptotic execution phase	1	237.9×	0.019	PRKCD
Effects of PIP2 hydrolysis	1	228.4×	0.019	PRKCD
Role of phospholipids in phagocytosis	1	228.4×	0.019	PRKCD
RHO GTPases Activate NADPH Oxidases	1	228.4×	0.019	PRKCD
Calmodulin induced events	1	190.3×	0.019	PRKCD
CaM pathway	1	190.3×	0.019	PRKCD
Ca-dependent events	1	184.2×	0.019	PRKCD
Signaling by ERBB2	1	173.0×	0.019	PRKCD
G-protein mediated events	1	163.1×	0.019	PRKCD
DAG and IP3 signaling	1	158.6×	0.019	PRKCD
Fcgamma receptor (FCGR) dependent phagocytosis	1	139.3×	0.019	PRKCD
Opioid Signalling	1	132.8×	0.019	PRKCD
PLC beta mediated events	1	132.8×	0.019	PRKCD
C-type lectin receptors (CLRs)	1	119.0×	0.019	PRKCD
G alpha (z) signalling events	1	116.5×	0.019	PRKCD
Regulation of Complement cascade	1	116.5×	0.019	C1R
Signaling by VEGF	1	109.8×	0.019	PRKCD
Apoptosis	1	84.0×	0.024	PRKCD
Programmed Cell Death	1	73.2×	0.025	PRKCD
CLEC7A (Dectin-1) signaling	1	71.4×	0.025	PRKCD
Cellular response to chemical stress	1	71.4×	0.025	PRKCD
VEGFA-VEGFR2 Pathway	1	69.6×	0.025	PRKCD
Interferon gamma signaling	1	62.8×	0.026	PRKCD

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of neutrophil mediated cytotoxicity	2	4213.0×	2e-06	DNASE1L3, DNASE1
regulation of acute inflammatory response	2	2106.5×	7e-06	DNASE1L3, DNASE1
neutrophil activation involved in immune response	2	936.2×	3e-05	DNASE1L3, DNASE1
positive regulation of phospholipid scramblase activity	1	4213.0×	0.003	PRKCD
positive regulation of glucosylceramide catabolic process	1	4213.0×	0.003	PRKCD
programmed cell death involved in cell development	1	2106.5×	0.004	DNASE1L3
positive regulation of sphingomyelin catabolic process	1	2106.5×	0.004	PRKCD
termination of signal transduction	1	1404.3×	0.004	PRKCD
regulation of ceramide biosynthetic process	1	1404.3×	0.004	PRKCD
protein kinase C signaling	1	1053.2×	0.005	PRKCD
negative regulation of filopodium assembly	1	842.6×	0.006	PRKCD
phospholipase C/protein kinase C signal transduction	1	702.2×	0.006	PRKCD
positive regulation of ceramide biosynthetic process	1	601.9×	0.007	PRKCD
cellular response to hydroperoxide	1	526.6×	0.007	PRKCD
negative regulation of glial cell apoptotic process	1	468.1×	0.008	PRKCD
negative regulation of platelet aggregation	1	351.1×	0.009	PRKCD
apoptotic DNA fragmentation	1	300.9×	0.010	DNASE1L3
DNA metabolic process	1	263.3×	0.010	DNASE1L3
neutrophil activation	1	247.8×	0.010	PRKCD
DNA catabolic process	1	234.1×	0.010	DNASE1
negative regulation of actin filament polymerization	1	234.1×	0.010	PRKCD
cellular response to angiotensin	1	234.1×	0.010	PRKCD
peptidyl-threonine phosphorylation	1	221.7×	0.010	PRKCD
positive regulation of superoxide anion generation	1	221.7×	0.010	PRKCD
intrinsic apoptotic signaling pathway in response to oxidative stress	1	210.7×	0.010	PRKCD
immunoglobulin mediated immune response	1	175.5×	0.011	PRKCD
Fc-gamma receptor signaling pathway involved in phagocytosis	1	175.5×	0.011	PRKCD
cellular response to fatty acid	1	175.5×	0.011	PRKCD
zymogen activation	1	168.5×	0.011	C1R
positive regulation of apoptotic signaling pathway	1	145.3×	0.012	PRKCD

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 1

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
DNASE1	GENTIAN VIOLET
PRKCD	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKCD	49	4
C1R	1	3
DNASE1	1	4
DNASE1L3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GENTIAN VIOLET	4	DNASE1
INGENOL MEBUTATE	4	PRKCD
MIDOSTAURIN	4	PRKCD
TAMOXIFEN	4	PRKCD
TOFACITINIB CITRATE	4	PRKCD
BARICITINIB	4	PRKCD
TOFACITINIB	4	PRKCD
CAPIVASERTIB	4	PRKCD
BOSUTINIB	4	PRKCD
ABEMACICLIB	4	PRKCD
NAFAMOSTAT	3	C1R
SURAMIN	3	PRKCD
FASUDIL	3	PRKCD
ALVOCIDIB	3	PRKCD
CURCUMIN	3	PRKCD
CRENOLANIB	3	PRKCD
ENZASTAURIN	3	PRKCD
RIPASUDIL	3	PRKCD
DOVITINIB	3	PRKCD
LESTAURTINIB	3	PRKCD
RUBOXISTAURIN	3	PRKCD
PHORBOL MYRISTATE ACETATE	2	PRKCD
EDELFOSINE	2	PRKCD
UPROSERTIB	2	PRKCD
UCN-01	2	PRKCD
DORAMAPIMOD	2	PRKCD
SAR-407899 FREE BASE	2	PRKCD
ZOTIRACICLIB	2	PRKCD
CENISERTIB	2	PRKCD
ILORASERTIB	2	PRKCD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PRKCD	804	Binding:790, Functional:14
C1R	29	Binding:29
DNASE1L3	5	Binding:5
DNASE1	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
C1R	3.4.21.41	complement subcomponent C1r
DNASE1	3.1.21.1	deoxyribonuclease I
PRKCD	2.7.11.13	protein kinase C

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PRKCD	804

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
GENTIAN VIOLET	4	DNASE1
INGENOL MEBUTATE	4	PRKCD
MIDOSTAURIN	4	PRKCD
TAMOXIFEN	4	PRKCD
TOFACITINIB CITRATE	4	PRKCD
BARICITINIB	4	PRKCD
TOFACITINIB	4	PRKCD
CAPIVASERTIB	4	PRKCD
BOSUTINIB	4	PRKCD
ABEMACICLIB	4	PRKCD
NAFAMOSTAT	3	C1R
SURAMIN	3	PRKCD
FASUDIL	3	PRKCD
ALVOCIDIB	3	PRKCD
CURCUMIN	3	PRKCD
CRENOLANIB	3	PRKCD
ENZASTAURIN	3	PRKCD
RIPASUDIL	3	PRKCD
DOVITINIB	3	PRKCD
LESTAURTINIB	3	PRKCD
RUBOXISTAURIN	3	PRKCD
PHORBOL MYRISTATE ACETATE	2	PRKCD
EDELFOSINE	2	PRKCD
UPROSERTIB	2	PRKCD
UCN-01	2	PRKCD
DORAMAPIMOD	2	PRKCD
SAR-407899 FREE BASE	2	PRKCD
ZOTIRACICLIB	2	PRKCD
CENISERTIB	2	PRKCD
ILORASERTIB	2	PRKCD

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	DNASE1, PRKCD
B	Phased (≥1) drug, not yet approved	1	C1R
C	Druggable family + PDB, no drug	1	DNASE1L3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DNASE1L3	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.