Chilblain lupus 1

Summary

Chilblain lupus 1 (MONDO:0012500) is a disease caused by TREX1 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: TREX1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 539

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	chilblain lupus 1
Mondo ID	MONDO:0012500
OMIM	610448
UMLS	C0024145
MedGen	9822
GARD	0018493
Is cancer (heuristic)	no

Also known as: CHBL1 · chilblain lupus · chilblain lupus 1 · chilblain lupus caused by mutation in TREX1 · chilblain lupus type 1 · TREX1 chilblain lupus

Data availability: 539 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › autoimmune disorder of cardiovascular system › chilblain lupus › familial chilblain lupus › chilblain lupus 1

Related subtypes (1): chilblain lupus 2

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

539 retrieved; paginated sample, class counts are floors:

321 uncertain significance, 133 likely benign, 29 pathogenic, 25 conflicting classifications of pathogenicity, 17 pathogenic/likely pathogenic, 6 likely pathogenic, 5 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068732	NC_000003.11:g.(?48507870)(50340407_?)del	AMIGO3	Pathogenic	criteria provided, single submitter
1069131	NM_033629.6(TREX1):c.403C>T (p.Gln135Ter)	ATRIP	Pathogenic	criteria provided, single submitter
1069943	NM_033629.6(TREX1):c.123_125dup (p.Cys42Ter)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1216160	NM_033629.6(TREX1):c.144del (p.Thr49fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126386	NM_033629.6(TREX1):c.366_368dup (p.Ala123_His124insAla)	ATRIP	Pathogenic	criteria provided, single submitter
126389	NM_033629.6(TREX1):c.500del (p.Ser167fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126390	NM_033629.6(TREX1):c.58dup (p.Glu20fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299626	NM_033629.6(TREX1):c.137dup (p.Ser46fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, single submitter
1333993	NM_033629.6(TREX1):c.621_622del (p.Ile207fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1430592	NM_033629.6(TREX1):c.153_166del (p.Gln51fs)	ATRIP	Pathogenic	criteria provided, single submitter
1433355	NM_033629.6(TREX1):c.296_299dup (p.Phe100fs)	ATRIP	Pathogenic	criteria provided, single submitter
1455316	NM_033629.6(TREX1):c.5del (p.Gly2fs)	ATRIP	Pathogenic	criteria provided, single submitter
1690729	NM_033629.6(TREX1):c.150_151del (p.Gln51fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2127740	NM_033629.6(TREX1):c.18dup (p.Pro7fs)	ATRIP	Pathogenic	criteria provided, single submitter
225499	NM_033629.6(TREX1):c.294dup (p.Cys99fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
282766	NM_033629.6(TREX1):c.144dup (p.Thr49fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
282767	NM_033629.6(TREX1):c.152_153del (p.Gln51fs)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2930302	NM_033629.6(TREX1):c.226_233dup (p.Ser78fs)	ATRIP	Pathogenic	criteria provided, single submitter
2936844	NM_033629.6(TREX1):c.349C>T (p.Gln117Ter)	ATRIP	Pathogenic	criteria provided, single submitter
2936991	NM_033629.6(TREX1):c.522_523delinsTT (p.Arg174_Lys175delinsSerTer)	ATRIP	Pathogenic	criteria provided, single submitter
2942588	NM_033629.6(TREX1):c.205_206del (p.Leu69fs)	ATRIP	Pathogenic	criteria provided, single submitter
2942595	NM_033629.6(TREX1):c.371_381del (p.His124fs)	ATRIP	Pathogenic	criteria provided, single submitter
2944466	NM_033629.6(TREX1):c.76_80dup (p.Gln28fs)	ATRIP	Pathogenic	criteria provided, single submitter
2945896	NM_033629.6(TREX1):c.69dup (p.Pro25fs)	ATRIP	Pathogenic	criteria provided, single submitter
2947312	NM_033629.6(TREX1):c.565C>T (p.Gln189Ter)	ATRIP	Pathogenic	criteria provided, single submitter
2948275	NM_033629.6(TREX1):c.366_367del (p.Ala123fs)	ATRIP	Pathogenic	criteria provided, single submitter
2952190	NM_033629.6(TREX1):c.141_151del (p.Pro48fs)	ATRIP	Pathogenic	criteria provided, single submitter
4179	NM_033629.6(TREX1):c.341G>A (p.Arg114His)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4180	NM_033629.6(TREX1):c.490C>T (p.Arg164Ter)	ATRIP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4184	NM_033629.6(TREX1):c.598G>A (p.Asp200Asn)	ATRIP	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 5 · 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
TREX1	Strong	Autosomal dominant	chilblain lupus 1	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TREX1	Orphanet:247691	Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations
TREX1	Orphanet:481662	Familial Chilblain lupus
TREX1	Orphanet:51	Aicardi-Goutières syndrome
TREX1	Orphanet:536	Systemic lupus erythematosus
ATRIP	Orphanet:808	Seckel syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TREX1	HGNC:12269	ENSG00000213689	Q9NSU2	Three-prime repair exonuclease 1	gencc,clinvar
AMIGO3	HGNC:24075	ENSG00000176020	Q86WK7	Amphoterin-induced protein 3	clinvar
ATRIP	HGNC:33499	ENSG00000164053	Q8WXE1	ATR-interacting protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TREX1	Three-prime repair exonuclease 1	Major cellular 3’-to-5’ DNA exonuclease which digests single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with mismatched 3’ termini.
AMIGO3	Amphoterin-induced protein 3	May mediate heterophilic cell-cell interaction.
ATRIP	ATR-interacting protein	Required for checkpoint signaling after DNA damage.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Antibody/Immunoglobulin	1	9.7×	0.298
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TREX1	Enzyme (other)	yes	3.1.11.2	RNaseH-like_sf, Ribonucl_H, RNaseH_sf
AMIGO3	Antibody/Immunoglobulin	yes		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, Ig_sub2
ATRIP	Other/Unknown	no		ATRIP

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
leukocyte	1
olfactory segment of nasal mucosa	1
hindlimb stylopod muscle	1
primordial germ cell in gonad	1
stromal cell of endometrium	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TREX1	134	ubiquitous	yes	olfactory segment of nasal mucosa, granulocyte, leukocyte
AMIGO3	129	broad	yes	primordial germ cell in gonad, hindlimb stylopod muscle, stromal cell of endometrium
ATRIP	170	ubiquitous	yes	left testis, right testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATRIP	1,544
TREX1	1,214
AMIGO3	778

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TREX1	Q9NSU2	12
ATRIP	Q8WXE1	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AMIGO3	Q86WK7	73.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Enrichment computed across 3 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
Regulation by TREX1	1	5710.0×	0.005	TREX1
IRF3-mediated induction of type I IFN	1	407.9×	0.016	TREX1
Diseases of DNA Double-Strand Break Repair	1	407.9×	0.016	ATRIP
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	407.9×	0.016	ATRIP
Diseases of DNA repair	1	285.5×	0.016	ATRIP
Homologous DNA Pairing and Strand Exchange	1	190.3×	0.016	ATRIP
Homology Directed Repair	1	154.3×	0.016	ATRIP
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	154.3×	0.016	ATRIP
Impaired BRCA2 binding to RAD51	1	154.3×	0.016	ATRIP
Activation of ATR in response to replication stress	1	150.3×	0.016	ATRIP
HDR through Single Strand Annealing (SSA)	1	146.4×	0.016	ATRIP
Fanconi Anemia Pathway	1	139.3×	0.016	ATRIP
Presynaptic phase of homologous DNA pairing and strand exchange	1	135.9×	0.016	ATRIP
DNA Double-Strand Break Repair	1	124.1×	0.016	ATRIP
HDR through Homologous Recombination (HRR)	1	95.2×	0.020	ATRIP
G2/M Checkpoints	1	67.2×	0.024	ATRIP
Regulation of TP53 Activity	1	66.4×	0.024	ATRIP
G2/M DNA damage checkpoint	1	60.1×	0.024	ATRIP
Regulation of TP53 Activity through Phosphorylation	1	58.9×	0.024	ATRIP
Processing of DNA double-strand break ends	1	57.1×	0.024	ATRIP
DNA Repair	1	49.2×	0.027	ATRIP
Cell Cycle Checkpoints	1	44.3×	0.029	ATRIP
Transcriptional Regulation by TP53	1	31.0×	0.039	ATRIP
Cell Cycle	1	18.0×	0.064	ATRIP
RNA Polymerase II Transcription	1	11.3×	0.097	ATRIP
Gene expression (Transcription)	1	8.9×	0.117	ATRIP
Generic Transcription Pathway	1	7.5×	0.133	ATRIP
Disease	1	6.5×	0.147	ATRIP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
immune response in brain or nervous system	1	5617.3×	0.004	TREX1
immune complex formation	1	5617.3×	0.004	TREX1
activation of immune response	1	2808.7×	0.004	TREX1
DNA modification	1	2808.7×	0.004	TREX1
DNA synthesis involved in UV-damage excision repair	1	2808.7×	0.004	TREX1
retrotransposition	1	1872.4×	0.005	TREX1
atrial cardiac muscle tissue development	1	1404.3×	0.005	TREX1
T cell antigen processing and presentation	1	1123.5×	0.005	TREX1
lymphoid progenitor cell differentiation	1	936.2×	0.005	TREX1
regulation of cellular respiration	1	936.2×	0.005	TREX1
regulation of lipid biosynthetic process	1	936.2×	0.005	TREX1
regulation of lysosome organization	1	936.2×	0.005	TREX1
DNA repair	2	42.6×	0.005	TREX1, ATRIP
regulation of immunoglobulin production	1	802.5×	0.005	TREX1
heart process	1	702.2×	0.005	TREX1
regulation of fatty acid metabolic process	1	624.1×	0.005	TREX1
regulation of T cell activation	1	624.1×	0.005	TREX1
regulation of type I interferon production	1	561.7×	0.005	TREX1
regulation of tumor necrosis factor production	1	561.7×	0.005	TREX1
cellular response to hydroxyurea	1	468.1×	0.006	TREX1
regulation of glycolytic process	1	401.2×	0.006	TREX1
macrophage activation involved in immune response	1	374.5×	0.006	TREX1
DNA metabolic process	1	351.1×	0.006	TREX1
mitotic G1 DNA damage checkpoint signaling	1	351.1×	0.006	TREX1
regulation of protein complex stability	1	351.1×	0.006	TREX1
negative regulation of cGAS/STING signaling pathway	1	351.1×	0.006	TREX1
inflammatory response to antigenic stimulus	1	312.1×	0.006	TREX1
DNA catabolic process	1	312.1×	0.006	TREX1
apoptotic cell clearance	1	295.6×	0.006	TREX1
negative regulation of type I interferon-mediated signaling pathway	1	255.3×	0.007	TREX1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATRIP	3	3
TREX1	0	0
AMIGO3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CERALASERTIB	3	ATRIP
ELIMUSERTIB	1	ATRIP
M4344	1	ATRIP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ATRIP	31	Binding:31

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TREX1	3.1.11.2	exodeoxyribonuclease III

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
CERALASERTIB	3	ATRIP
ELIMUSERTIB	1	ATRIP
M4344	1	ATRIP

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	ATRIP
C	Druggable family + PDB, no drug	1	TREX1
D	Druggable family + AlphaFold only, no drug	1	AMIGO3
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TREX1	0	—
AMIGO3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.