Chilblain lupus 2

Summary

Chilblain lupus 2 (MONDO:0013739) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 74

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	chilblain lupus 2
Mondo ID	MONDO:0013739
OMIM	614415
UMLS	C3280721
MedGen	482351
GARD	0018494
Is cancer (heuristic)	no

Also known as: CHBL2 · chilblain lupus 2 · chilblain lupus caused by mutation in SAMHD1 · Chilblain lupus type 2 · SAMHD1 chilblain lupus

Data availability: 74 ClinVar variants · 1 GenCC gene-disease record.

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 2

Related subtypes (1): chilblain lupus 1

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

74 retrieved; paginated sample, class counts are floors:

21 conflicting classifications of pathogenicity, 20 uncertain significance, 13 pathogenic/likely pathogenic, 9 benign, 5 pathogenic, 3 benign/likely benign, 2 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076058	NM_015474.4(SAMHD1):c.68C>G (p.Ser23Ter)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126407	NM_015474.4(SAMHD1):c.1411-2A>G	SAMHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1453548	NM_015474.4(SAMHD1):c.703C>T (p.Gln235Ter)	SAMHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1500266	NM_015474.4(SAMHD1):c.626-1G>C	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1704574	NM_015474.4(SAMHD1):c.1436del (p.Glu479fs)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2857253	NM_015474.4(SAMHD1):c.944_945dup (p.Phe316fs)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30605	NM_015474.4(SAMHD1):c.602T>A (p.Ile201Asn)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3587211	NM_015474.4(SAMHD1):c.724G>T (p.Glu242Ter)	SAMHD1	Pathogenic	criteria provided, single submitter
3587213	NM_015474.4(SAMHD1):c.664_673del (p.Ile222fs)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4067	NM_015474.4(SAMHD1):c.433C>T (p.Arg145Ter)	SAMHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
4069	NM_015474.4(SAMHD1):c.490C>T (p.Arg164Ter)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4071	NM_015474.4(SAMHD1):c.1642C>T (p.Gln548Ter)	SAMHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
546088	NM_015474.4(SAMHD1):c.1343T>C (p.Ile448Thr)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
645045	NM_015474.4(SAMHD1):c.400C>T (p.Arg134Ter)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
659536	NM_015474.4(SAMHD1):c.658C>T (p.Arg220Ter)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
659887	NM_015474.4(SAMHD1):c.1476del (p.Lys492fs)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800933	NM_015474.4(SAMHD1):c.646_647del (p.Met216fs)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
861422	NM_015474.4(SAMHD1):c.580C>T (p.Arg194Ter)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3587210	NM_015474.4(SAMHD1):c.1615C>T (p.Gln539Ter)	SAMHD1	Likely pathogenic	criteria provided, single submitter
1341697	NM_015474.4(SAMHD1):c.676C>G (p.Arg226Gly)	SAMHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2201078	NM_015474.4(SAMHD1):c.1681_1682del (p.Ser561fs)	SAMHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338335	NM_015474.4(SAMHD1):c.*240G>A	SAMHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338336	NM_015474.4(SAMHD1):c.*95T>C	SAMHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338342	NM_015474.4(SAMHD1):c.1593G>C (p.Arg531Ser)	SAMHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338343	NM_015474.4(SAMHD1):c.1393C>A (p.Gln465Lys)	SAMHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338345	NM_015474.4(SAMHD1):c.840C>T (p.Val280=)	SAMHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338346	NM_015474.4(SAMHD1):c.697-11A>G	SAMHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338347	NM_015474.4(SAMHD1):c.401G>A (p.Arg134Gln)	SAMHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338349	NM_015474.4(SAMHD1):c.195G>T (p.Leu65=)	SAMHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338350	NM_015474.4(SAMHD1):c.77C>T (p.Pro26Leu)	SAMHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
SAMHD1	Supportive	Autosomal dominant	familial chilblain lupus	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SAMHD1	Orphanet:481662	Familial Chilblain lupus
SAMHD1	Orphanet:51	Aicardi-Goutières syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SAMHD1	HGNC:15925	ENSG00000101347	Q9Y3Z3	Deoxynucleoside triphosphate triphosphohydrolase SAMHD1	gencc,clinvar
TLDC2	HGNC:16112	ENSG00000101342	A0PJX2	TLD domain-containing protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SAMHD1	Deoxynucleoside triphosphate triphosphohydrolase SAMHD1	Protein that acts both as a host restriction factor involved in defense response to virus and as a regulator of DNA end resection at stalled replication forks.
TLDC2	TLD domain-containing protein 2	Inhibits the activity of the vacuolar-type ATPase (V-ATPase) by inducing disassembly of the V-ATPase complex.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SAMHD1	Transcription factor	no	3.1.5.B1	SAM, HD/PDEase_dom, HD_domain
TLDC2	Other/Unknown	no		TLDc_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	1
mononuclear cell	1
pericardium	1
male germ line stem cell (sensu Vertebrata) in testis	1
mucosa of transverse colon	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SAMHD1	291	ubiquitous	marker	monocyte, mononuclear cell, pericardium
TLDC2	160	tissue_specific	marker	sural nerve, mucosa of transverse colon, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SAMHD1	2,186
TLDC2	254

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SAMHD1	Q9Y3Z3	76

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TLDC2	A0PJX2	85.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Nucleotide catabolism	1	1268.9×	0.006	SAMHD1
Metabolism of nucleotides	1	300.5×	0.012	SAMHD1
Interferon alpha/beta signaling	1	152.3×	0.015	SAMHD1
Interferon Signaling	1	120.2×	0.015	SAMHD1
Cytokine Signaling in Immune system	1	40.8×	0.034	SAMHD1
Immune System	1	13.0×	0.086	SAMHD1
Metabolism	1	11.6×	0.086	SAMHD1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dGTP catabolic process	1	4213.0×	0.001	SAMHD1
deoxyribonucleotide catabolic process	1	4213.0×	0.001	SAMHD1
dATP catabolic process	1	4213.0×	0.001	SAMHD1
DNA strand resection involved in replication fork processing	1	1053.2×	0.003	SAMHD1
somatic hypermutation of immunoglobulin genes	1	526.6×	0.005	SAMHD1
negative regulation of type I interferon-mediated signaling pathway	1	383.0×	0.006	SAMHD1
regulation of innate immune response	1	324.1×	0.006	SAMHD1
protein homotetramerization	1	118.7×	0.015	SAMHD1
double-strand break repair via homologous recombination	1	78.0×	0.020	SAMHD1
response to oxidative stress	1	65.3×	0.021	TLDC2
defense response to virus	1	34.7×	0.036	SAMHD1
DNA damage response	1	26.8×	0.043	SAMHD1
immune response	1	23.5×	0.045	SAMHD1
innate immune response	1	16.8×	0.059	SAMHD1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SAMHD1	0	0
TLDC2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SAMHD1	4	Binding:3, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SAMHD1	3.1.5.B1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SAMHD1, TLDC2

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)
SAMHD1	4	—
TLDC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.