Autoimmune interstitial lung disease-arthritis syndrome

Summary

Autoimmune interstitial lung disease-arthritis syndrome (MONDO:0014629) is a disease caused by COPA (GenCC Strong), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COPA (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 901

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autoimmune interstitial lung disease-arthritis syndrome
Mondo ID	MONDO:0014629
OMIM	616414
Orphanet	444092
DOID	DOID:0081242
GARD	0017762
NORD	1973
Is cancer (heuristic)	no

Also known as: AILJK · autoimmune interstitial lung, joint, and kidney disease · autoinflammation and autoimmunity, systemic, with immune dysregulation · COPA Syndrome

Data availability: 901 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › autoimmune interstitial lung disease-arthritis syndrome

Related subtypes (58): lower respiratory tract disorder, respiratory system cancer, respiratory system benign neoplasm, allergic respiratory disease, paranasal sinus disorder, upper respiratory tract disorder, pertussis, severe acute respiratory syndrome, sleep apnea syndrome, diaphragm disorder, pulmonary tuberculosis, altitude sickness, perinatal asphyxia, pulmonary nodular lymphoid hyperplasia, tracheobronchopathia osteochondroplastica, Williams-Campbell syndrome, cystic fibrosis, growth delay-hydrocephaly-lung hypoplasia syndrome, laryngo-onycho-cutaneous syndrome, congenital pulmonary lymphangiectasia, familial primary pulmonary hypoplasia, Mounier-Kuhn syndrome, Young syndrome, lung agenesis-heart defect-thumb anomalies syndrome, sudden infant death-dysgenesis of the testes syndrome, alpha 1-antitrypsin deficiency, hereditary sclerosing poikiloderma with tendon and pulmonary involvement, mucopolysaccharidosis-plus syndrome, congenital bronchobiliary fistula, bronchogenic cyst, primary ciliary dyskinesia, congenital pulmonary airway malformation, transient hyperammonemia of the newborn, congenital pulmonary sequestration, Siegler-Brewer-Carey syndrome, tracheal agenesis, 16q24.1 microdeletion syndrome, staphylococcal necrotizing pneumonia, pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis, plastic bronchitis, recurrent respiratory papillomatosis, IgG4-related mediastinitis, bronchopulmonary dysplasia, infantile apnea, diffuse alveolar hemorrhage, respiratory or thoracic malformation, pulmonary agenesis, eosinophilic granuloma, disorder of pharynx, respiratory tract neoplasm, pulmonary alveolar proteinosis with hypogammaglobulinemia, respiratory tract infectious disorder, Middle East respiratory syndrome, reactive airway disease, acinar dysplasia, pulmonary hypoplasia, isolated left bronchial isomerism, bronchiectasis and nasal polyposis

Subtypes (2): autoinflammation and autoimmunity with immune dysregulation 1, autoinflammation and autoimmunity with immune dysregulation 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

600 retrieved; paginated sample, class counts are floors:

308 likely benign, 225 uncertain significance, 29 benign, 28 conflicting classifications of pathogenicity, 4 benign/likely benign, 3 pathogenic, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
199254	NM_004371.4(COPA):c.698G>A (p.Arg233His)	COPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199256	NM_004371.4(COPA):c.721G>A (p.Glu241Lys)	COPA	Pathogenic	criteria provided, multiple submitters, no conflicts
218941	NM_004371.4(COPA):c.690G>T (p.Lys230Asn)	COPA	Pathogenic	criteria provided, single submitter
3370278	NM_004371.4(COPA):c.3424C>T (p.Arg1142Ter)	COPA	Pathogenic	no assertion criteria provided
1526108	NM_004371.4(COPA):c.725T>C (p.Val242Ala)	COPA	Likely pathogenic	criteria provided, single submitter
3065463	NM_004371.4(COPA):c.1742T>A (p.Leu581Gln)	COPA	Likely pathogenic	criteria provided, single submitter
1002708	NM_004371.4(COPA):c.3248G>A (p.Arg1083His)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1020294	NM_004371.4(COPA):c.2822G>A (p.Arg941Gln)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1023759	NM_004371.4(COPA):c.3281C>T (p.Ser1094Leu)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1121067	NM_004371.4(COPA):c.2749A>G (p.Thr917Ala)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1346390	NM_004371.4(COPA):c.3196G>T (p.Val1066Leu)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1351069	NM_004371.4(COPA):c.481G>A (p.Val161Ile)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1370038	NM_004371.4(COPA):c.2377A>G (p.Lys793Glu)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1414255	NM_004371.4(COPA):c.3377G>A (p.Arg1126Gln)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1423956	NM_004371.4(COPA):c.2993C>T (p.Ala998Val)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1436563	NM_004371.4(COPA):c.1292G>A (p.Arg431Gln)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1447714	NM_004371.4(COPA):c.2791A>G (p.Ile931Val)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1483758	NM_004371.4(COPA):c.2515A>T (p.Thr839Ser)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1488228	NM_004371.4(COPA):c.3533G>A (p.Arg1178His)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1504150	NM_004371.4(COPA):c.2373T>G (p.Asn791Lys)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1560731	NM_004371.4(COPA):c.2503A>G (p.Ile835Val)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1670842	NM_004371.4(COPA):c.1563A>T (p.Leu521Phe)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1905738	NM_004371.4(COPA):c.2692G>A (p.Ala898Thr)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1922165	NM_004371.4(COPA):c.3413C>T (p.Ala1138Val)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1955267	NM_004371.4(COPA):c.1674C>A (p.His558Gln)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1960295	NM_004371.4(COPA):c.2401A>G (p.Ile801Val)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
199255	NM_004371.4(COPA):c.728A>G (p.Asp243Gly)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2050354	NM_004371.4(COPA):c.646A>G (p.Thr216Ala)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2058240	NM_004371.4(COPA):c.1826A>T (p.Asp609Val)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2162616	NM_004371.4(COPA):c.2378A>G (p.Lys793Arg)	COPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
COPA	Strong	Autosomal dominant	autoimmune interstitial lung disease-arthritis syndrome	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COPA	Orphanet:444092	Autoimmune interstitial lung disease-arthritis syndrome
NLRP12	Orphanet:247868	NLRP12-associated hereditary periodic fever syndrome
CPLANE1	Orphanet:2754	Orofaciodigital syndrome type 6
CPLANE1	Orphanet:475	Isolated Joubert syndrome
CPLANE1	Orphanet:65684	Monomelic amyotrophy

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
COPA	HGNC:2230	ENSG00000122218	P53621	Coatomer subunit alpha	gencc,clinvar
NLRP12	HGNC:22938	ENSG00000142405	P59046	NACHT, LRR and PYD domains-containing protein 12	clinvar
CPLANE1	HGNC:25801	ENSG00000197603	Q9H799	Ciliogenesis and planar polarity effector 1	clinvar
FCRL6	HGNC:31910	ENSG00000181036	Q6DN72	Fc receptor-like protein 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COPA	Coatomer subunit alpha	The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Go…
NLRP12	NACHT, LRR and PYD domains-containing protein 12	Plays an essential role as an potent mitigator of inflammation.
CPLANE1	Ciliogenesis and planar polarity effector 1	Involved in ciliogenesis.
FCRL6	Fc receptor-like protein 6	Acts as a MHC class II receptor.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.25

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
Scaffold/PPI	2	8.6×	0.056
Antibody/Immunoglobulin	1	7.3×	0.195
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COPA	Scaffold/PPI	no		WD40_rpt, Beta-prop_COPA/B_2nd, Coatomer_asu_C
NLRP12	Other/Unknown	no		Leu-rich_rpt, DAPIN, NACHT_NTPase
CPLANE1	Scaffold/PPI	no		CPLANE1, WD40_repeat_dom_sf
FCRL6	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom

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
blood	2
islet of Langerhans	1
pituitary gland	1
stromal cell of endometrium	1
leukocyte	1
monocyte	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
sural nerve	1
granulocyte	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COPA	303	ubiquitous	marker	stromal cell of endometrium, islet of Langerhans, pituitary gland
NLRP12	117	tissue_specific	marker	blood, monocyte, leukocyte
CPLANE1	195	ubiquitous	marker	sural nerve, calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis
FCRL6	128	tissue_specific	marker	granulocyte, thymus, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COPA	2,506
NLRP12	1,451
FCRL6	482
CPLANE1	439

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COPA	P53621	3
NLRP12	P59046	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FCRL6	Q6DN72	76.29
CPLANE1	Q9H799

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
SARS-CoV-2-host interactions	1	59.5×	0.044	NLRP12
COPI-dependent Golgi-to-ER retrograde traffic	1	55.4×	0.044	COPA
COPI-mediated anterograde transport	1	54.9×	0.044	COPA
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	44.6×	0.044	NLRP12
SARS-CoV-2 Infection	1	40.2×	0.044	NLRP12
SARS-CoV Infections	1	27.7×	0.054	NLRP12
Viral Infection Pathways	1	15.4×	0.082	NLRP12
Infectious disease	1	12.4×	0.089	NLRP12
Disease	1	6.5×	0.147	NLRP12

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 interleukin-18 production	1	4213.0×	0.006	NLRP12
negative regulation of Toll signaling pathway	1	2106.5×	0.006	NLRP12
protein localization to cell leading edge	1	1053.2×	0.006	COPA
pancreatic juice secretion	1	842.6×	0.006	COPA
protein localization to axon	1	842.6×	0.006	COPA
negative regulation of interleukin-1 production	1	702.2×	0.006	NLRP12
positive regulation of MHC class I biosynthetic process	1	702.2×	0.006	NLRP12
dendritic cell migration	1	468.1×	0.008	NLRP12
cellular response to cytokine stimulus	1	135.9×	0.019	NLRP12
intra-Golgi vesicle-mediated transport	1	131.7×	0.019	COPA
negative regulation of cytokine production	1	127.7×	0.019	NLRP12
negative regulation of non-canonical NF-kappaB signal transduction	1	127.7×	0.019	NLRP12
regulation of canonical NF-kappaB signal transduction	1	120.4×	0.019	NLRP12
negative regulation of signal transduction	1	93.6×	0.022	NLRP12
negative regulation of interleukin-6 production	1	87.8×	0.022	NLRP12
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	84.3×	0.022	COPA
ERK1 and ERK2 cascade	1	79.5×	0.022	NLRP12
positive regulation of interleukin-1 beta production	1	64.8×	0.025	NLRP12
positive regulation of non-canonical NF-kappaB signal transduction	1	63.8×	0.025	NLRP12
negative regulation of ERK1 and ERK2 cascade	1	54.0×	0.028	NLRP12
negative regulation of canonical NF-kappaB signal transduction	1	43.0×	0.032	NLRP12
regulation of inflammatory response	1	42.1×	0.032	NLRP12
positive regulation of inflammatory response	1	36.3×	0.035	NLRP12
negative regulation of inflammatory response	1	34.2×	0.035	NLRP12
endoplasmic reticulum to Golgi vesicle-mediated transport	1	34.0×	0.035	COPA
cilium assembly	1	18.4×	0.061	CPLANE1
intracellular protein transport	1	16.2×	0.065	COPA
cell surface receptor signaling pathway	1	16.0×	0.065	FCRL6
immune response	1	11.8×	0.085	FCRL6
signal transduction	1	4.0×	0.227	NLRP12

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COPA	0	0
NLRP12	0	0
CPLANE1	0	0
FCRL6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
COPA	1	Binding:1

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

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	1	FCRL6
E	Difficult family or no structure, no drug	3	COPA, NLRP12, CPLANE1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COPA	1	—
NLRP12	0	—
CPLANE1	0	—
FCRL6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.