Cryopyrin-associated periodic syndrome

Summary

Cryopyrin-associated periodic syndrome (MONDO:0016168) is a disease caused by NLRP3 (GenCC Definitive), with 2 cohort genes and 15 clinical trials. Top therapeutic interventions include canakinumab, anakinra, and tranilast.

At a glance

• Prevalence: 1-9 / 1 000 000 (France) [Orphanet-validated]
• Causal gene: NLRP3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 872
• Clinical trials: 15

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.28	France	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	cryopyrin-associated periodic syndrome
Mondo ID	MONDO:0016168
MeSH	D056587
Orphanet	208650
ICD-11	2139918612
NCIT	C84657
SNOMED CT	430079001
UMLS	C2316212
MedGen	412215
GARD	0010927
MedDRA	10068850
Is cancer (heuristic)	no

Also known as: caps · Cryopyrinopathy

Data availability: 872 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › cryopyrin-associated periodic syndrome

Related subtypes (46): hypersensitivity reaction disease, immune system cancer, immune system organ benign neoplasm, bone marrow disorder, thymus gland disorder, inborn error of immunity, leukocyte disorder, psoriasis, spondyloarthropathy, aggressive insulitis, benign insulitis, inflammatory bowel disease, autoimmune disease, TNF receptor 1-associated periodic fever syndrome, epidermodysplasia verruciformis, Vici syndrome, proteosome-associated autoinflammatory syndrome, hyperimmunoglobulinemia D with periodic fever, transcobalamin II deficiency, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, granulomatosis with polyangiitis, autosomal recessive osteopetrosis 7, graft versus host disease, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome, Roifman syndrome, anti-HLA hyperimmunization, acquired immunodeficiency, erythroderma desquamativum, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, familial Mediterranean fever, 22q11.2 deletion syndrome, T-cell large granular lymphocyte leukemia, twin to twin transfusion syndrome, immunodeficiency disease, immunoproliferative disorder, cytokine receptor deficiency, immunodeficiency-related disorder, phagocytic cell dysfunction, thrombocytopenic purpura, lymphoid system disorder, immune reconstitution inflammatory syndrome, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, cytokine release syndrome, early-onset autoimmunity-autoinflammation-immunodeficiency syndrome, CADINS disease, autoinflammation, panniculitis, and dermatosis syndrome

Subtypes (3): Muckle-Wells syndrome, CINCA syndrome, familial cold autoinflammatory syndrome

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:

307 uncertain significance, 208 likely benign, 44 conflicting classifications of pathogenicity, 22 benign/likely benign, 10 benign, 4 pathogenic, 3 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1188124	NM_001243133.2(NLRP3):c.2575T>C (p.Tyr859His)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1701129	NM_001243133.2(NLRP3):c.778_780delinsTGG (p.Arg260Trp)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2029953	NM_001243133.2(NLRP3):c.779_780delinsCG (p.Arg260Pro)	NLRP3	Pathogenic	criteria provided, single submitter
2109144	NM_001243133.2(NLRP3):c.1305G>C (p.Lys435Asn)	NLRP3	Pathogenic	criteria provided, single submitter
2203018	NM_001243133.2(NLRP3):c.2263G>A (p.Gly755Arg)	NLRP3	Pathogenic	criteria provided, single submitter
3633876	NM_001243133.2(NLRP3):c.1698C>G (p.Phe566Leu)	NLRP3	Pathogenic	criteria provided, single submitter
1066319	NM_001243133.2(NLRP3):c.1218G>A (p.Met406Ile)	NLRP3	Likely pathogenic	criteria provided, single submitter
1487108	NM_001243133.2(NLRP3):c.1700A>C (p.Glu567Ala)	NLRP3	Likely pathogenic	criteria provided, single submitter
2055218	NM_001243133.2(NLRP3):c.1706G>A (p.Gly569Glu)	NLRP3	Likely pathogenic	criteria provided, single submitter
1013561	NM_001243133.2(NLRP3):c.2732A>G (p.Asn911Ser)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028307	NM_001243133.2(NLRP3):c.1937A>G (p.Asp646Gly)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1058144	NM_001243133.2(NLRP3):c.1371G>T (p.Glu457Asp)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1061267	NM_001243133.2(NLRP3):c.299C>T (p.Ser100Leu)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1077243	NM_001243133.2(NLRP3):c.220G>A (p.Ala74Thr)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1144947	NM_001243133.2(NLRP3):c.1659C>T (p.Ser553=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1176537	NM_001243133.2(NLRP3):c.2358C>T (p.Phe786=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1193207	NM_001243133.2(NLRP3):c.2553C>G (p.Thr851=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1307162	NM_001243133.2(NLRP3):c.282A>T (p.Ser94=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138532	NM_001243133.2(NLRP3):c.1584C>T (p.Ala528=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138534	NM_001243133.2(NLRP3):c.2118C>T (p.Leu706=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1434806	NM_001243133.2(NLRP3):c.2835A>G (p.Glu945=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1446237	NM_001243133.2(NLRP3):c.2273T>C (p.Val758Ala)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1548717	NM_001243133.2(NLRP3):c.1650G>A (p.Lys550=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694428	NM_001243133.2(NLRP3):c.1057C>T (p.Leu353=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694431	NM_001243133.2(NLRP3):c.1269G>A (p.Gln423=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694434	NM_001243133.2(NLRP3):c.251A>G (p.Lys84Arg)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694439	NM_001243133.2(NLRP3):c.938T>C (p.Ile313Thr)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1980828	NM_001243133.2(NLRP3):c.800A>G (p.Gln267Arg)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1983691	NM_001243133.2(NLRP3):c.974G>A (p.Arg325Gln)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234286	NM_001243133.2(NLRP3):c.224C>T (p.Ala75Val)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · 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
NLRP3	Definitive	Autosomal dominant	cryopyrin-associated periodic syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NLRP3	Orphanet:1451	CINCA syndrome
NLRP3	Orphanet:47045	Familial cold urticaria
NLRP3	Orphanet:575	Muckle-Wells syndrome
NLRP3	Orphanet:647815	Keratitis fugax hereditaria

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
NLRP3	HGNC:16400	ENSG00000162711	Q96P20	NACHT, LRR and PYD domains-containing protein 3	gencc,clinvar
OR1C1	HGNC:8182	ENSG00000221888	Q15619	Olfactory receptor 1C1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NLRP3	NACHT, LRR and PYD domains-containing protein 3	Sensor component of the NLRP3 inflammasome, which mediates inflammasome activation in response to defects in membrane integrity, leading to secretion of inflammatory cytokines IL1B and IL18 and pyroptosis.
OR1C1	Olfactory receptor 1C1	Odorant receptor.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
GPCR	1	12.0×	0.164
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NLRP3	Other/Unknown	no		Leu-rich_rpt, DAPIN, NACHT_NTPase
OR1C1	GPCR	yes		GPCR_Rhodpsn, Olfact_rcpt, GPCR_Rhodpsn_7TM

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)	1
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1
colonic epithelium	1
skin of hip	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NLRP3	172	broad	marker	monocyte, mononuclear cell, leukocyte
OR1C1	0		marker	skin of hip, sural nerve, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NLRP3	3,797
OR1C1	271

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NLRP3	Q96P20	24

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OR1C1	Q15619	87.60

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 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
The NLRP3 inflammasome	1	335.9×	0.013	NLRP3
Purinergic signaling in leishmaniasis infection	1	211.5×	0.013	NLRP3
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	178.4×	0.013	NLRP3
Metalloprotease DUBs	1	150.3×	0.013	NLRP3
SARS-CoV-1 activates/modulates innate immune responses	1	135.9×	0.013	NLRP3
Cytoprotection by HMOX1	1	92.1×	0.016	NLRP3
Olfactory Signaling Pathway	1	72.3×	0.018	OR1C1
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	44.6×	0.025	NLRP3
Expression and translocation of olfactory receptors	1	14.1×	0.070	OR1C1

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
detection of biotic stimulus	1	2106.5×	0.005	NLRP3
negative regulation of acute inflammatory response	1	1203.7×	0.005	NLRP3
positive regulation of type 2 immune response	1	1203.7×	0.005	NLRP3
NLRP3 inflammasome complex assembly	1	1203.7×	0.005	NLRP3
positive regulation of T-helper 2 cell differentiation	1	1053.2×	0.005	NLRP3
osmosensory signaling pathway	1	766.0×	0.005	NLRP3
positive regulation of T-helper 2 cell cytokine production	1	766.0×	0.005	NLRP3
pattern recognition receptor signaling pathway	1	495.6×	0.007	NLRP3
positive regulation of interleukin-4 production	1	280.9×	0.009	NLRP3
negative regulation of interleukin-1 beta production	1	255.3×	0.009	NLRP3
pyroptotic inflammatory response	1	255.3×	0.009	NLRP3
negative regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.009	NLRP3
signal transduction	2	16.1×	0.009	NLRP3, OR1C1
positive regulation of interleukin-1 beta production	1	129.6×	0.015	NLRP3
positive regulation of non-canonical NF-kappaB signal transduction	1	127.7×	0.015	NLRP3
defense response	1	108.0×	0.016	NLRP3
obsolete positive regulation of NF-kappaB transcription factor activity	1	102.8×	0.016	NLRP3
cellular response to virus	1	100.3×	0.016	NLRP3
regulation of inflammatory response	1	84.3×	0.018	NLRP3
protein maturation	1	81.8×	0.018	NLRP3
sensory perception of smell	1	78.0×	0.018	OR1C1
positive regulation of inflammatory response	1	72.6×	0.018	NLRP3
negative regulation of inflammatory response	1	68.5×	0.018	NLRP3
protein homooligomerization	1	61.1×	0.020	NLRP3
cellular response to lipopolysaccharide	1	49.0×	0.024	NLRP3
inflammatory response	1	18.9×	0.058	NLRP3
innate immune response	1	16.8×	0.063	NLRP3
apoptotic process	1	14.3×	0.071	NLRP3
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	NLRP3

Therapeutics

Drugs indicated for this disease

3 approved. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Anakinra	Approved (phase 4)
Canakinumab	Approved (phase 4)
Rilonacept	Approved (phase 4)

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) 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
NLRP3	CLOMIPHENE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NLRP3	11	4
OR1C1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOMIPHENE	4	NLRP3
GLYBURIDE	4	NLRP3
CURCUMIN	3	NLRP3
JT-001	3	NLRP3
TRICLOCARBAN	2	NLRP3
CLIOXANIDE	2	NLRP3
DAPANSUTRILE	2	NLRP3
USNOFLAST	2	NLRP3
INZOMELID	1	NLRP3
BMS-986299	1	NLRP3
NT-0796	1	NLRP3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NLRP3	534	Binding:527, Functional:6, ADMET:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NLRP3	534

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

10 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)
CLOMIPHENE	4	NLRP3
GLYBURIDE	4	NLRP3
CURCUMIN	3	NLRP3
JT-001	3	NLRP3
TRICLOCARBAN	2	NLRP3
CLIOXANIDE	2	NLRP3
DAPANSUTRILE	2	NLRP3
INZOMELID	1	NLRP3
BMS-986299	1	NLRP3
NT-0796	1	NLRP3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NLRP3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	OR1C1
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)
OR1C1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 15.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	5
PHASE2	4
Not specified	4
PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00685373	PHASE3	COMPLETED	Efficacy and Safety of ACZ885 in Patients With the Following Cryopyrin-associated Periodic Syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Neonatal Onset Multisystem Inflammatory Disease
NCT00991146	PHASE3	COMPLETED	Efficacy and Safety Study of Canakinumab Administered for 6 Months (24 Weeks) in Japanese Patients With Cryopyrin-associated Periodic Syndromes Followed by an Extension Phase
NCT01105507	PHASE3	COMPLETED	The Safety and Efficacy of Canakinumab in Patients Aged 4 Years or Older Diagnosed With Cryopyrin-associated Periodic Syndromes (CAPS) in Canada
NCT01302860	PHASE3	COMPLETED	Efficacy, Safety and Tolerability of ACZ885 in Pediatric Patients With the Following Cryopyrin-associated Periodic Syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Neonatal Onset Multisystem Inflammatory Disease
NCT01576367	PHASE3	COMPLETED	Efficacy, Safety and Tolerability of ACZ885 in Pediatric Patients With the Following Cryopyrin-associated Periodic Syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Neonatal Onset Multisystem Inflammatory Disease
NCT03923140	PHASE2	UNKNOWN	A Clinical Study of Tranilast in the Treatment of Cryopyrin-Associated Periodic Syndrome (CAPS)
NCT04524858	PHASE2	TERMINATED	Study of ATI-450 in Patients With Cryopyrin-Associated Periodic Syndrome (CAPS)
NCT05186051	PHASE2	COMPLETED	A Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ZYIL1 in Subjects With Cryopyrin Associated Periodic Syndromes (CAPS)
NCT05812781	PHASE2	COMPLETED	A Study to Evaluate VTX2735 in Patients With Cryopyrin-associated Periodic Syndrome
NCT06974877	PHASE1	RECRUITING	Repeat PET/CT Imaging in People With CAPS and Anakinra-Induced Amyloidosis Using an Amyloid-Reactive Peptide to Measure Changes in Organ-Specific Amyloid Load
NCT04086602	PHASE1	COMPLETED	Safety and Tolerability, Pharmacokinetic and Pharmacodynamic Study With IZD334
NCT05292768	Not specified	NOT_YET_RECRUITING	Are Mast Cells Involved in Autoinflammatory Diseases
NCT06544018	Not specified	RECRUITING	Circadian Rhythm Deregulation in Patients With CAPS
NCT02326376	Not specified	COMPLETED	Kineret CAPS Post Authorisation Study
NCT04856540	Not specified	COMPLETED	Adult Outcomes of Children With CAPS

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CANAKINUMAB	4	4
ANAKINRA	4	1
TRANILAST	3	1
IODINE I124 EVUZAMITIDE	2	1
USNOFLAST	2	1
ZUNSEMETINIB	2	1
SELNOFLAST POTASSIUM	1	1
CHEMBL1081780	0	1