Familial cold autoinflammatory syndrome

Summary

Familial cold autoinflammatory syndrome (MONDO:0018768) is a disease caused by NLRP3 (GenCC Definitive), with 2 cohort genes and 7 clinical trials. Top therapeutic interventions include canakinumab and rilonacept.

At a glance

• Prevalence: Unknown (Europe) [Orphanet-validated]
• Causal gene: NLRP3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1
• Phenotypes (HPO): 17
• Clinical trials: 7

Clinical features

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000975	Hyperhidrosis	Very frequent (80-99%)
HP:0000989	Pruritus	Very frequent (80-99%)
HP:0001025	Urticaria	Very frequent (80-99%)
HP:0001369	Arthritis	Very frequent (80-99%)
HP:0001945	Fever	Very frequent (80-99%)
HP:0003326	Myalgia	Very frequent (80-99%)
HP:0010783	Erythema	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0012534	Dysesthesia	Very frequent (80-99%)
HP:0002017	Nausea and vomiting	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000509	Conjunctivitis	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0001959	Polydipsia	Occasional (5-29%)
HP:0002027	Abdominal pain	Occasional (5-29%)
HP:0002829	Arthralgia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial cold autoinflammatory syndrome
Mondo ID	MONDO:0018768
OMIM	120100
Orphanet	47045
DOID	DOID:0090061
ICD-11	1932140025
NCIT	C119053
UMLS	C0343068
MedGen	137986
GARD	0009535
MedDRA	10064570
NORD	1122
Is cancer (heuristic)	no

Also known as: familial cold autoinflammatory syndrome · familial polymorphous cold eruption · FCAS · FCU

Data availability: 1 ClinVar variant · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

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

Related subtypes (2): Muckle-Wells syndrome, CINCA syndrome

Subtypes (4): familial cold autoinflammatory syndrome 1, familial cold autoinflammatory syndrome 2, familial cold autoinflammatory syndrome 3, familial cold autoinflammatory syndrome 4

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

1 retrieved; paginated sample, class counts are floors:

1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1298669	NM_002661.5(PLCG2):c.2055-7G>A	PLCG2	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 6 · 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	familial cold autoinflammatory 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
PLCG2	Orphanet:300359	PLCG2-associated antibody deficiency and immune dysregulation
PLCG2	Orphanet:324530	Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

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
PLCG2	HGNC:9066	ENSG00000197943	P16885	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2	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.
PLCG2	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2	The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.

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
Scaffold/PPI	1	8.6×	0.225
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
PLCG2	Scaffold/PPI	no	3.1.4.11	C2_dom, PLipase_C_PInositol-sp_X_dom, SH2

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
leukocyte	1
monocyte	1
mononuclear cell	1
blood	1
bone marrow cell	1
renal glomerulus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NLRP3	172	broad	marker	monocyte, mononuclear cell, leukocyte
PLCG2	249	ubiquitous	marker	renal glomerulus, bone marrow cell, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NLRP3	3,797
PLCG2	2,421

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NLRP3	Q96P20	24
PLCG2	P16885	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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
Erythropoietin activates Phospholipase C gamma (PLCG)	1	815.7×	0.009	PLCG2
The NLRP3 inflammasome	1	335.9×	0.009	NLRP3
Role of phospholipids in phagocytosis	1	228.4×	0.009	PLCG2
Synthesis of IP3 and IP4 in the cytosol	1	211.5×	0.009	PLCG2
Dectin-2 family	1	211.5×	0.009	PLCG2
Purinergic signaling in leishmaniasis infection	1	211.5×	0.009	NLRP3
DAP12 signaling	1	184.2×	0.009	PLCG2
FCERI mediated Ca+2 mobilization	1	178.4×	0.009	PLCG2
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	178.4×	0.009	PLCG2
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	178.4×	0.009	NLRP3
Generation of second messenger molecules	1	173.0×	0.009	PLCG2
FCERI mediated MAPK activation	1	173.0×	0.009	PLCG2
Signaling by CSF1 (M-CSF) in myeloid cells	1	173.0×	0.009	PLCG2
GPVI-mediated activation cascade	1	154.3×	0.009	PLCG2
Metalloprotease DUBs	1	150.3×	0.009	NLRP3
FCGR3A-mediated IL10 synthesis	1	146.4×	0.009	PLCG2
SARS-CoV-1 activates/modulates innate immune responses	1	135.9×	0.010	NLRP3
Cytoprotection by HMOX1	1	92.1×	0.013	NLRP3
CLEC7A (Dectin-1) signaling	1	71.4×	0.016	PLCG2
Toll Like Receptor 4 (TLR4) Cascade	1	65.6×	0.017	PLCG2
Potential therapeutics for SARS	1	57.1×	0.018	PLCG2
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	44.6×	0.022	NLRP3

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
cellular response to lectin	1	4213.0×	0.006	PLCG2
inositol trisphosphate biosynthetic process	1	2808.7×	0.006	PLCG2
follicular B cell differentiation	1	2106.5×	0.006	PLCG2
detection of biotic stimulus	1	2106.5×	0.006	NLRP3
regulation of calcineurin-NFAT signaling cascade	1	2106.5×	0.006	PLCG2
positive regulation of dendritic cell cytokine production	1	1685.2×	0.006	PLCG2
negative regulation of acute inflammatory response	1	1203.7×	0.006	NLRP3
positive regulation of type 2 immune response	1	1203.7×	0.006	NLRP3
positive regulation of interleukin-23 production	1	1203.7×	0.006	PLCG2
NLRP3 inflammasome complex assembly	1	1203.7×	0.006	NLRP3
response to yeast	1	1053.2×	0.006	PLCG2
positive regulation of T-helper 2 cell differentiation	1	1053.2×	0.006	NLRP3
cell activation	1	842.6×	0.007	PLCG2
osmosensory signaling pathway	1	766.0×	0.007	NLRP3
positive regulation of T-helper 2 cell cytokine production	1	766.0×	0.007	NLRP3
programmed cell death	1	648.1×	0.007	PLCG2
positive regulation of phagocytosis, engulfment	1	648.1×	0.007	PLCG2
phospholipid catabolic process	1	601.9×	0.007	PLCG2
positive regulation of neuroinflammatory response	1	601.9×	0.007	PLCG2
macrophage activation involved in immune response	1	561.7×	0.007	PLCG2
positive regulation of cell cycle G1/S phase transition	1	561.7×	0.007	PLCG2
positive regulation of reactive oxygen species biosynthetic process	1	561.7×	0.007	PLCG2
pattern recognition receptor signaling pathway	1	495.6×	0.007	NLRP3
antifungal innate immune response	1	468.1×	0.007	PLCG2
phosphatidylinositol metabolic process	1	443.5×	0.007	PLCG2
stimulatory C-type lectin receptor signaling pathway	1	366.4×	0.007	PLCG2
Fc-epsilon receptor signaling pathway	1	366.4×	0.007	PLCG2
negative regulation of programmed cell death	1	366.4×	0.007	PLCG2
positive regulation of macrophage cytokine production	1	366.4×	0.007	PLCG2
positive regulation of receptor internalization	1	351.1×	0.007	PLCG2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
PLCG2	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): 1.

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

Symbol	Assays	Type breakdown
NLRP3	534	Binding:527, Functional:6, ADMET:1
PLCG2	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLCG2	3.1.4.11	phosphoinositide phospholipase C

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

11 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
USNOFLAST	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	0
E	Difficult family or no structure, no drug	1	PLCG2

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)
PLCG2	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	5
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00288704	PHASE3	COMPLETED	Rilonacept for Treatment of Cryopyrin-Associated Periodic Syndromes (CAPS)
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
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
NCT04868968	PHASE2	COMPLETED	Study of Safety, Tolerability and Efficacy of DFV890 in Participants With Familial Cold Auto-inflammatory Syndrome (FCAS)
NCT00887939	Not specified	COMPLETED	Pathogenesis of Physical Induced Urticarial Syndromes

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CANAKINUMAB	4	4
RILONACEPT	4	1