Familial cold autoinflammatory syndrome 1

Summary

Familial cold autoinflammatory syndrome 1 (MONDO:0007349) is a disease caused by NLRP3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: NLRP3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 328

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial cold autoinflammatory syndrome 1
Mondo ID	MONDO:0007349
OMIM	120100
DOID	DOID:0090062
SNOMED CT	238687000
UMLS	C4551895
MedGen	1647324
GARD	0015051
Is cancer (heuristic)	no

Also known as: familial cold autoinflammatory syndrome 1 · familial cold autoinflammatory syndrome caused by mutation in NLRP3 · familial cold autoinflammatory syndrome type 1 · familial cold inflammatory syndrome 1 · FCAS1 · NLRP3 familial cold autoinflammatory syndrome

Data availability: 328 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › cryopyrin-associated periodic syndrome › familial cold autoinflammatory syndrome › familial cold autoinflammatory syndrome 1

Related subtypes (3): 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

328 retrieved; paginated sample, class counts are floors:

147 uncertain significance, 47 conflicting classifications of pathogenicity, 38 not provided, 27 benign/likely benign, 20 benign, 16 pathogenic, 13 likely benign, 10 pathogenic/likely pathogenic, 10 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
4370	NM_001243133.2(NLRP3):c.1316C>T (p.Ala439Val)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4373	NM_001243133.2(NLRP3):c.1055C>T (p.Ala352Val)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4374	NM_001243133.2(NLRP3):c.778C>T (p.Arg260Ter)	NLRP3	Pathogenic	criteria provided, multiple submitters, no conflicts
4376	NM_001243133.2(NLRP3):c.1718T>C (p.Phe573Ser)	NLRP3	Pathogenic	no assertion criteria provided
4377	NM_001243133.2(NLRP3):c.907G>A (p.Asp303Asn)	NLRP3	Pathogenic	criteria provided, multiple submitters, no conflicts
4378	NM_001243133.2(NLRP3):c.926T>C (p.Phe309Ser)	NLRP3	Pathogenic	no assertion criteria provided
4379	NM_001243133.2(NLRP3):c.1058T>C (p.Leu353Pro)	NLRP3	Pathogenic	criteria provided, multiple submitters, no conflicts
97909	NM_001243133.2(NLRP3):c.1043C>T (p.Thr348Met)	NLRP3	Pathogenic	criteria provided, multiple submitters, no conflicts
97916	NM_001243133.2(NLRP3):c.1213A>C (p.Thr405Pro)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97924	NM_001243133.2(NLRP3):c.1307C>T (p.Thr436Ile)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97925	NM_001243133.2(NLRP3):c.1315G>A (p.Ala439Thr)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97936	NM_001243133.2(NLRP3):c.1568T>G (p.Phe523Cys)	NLRP3	Pathogenic	criteria provided, single submitter
97939	NM_001243133.2(NLRP3):c.1573G>A (p.Glu525Lys)	NLRP3	Pathogenic	criteria provided, single submitter
97944	NM_001243133.2(NLRP3):c.1699G>A (p.Glu567Lys)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97945	NM_001243133.2(NLRP3):c.1706G>C (p.Gly569Ala)	NLRP3	Pathogenic	criteria provided, single submitter
97946	NM_001243133.2(NLRP3):c.1709A>G (p.Tyr570Cys)	NLRP3	Pathogenic	criteria provided, single submitter
97960	NM_001243133.2(NLRP3):c.2576A>G (p.Tyr859Cys)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97978	NM_001243133.2(NLRP3):c.902G>A (p.Gly301Asp)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97979	NM_001243133.2(NLRP3):c.907G>C (p.Asp303His)	NLRP3	Pathogenic	criteria provided, single submitter
97980	NM_001243133.2(NLRP3):c.908A>G (p.Asp303Gly)	NLRP3	Pathogenic	criteria provided, single submitter
97981	NM_001243133.2(NLRP3):c.910G>A (p.Glu304Lys)	NLRP3	Pathogenic	criteria provided, multiple submitters, no conflicts
97982	NM_001243133.2(NLRP3):c.914T>C (p.Leu305Pro)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97985	NM_001243133.2(NLRP3):c.920G>T (p.Gly307Val)	NLRP3	Pathogenic	criteria provided, single submitter
97987	NM_001243133.2(NLRP3):c.931G>A (p.Glu311Lys)	NLRP3	Pathogenic	criteria provided, multiple submitters, no conflicts
97992	NM_001243133.2(NLRP3):c.977G>A (p.Gly326Glu)	NLRP3	Pathogenic	criteria provided, single submitter
4372	NM_001243133.2(NLRP3):c.1880A>G (p.Glu627Gly)	NLRP3	Likely pathogenic	criteria provided, single submitter
4375	NM_001243133.2(NLRP3):c.1705G>C (p.Gly569Arg)	NLRP3	Likely pathogenic	criteria provided, single submitter
97912	NM_001243133.2(NLRP3):c.1054G>A (p.Ala352Thr)	NLRP3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
97915	NM_001243133.2(NLRP3):c.1121C>A (p.Ala374Asp)	NLRP3	Likely pathogenic	criteria provided, single submitter

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	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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NLRP3	HGNC:16400	ENSG00000162711	Q96P20	NACHT, LRR and PYD domains-containing protein 3	gencc,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.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NLRP3	Other/Unknown	no		Leu-rich_rpt, DAPIN, NACHT_NTPase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NLRP3	172	broad	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NLRP3	3,797

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NLRP3	Q96P20	24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 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
The NLRP3 inflammasome	1	671.8×	0.005	NLRP3
Purinergic signaling in leishmaniasis infection	1	423.0×	0.005	NLRP3
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	356.9×	0.005	NLRP3
Metalloprotease DUBs	1	300.5×	0.005	NLRP3
SARS-CoV-1 activates/modulates innate immune responses	1	271.9×	0.005	NLRP3
Cytoprotection by HMOX1	1	184.2×	0.006	NLRP3
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	89.2×	0.011	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 1 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	4213.0×	0.003	NLRP3
negative regulation of acute inflammatory response	1	2407.4×	0.003	NLRP3
positive regulation of type 2 immune response	1	2407.4×	0.003	NLRP3
NLRP3 inflammasome complex assembly	1	2407.4×	0.003	NLRP3
positive regulation of T-helper 2 cell differentiation	1	2106.5×	0.003	NLRP3
osmosensory signaling pathway	1	1532.0×	0.003	NLRP3
positive regulation of T-helper 2 cell cytokine production	1	1532.0×	0.003	NLRP3
pattern recognition receptor signaling pathway	1	991.3×	0.004	NLRP3
positive regulation of interleukin-4 production	1	561.7×	0.005	NLRP3
negative regulation of interleukin-1 beta production	1	510.7×	0.005	NLRP3
pyroptotic inflammatory response	1	510.7×	0.005	NLRP3
negative regulation of non-canonical NF-kappaB signal transduction	1	510.7×	0.005	NLRP3
positive regulation of interleukin-1 beta production	1	259.3×	0.008	NLRP3
positive regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.008	NLRP3
defense response	1	216.1×	0.008	NLRP3
obsolete positive regulation of NF-kappaB transcription factor activity	1	205.5×	0.008	NLRP3
cellular response to virus	1	200.6×	0.008	NLRP3
regulation of inflammatory response	1	168.5×	0.009	NLRP3
protein maturation	1	163.6×	0.009	NLRP3
positive regulation of inflammatory response	1	145.3×	0.010	NLRP3
negative regulation of inflammatory response	1	137.0×	0.010	NLRP3
protein homooligomerization	1	122.1×	0.010	NLRP3
cellular response to lipopolysaccharide	1	98.0×	0.012	NLRP3
inflammatory response	1	37.7×	0.031	NLRP3
innate immune response	1	33.6×	0.033	NLRP3
apoptotic process	1	28.7×	0.038	NLRP3
signal transduction	1	16.1×	0.065	NLRP3
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	NLRP3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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

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: 1; 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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.