Familial cold autoinflammatory syndrome 3

Summary

Familial cold autoinflammatory syndrome 3 (MONDO:0013766) is a disease caused by PLCG2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PLCG2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 1,592

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	familial cold autoinflammatory syndrome 3
Mondo ID	MONDO:0013766
OMIM	614468
Orphanet	300359
DOID	DOID:0090064
UMLS	C3280914
MedGen	482544
GARD	0017369
Is cancer (heuristic)	no

Also known as: FACU · familial atypical cold urticaria · familial cold autoinflammatory syndrome 3 · familial cold autoinflammatory syndrome caused by mutation in PLCG2 · familial cold autoinflammatory syndrome type 3 · familial cold urticaria with common variable immunodeficiency · FCAS3 · PLAID · plaid · PLCG2 familial cold autoinflammatory syndrome

Data availability: 1,592 ClinVar variants · 4 GenCC gene-disease records.

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 3

Related subtypes (3): familial cold autoinflammatory syndrome 1, familial cold autoinflammatory syndrome 2, 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

600 retrieved; paginated sample, class counts are floors:

305 likely benign, 255 uncertain significance, 18 benign, 14 conflicting classifications of pathogenicity, 6 benign/likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1339554	NM_002661.5(PLCG2):c.2095G>A (p.Gly699Ser)	PLCG2	Likely pathogenic	criteria provided, single submitter
1719981	NM_002661.5(PLCG2):c.3420T>A (p.Asp1140Glu)	PLCG2	Likely pathogenic	criteria provided, single submitter
1003693	NM_002661.5(PLCG2):c.97T>C (p.Phe33Leu)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007792	NM_002661.5(PLCG2):c.3516C>T (p.Ser1172=)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1013109	NM_002661.5(PLCG2):c.3575G>C (p.Ser1192Thr)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1018565	NM_002661.5(PLCG2):c.2739+19G>A	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1022322	NM_002661.5(PLCG2):c.2503C>A (p.Leu835Ile)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033529	NM_002661.5(PLCG2):c.564+19C>T	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1102342	NM_002661.5(PLCG2):c.88G>T (p.Val30Leu)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1163585	NM_002661.5(PLCG2):c.3493G>A (p.Val1165Ile)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1177850	NM_002661.5(PLCG2):c.2486C>T (p.Thr829Ile)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1314494	NM_002661.5(PLCG2):c.1855G>A (p.Glu619Lys)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1330958	NM_002661.5(PLCG2):c.3198+6G>A	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1446154	NM_002661.5(PLCG2):c.3682C>T (p.Arg1228Trp)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1584241	NM_002661.5(PLCG2):c.2036C>G (p.Ser679Cys)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2047104	NM_002661.5(PLCG2):c.1292C>T (p.Thr431Met)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001161	NM_002661.5(PLCG2):c.1423C>G (p.His475Asp)	PLCG2	Uncertain significance	criteria provided, single submitter
1002476	NM_002661.5(PLCG2):c.2209C>G (p.Pro737Ala)	PLCG2	Uncertain significance	criteria provided, single submitter
1002723	NM_002661.5(PLCG2):c.839C>G (p.Thr280Ser)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1003896	NM_002661.5(PLCG2):c.1127G>A (p.Arg376Gln)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1004113	NM_002661.5(PLCG2):c.848C>G (p.Pro283Arg)	PLCG2	Uncertain significance	criteria provided, single submitter
1005139	NM_002661.5(PLCG2):c.2164A>G (p.Lys722Glu)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1005416	NM_002661.5(PLCG2):c.2948C>T (p.Thr983Ile)	PLCG2	Uncertain significance	criteria provided, single submitter
1007262	NM_002661.5(PLCG2):c.406G>A (p.Ala136Thr)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1007528	NM_002661.5(PLCG2):c.1562T>C (p.Ile521Thr)	PLCG2	Uncertain significance	criteria provided, single submitter
1007685	NM_002661.5(PLCG2):c.581A>T (p.Lys194Ile)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1007942	NM_002661.5(PLCG2):c.2236G>C (p.Glu746Gln)	PLCG2	Uncertain significance	criteria provided, single submitter
1009418	NM_002661.5(PLCG2):c.2866C>T (p.Arg956Cys)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1009426	NM_002661.5(PLCG2):c.3747C>G (p.Cys1249Trp)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1010041	NM_002661.5(PLCG2):c.2088C>G (p.Asn696Lys)	PLCG2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
PLCG2	Strong	Autosomal dominant	familial cold autoinflammatory syndrome 3	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLCG2	Orphanet:300359	PLCG2-associated antibody deficiency and immune dysregulation
PLCG2	Orphanet:324530	Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation
BCO1	Orphanet:199285	Hereditary hypercarotenemia and vitamin A deficiency

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
PLCG2	HGNC:9066	ENSG00000197943	P16885	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2	gencc,clinvar
BCO1	HGNC:13815	ENSG00000135697	Q9HAY6	Beta,beta-carotene 15,15’-dioxygenase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
BCO1	Beta,beta-carotene 15,15’-dioxygenase	Symmetrically cleaves beta-carotene into two molecules of retinal using a dioxygenase mechanism.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	8.6×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLCG2	Scaffold/PPI	no	3.1.4.11	C2_dom, PLipase_C_PInositol-sp_X_dom, SH2
BCO1	Enzyme (other)	yes	1.13.11.63	Carotenoid_Oase

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
blood	1
bone marrow cell	1
renal glomerulus	1
jejunal mucosa	1
pigmented layer of retina	1
retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLCG2	249	ubiquitous	marker	renal glomerulus, bone marrow cell, blood
BCO1	130	tissue_specific	marker	pigmented layer of retina, retina, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLCG2	2,421
BCO1	821

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLCG2	P16885	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BCO1	Q9HAY6	90.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. 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×	0.011	PLCG2
Role of phospholipids in phagocytosis	1	228.4×	0.011	PLCG2
Synthesis of IP3 and IP4 in the cytosol	1	211.5×	0.011	PLCG2
Dectin-2 family	1	211.5×	0.011	PLCG2
Metabolism of fat-soluble vitamins	1	190.3×	0.011	BCO1
DAP12 signaling	1	184.2×	0.011	PLCG2
FCERI mediated Ca+2 mobilization	1	178.4×	0.011	PLCG2
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	178.4×	0.011	PLCG2
Generation of second messenger molecules	1	173.0×	0.011	PLCG2
FCERI mediated MAPK activation	1	173.0×	0.011	PLCG2
Signaling by CSF1 (M-CSF) in myeloid cells	1	173.0×	0.011	PLCG2
GPVI-mediated activation cascade	1	154.3×	0.011	PLCG2
FCGR3A-mediated IL10 synthesis	1	146.4×	0.011	PLCG2
Visual phototransduction	1	129.8×	0.011	BCO1
Retinoid metabolism and transport	1	124.1×	0.011	BCO1
CLEC7A (Dectin-1) signaling	1	71.4×	0.018	PLCG2
Toll Like Receptor 4 (TLR4) Cascade	1	65.6×	0.019	PLCG2
Metabolism of vitamins and cofactors	1	58.3×	0.019	BCO1
Potential therapeutics for SARS	1	57.1×	0.019	PLCG2
Sensory Perception	1	47.6×	0.022	BCO1
Metabolism	1	5.8×	0.165	BCO1

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
vitamin A biosynthetic process	1	8426.0×	0.004	BCO1
beta-carotene metabolic process	1	8426.0×	0.004	BCO1
carotene catabolic process	1	4213.0×	0.004	BCO1
cellular response to lectin	1	4213.0×	0.004	PLCG2
inositol trisphosphate biosynthetic process	1	2808.7×	0.004	PLCG2
follicular B cell differentiation	1	2106.5×	0.004	PLCG2
regulation of calcineurin-NFAT signaling cascade	1	2106.5×	0.004	PLCG2
positive regulation of dendritic cell cytokine production	1	1685.2×	0.004	PLCG2
positive regulation of interleukin-23 production	1	1203.7×	0.005	PLCG2
response to yeast	1	1053.2×	0.006	PLCG2
cell activation	1	842.6×	0.006	PLCG2
programmed cell death	1	648.1×	0.006	PLCG2
positive regulation of phagocytosis, engulfment	1	648.1×	0.006	PLCG2
phospholipid catabolic process	1	601.9×	0.006	PLCG2
positive regulation of neuroinflammatory response	1	601.9×	0.006	PLCG2
macrophage activation involved in immune response	1	561.7×	0.006	PLCG2
positive regulation of cell cycle G1/S phase transition	1	561.7×	0.006	PLCG2
positive regulation of reactive oxygen species biosynthetic process	1	561.7×	0.006	PLCG2
retinal metabolic process	1	468.1×	0.006	BCO1
antifungal innate immune response	1	468.1×	0.006	PLCG2
phosphatidylinositol metabolic process	1	443.5×	0.006	PLCG2
stimulatory C-type lectin receptor signaling pathway	1	366.4×	0.006	PLCG2
Fc-epsilon receptor signaling pathway	1	366.4×	0.006	PLCG2
negative regulation of programmed cell death	1	366.4×	0.006	PLCG2
positive regulation of macrophage cytokine production	1	366.4×	0.006	PLCG2
positive regulation of receptor internalization	1	351.1×	0.006	PLCG2
phosphatidylinositol-mediated signaling	1	351.1×	0.006	PLCG2
positive regulation of intracellular signal transduction	1	324.1×	0.006	PLCG2
toll-like receptor signaling pathway	1	300.9×	0.007	PLCG2
positive regulation of NLRP3 inflammasome complex assembly	1	290.6×	0.007	PLCG2

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
PLCG2	0	0
BCO1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PLCG2	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLCG2	3.1.4.11	phosphoinositide phospholipase C
BCO1	1.13.11.63	beta-carotene 15,15’-dioxygenase

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	1	BCO1
E	Difficult family or no structure, no drug	1	PLCG2

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)
PLCG2	11	—
BCO1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.