autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

Summary

autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (MONDO:0013944) is a disease caused by PLCG2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PLCG2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 222

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation
Mondo ID	MONDO:0013944
OMIM	614878
Orphanet	324530
DOID	DOID:0070615
UMLS	C3553961
MedGen	766875
GARD	0017486
Is cancer (heuristic)	no

Also known as: APLAID · AUTOINFLAMMATION, antibody deficiency, and immune dysregulation, PLCG2-associated

Data availability: 222 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › autoinflammatory syndrome › autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

Related subtypes (36): cherubism, chronic recurrent multifocal osteomyelitis, Pelger-Huet-like anomaly and episodic fever with abdominal pain, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, psoriasis 14, pustular, periodic fever syndrome, infantile onset panniculitis with uveitis and systemic granulomatosis, idiopathic recurrent pericarditis, pyoderma gangrenosum-acne-suppurative hidradenitis syndrome, neonatal inflammatory skin and bowel disease, magic syndrome, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, Schnitzler syndrome, PFAPA syndrome, pyoderma gangrenosum, SAPHO syndrome, sarcoidosis, adult-onset Still disease, systemic-onset juvenile idiopathic arthritis, VEXAS syndrome, autoinflammatory syndrome, familial, Behcet-like, CEBPE-associated autoinflammation-immunodeficiency-neutrophil dysfunction syndrome, type 1 interferonopathy, autoinflammatory disease, X-linked, autoinflammatory syndrome with immunodeficiency, early-onset pulmonary and cutaneous vasculitis, autoinflammatory syndrome due to TBK1 deficiency, F12-associated cold autoinflammatory syndrome, neonatal-onset severe multisystemic autoinflammatory disease with increased IL18, SAMD9L-associated autoinflammatory syndrome, autoinflammatory syndrome of childhood, autoinflammatory disease, systemic, with vasculitis, granulomatous autoinflammatory syndrome of childhood, autoinflammatory disease, multisystem, with immune dysregulation, X-linked, PAPASH syndrome, Sharpin-related 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

222 retrieved; paginated sample, class counts are floors:

101 uncertain significance, 56 likely benign, 34 benign/likely benign, 15 conflicting classifications of pathogenicity, 13 benign, 2 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
39696	NM_002661.5(PLCG2):c.2120C>A (p.Ser707Tyr)	PLCG2	Pathogenic	no assertion criteria provided
1251962	NM_002661.5(PLCG2):c.2119T>C (p.Ser707Pro)	PLCG2	Likely pathogenic	no assertion criteria provided
1693266	NM_002661.5(PLCG2):c.2534T>C (p.Leu845Ser)	PLCG2	Likely pathogenic	no assertion criteria provided
1007792	NM_002661.5(PLCG2):c.3516C>T (p.Ser1172=)	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
1163585	NM_002661.5(PLCG2):c.3493G>A (p.Val1165Ile)	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
1446154	NM_002661.5(PLCG2):c.3682C>T (p.Arg1228Trp)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
432319	NM_002661.5(PLCG2):c.502A>G (p.Thr168Ala)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
472906	NM_002661.5(PLCG2):c.923C>T (p.Ala308Val)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
618829	NM_002661.5(PLCG2):c.77C>T (p.Thr26Met)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626149	NM_002661.5(PLCG2):c.2031C>T (p.Ser677=)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
650329	NM_002661.5(PLCG2):c.421A>G (p.Ile141Val)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
656441	NM_002661.5(PLCG2):c.2581+10C>G	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
661436	NM_002661.5(PLCG2):c.313G>A (p.Val105Ile)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
859161	NM_002661.5(PLCG2):c.3343C>T (p.Pro1115Ser)	PLCG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002723	NM_002661.5(PLCG2):c.839C>G (p.Thr280Ser)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1005139	NM_002661.5(PLCG2):c.2164A>G (p.Lys722Glu)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1007262	NM_002661.5(PLCG2):c.406G>A (p.Ala136Thr)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1007685	NM_002661.5(PLCG2):c.581A>T (p.Lys194Ile)	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
1014340	NM_002661.5(PLCG2):c.3002G>A (p.Arg1001His)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1017518	NM_002661.5(PLCG2):c.2399C>G (p.Ser800Cys)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1018728	NM_002661.5(PLCG2):c.628A>C (p.Met210Leu)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1021222	NM_002661.5(PLCG2):c.3750C>G (p.Asn1250Lys)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1023072	NM_002661.5(PLCG2):c.3289A>G (p.Asn1097Asp)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029618	NM_002661.5(PLCG2):c.906G>C (p.Trp302Cys)	PLCG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033527	NM_002661.5(PLCG2):c.1868G>T (p.Arg623Leu)	PLCG2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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	autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation	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

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
PLCG2	HGNC:9066	ENSG00000197943	P16885	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2	gencc,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.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	17.3×	0.058

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

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
blood	1
bone marrow cell	1
renal glomerulus	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLCG2	2,421

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLCG2	P16885	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
Erythropoietin activates Phospholipase C gamma (PLCG)	1	1631.4×	0.004	PLCG2
Role of phospholipids in phagocytosis	1	456.8×	0.004	PLCG2
Synthesis of IP3 and IP4 in the cytosol	1	423.0×	0.004	PLCG2
Dectin-2 family	1	423.0×	0.004	PLCG2
DAP12 signaling	1	368.4×	0.004	PLCG2
FCERI mediated Ca+2 mobilization	1	356.9×	0.004	PLCG2
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	356.9×	0.004	PLCG2
Generation of second messenger molecules	1	346.1×	0.004	PLCG2
FCERI mediated MAPK activation	1	346.1×	0.004	PLCG2
Signaling by CSF1 (M-CSF) in myeloid cells	1	346.1×	0.004	PLCG2
GPVI-mediated activation cascade	1	308.6×	0.004	PLCG2
FCGR3A-mediated IL10 synthesis	1	292.8×	0.004	PLCG2
CLEC7A (Dectin-1) signaling	1	142.8×	0.008	PLCG2
Toll Like Receptor 4 (TLR4) Cascade	1	131.3×	0.008	PLCG2
Potential therapeutics for SARS	1	114.2×	0.009	PLCG2

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
cellular response to lectin	1	8426.0×	0.003	PLCG2
inositol trisphosphate biosynthetic process	1	5617.3×	0.003	PLCG2
follicular B cell differentiation	1	4213.0×	0.003	PLCG2
regulation of calcineurin-NFAT signaling cascade	1	4213.0×	0.003	PLCG2
positive regulation of dendritic cell cytokine production	1	3370.4×	0.003	PLCG2
positive regulation of interleukin-23 production	1	2407.4×	0.003	PLCG2
response to yeast	1	2106.5×	0.003	PLCG2
cell activation	1	1685.2×	0.003	PLCG2
programmed cell death	1	1296.3×	0.003	PLCG2
positive regulation of phagocytosis, engulfment	1	1296.3×	0.003	PLCG2
phospholipid catabolic process	1	1203.7×	0.003	PLCG2
positive regulation of neuroinflammatory response	1	1203.7×	0.003	PLCG2
macrophage activation involved in immune response	1	1123.5×	0.003	PLCG2
positive regulation of cell cycle G1/S phase transition	1	1123.5×	0.003	PLCG2
positive regulation of reactive oxygen species biosynthetic process	1	1123.5×	0.003	PLCG2
antifungal innate immune response	1	936.2×	0.003	PLCG2
phosphatidylinositol metabolic process	1	887.0×	0.003	PLCG2
stimulatory C-type lectin receptor signaling pathway	1	732.7×	0.003	PLCG2
Fc-epsilon receptor signaling pathway	1	732.7×	0.003	PLCG2
negative regulation of programmed cell death	1	732.7×	0.003	PLCG2
positive regulation of macrophage cytokine production	1	732.7×	0.003	PLCG2
positive regulation of receptor internalization	1	702.2×	0.003	PLCG2
phosphatidylinositol-mediated signaling	1	702.2×	0.003	PLCG2
positive regulation of intracellular signal transduction	1	648.1×	0.003	PLCG2
toll-like receptor signaling pathway	1	601.9×	0.003	PLCG2
positive regulation of NLRP3 inflammasome complex assembly	1	581.1×	0.003	PLCG2
lipopolysaccharide-mediated signaling pathway	1	526.6×	0.003	PLCG2
response to axon injury	1	510.7×	0.003	PLCG2
cellular response to lipid	1	495.6×	0.003	PLCG2
regulation of canonical NF-kappaB signal transduction	1	481.5×	0.003	PLCG2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

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

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	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: 0.