PLCG2

Chr 16AD

phospholipase C gamma 2

Also known as: APLAID, FCAS3, PLC-IV, PLC-gamma-2

NCBI Gene: 5336ENSG00000197943UniProt: P16885

The protein encoded by this gene is a transmembrane signaling enzyme that catalyzes the conversion of 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate to 1D-myo-inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) using calcium as a cofactor. IP3 and DAG are second messenger molecules important for transmitting signals from growth factor receptors and immune system receptors across the cell membrane. Mutations in this gene have been found in autoinflammation, antibody deficiency, and immune dysregulation syndrome and familial cold autoinflammatory syndrome 3. [provided by RefSeq, Mar 2014]

Primary Disease Associations & Inheritance

Autoinflammation, antibody deficiency, and immune dysregulation syndromeMIM #614878
AD
Familial cold autoinflammatory syndrome 3MIM #614468
AD
1896
ClinVar variants
4
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— PLCG2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
4 Pathogenic / Likely Pathogenic· 232 VUS of 1896 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.28LOEUF
pLI 0.996
Z-score 6.87
OE 0.18 (0.12–0.28)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.82Z-score
OE missense 0.92 (0.86–0.98)
711 obs / 774.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.18 (0.12–0.28)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.86–0.98)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.36
0≤1.21.6
LoF obs/exp: 15 / 82.2Missense obs/exp: 711 / 774.8Syn Z: -5.04

ClinVar Variant Classifications

1896 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
VUS232
Likely Benign141
4
Pathogenic
232
VUS
141
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
4
0
4
Likely Pathogenic
0
0
0
0
0
VUS
5
197
23
7
232
Likely Benign
0
2
76
63
141
Benign
0
0
0
0
0
Total519910370377

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PLCG2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PLCG2-related autoinflammation, antibody deficiency, and immune dysregulation syndrome

limited
ADUndeterminedAltered Gene Product Structure
Dev. DisordersSkin
G2P ↗
missense variantinframe deletioninframe insertion

PLCG2-related familial cold autoinflammatory syndrome

limited
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Autoinflammation, antibody deficiency, and immune dysregulation syndrome

MIM #614878

Molecular basis of disorder known

Autosomal dominant

Familial cold autoinflammatory syndrome 3

MIM #614468

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer.
Chan JM et al.·Cancer Cell
2021
Cold Urticaria Syndromes: Diagnosis and Management.
Diaz VL et al.·J Allergy Clin Immunol Pract
2023Review
PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants.
Baysac K et al.·J Allergy Clin Immunol
2024Functional
PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor in ovarian cancer.
Liu C et al.·Mol Cancer
2024
Monoallelic expression can govern penetrance of inborn errors of immunity.
Stewart O et al.·Nature
2025
Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
de Rojas I et al.·Nat Commun
2021
Targeting PLCG2 Suppresses Tumor Progression, Orchestrates the Tumor Immune Microenvironment and Potentiates Immune Checkpoint Blockade Therapy for Colorectal Cancer.
Zhou X et al.·Int J Biol Sci
2024
Mutational profile in previously treated patients with chronic lymphocytic leukemia progression on acalabrutinib or ibrutinib.
Woyach JA et al.·Blood
2024Clinical trial
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.
Sims R et al.·Nat Genet
2017
Resistance to targeted therapies in chronic lymphocytic leukemia: Current status and perspectives for clinical and diagnostic practice.
Blombery P et al.·Leukemia
2025Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
B-cell MalignancyChronic Lymphocytic LeukemiaSmall Lymphocytic Lymphoma

AS-1763 in Patients With Previously Treated CLL/SLL or Non-Hodgkin Lymphoma

RECRUITING
NCT05602363Phase PHASE1Carna Biosciences, Inc.Started 2023-08-01
Docirbrutinib

External Resources

Links to major genomics databases and tools