PLCG2

Chr 16AD

phospholipase C gamma 2

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

NCBI Gene: 5336 ENSG00000197943 UniProt: P16885 OMIM: 600220

The encoded phospholipase C gamma 2 enzyme catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate to the second messengers IP3 and diacylglycerol, which are crucial for transmitting signals from growth factor and immune system receptors across cell membranes. Mutations cause autoinflammation, antibody deficiency, and immune dysregulation syndrome as well as familial cold autoinflammatory syndrome 3, both inherited in an autosomal dominant pattern. This gene is highly constrained against loss-of-function mutations, indicating that protein function is essential for normal cellular processes.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.282 OMIM phenotypes

Clinical Summary— PLCG2

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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.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

0.82Z-score

OE missense 0.92 (0.86–0.98)

711 obs / 774.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.18 (0.12–0.28)

0≤0.351.4

Missense OE?0.92 (0.86–0.98)

0≤0.61.4

Synonymous OE?1.36

0≤1.21.6

LoF obs/exp: 15 / 82.2Missense obs/exp: 711 / 774.8Syn Z: -5.04

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedPLCG2-related autoinflammation, antibody deficiency, and immune dysregulation syndromeOTHERAD

limitedPLCG2-related familial cold autoinflammatory syndromeLOFAD

This gene — mechanism propensity

0.3991th %ile

GOF

0.5268th %ile

LOF

0.56top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.28

GOF1 literature citation

Literature Evidence

GOFGenomic deletions in PLCG2 cause gain of PLCg(2) function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References