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…

Primary Disease Associations & Inheritance

Autoinflammation, antibody deficiency, and immune dysregulation syndromeMIM #614878

Familial cold autoinflammatory syndrome 3MIM #614468

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Autoinflammation, antibody deficiency, and immune dysregulation syndrome; Familial cold autoinflammatory syndrome 3; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.28

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in PLCG2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 32

1,918 rare PASS variants

Rare truncating (LoF)

1 in 1,500

131 rare PASS variants

Rare synonymous (reference)

1 in 36

884 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PLCG2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 43	1 in 2,100
South Asian	~43k	1 in 39	1 in 2,900
Remaining (unassigned)	~30k	1 in 34	1 in 3,000
European (Finnish)	~27k	1 in 77	1 in 2,000
Admixed American	~22k	1 in 38	1 in 1,200
African / African American	~21k	1 in 32	1 in 960
East Asian	~20k	1 in 42	1 in 1,100
Ashkenazi Jewish	~13k	1 in 100	≈ 1 in 4,300
Middle Eastern	~2,884	1 in 38	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 23 of 32 coding exons well covered in gnomAD exomes; exons 5, 7, 10, 11, 21 and 4 more marginal. Genomes: 31 of 32 (exon 10 below).? see exons ↓