PLCB4

Chr 20

phospholipase C beta 4

Also known as: ARCND2, ARCND2A, ARCND2B, PI-PLC

NCBI Gene: 5332 ENSG00000101333 UniProt: Q15147

The encoded phospholipase C beta 4 enzyme catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate, serving as a direct effector in endothelin receptor signaling pathways essential for lower jaw and middle ear development. Mutations cause auriculocondylar syndrome 2A and 2B, craniofacial malformation disorders affecting jaw and ear structures. The gene shows both autosomal dominant and autosomal recessive inheritance patterns and is highly constrained against loss-of-function variants.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of many extracellular signals in the retina. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2010]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.45

Clinical Summary— PLCB4

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Gene-Disease Validity (ClinGen)

auriculocondylar syndrome 2 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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ClinVar Variants

27 unique Pathogenic / Likely Pathogenic· 179 VUS of 383 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.45LOEUF

pLI 0.000

Z-score 5.55

OE 0.32 (0.23–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.57Z-score

OE missense 0.60 (0.55–0.65)

382 obs / 635.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.32 (0.23–0.45)

0≤0.351.4

Missense OE?0.60 (0.55–0.65)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 25 / 77.8Missense obs/exp: 382 / 635.4Syn Z: 0.13

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPLCB4-related auriculocondylar syndromeOTHERAD

This gene — mechanism propensity

0.6261th %ile

GOF

0.6052th %ile

LOF

0.3453th %ile

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

DNprediction above median · 1 literature citation

LOF30% of P/LP variants are LoF · LOEUF 0.45

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNRecently, phospholipase C, b 4 (PLCB4) mutations were identified as the major cause of autosomal dominant ACS, with mutations of the PLCB4 catalytic domain predicted to have a dominant negative effect.1

GOFTaken together these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signaling pathway, promoting UM tumorigenesis.2

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

References

ClinVar Variant Classifications

383 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic12

VUS179

Likely Benign46

Benign90

Conflicting10

Pathogenic

Likely Pathogenic

179

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	11	0	0	15
Likely Pathogenic	4	7	1	0	12
VUS	3	135	38	3	179
Likely Benign	0	10	15	21	46
Benign	0	8	73	9	90
Conflicting	—				10
Total	11	171	127	33	352

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 48) ClinVar copy-number / structural variants overlap PLCB4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →