PLCB4

Chr 20ADAR

phospholipase C beta 4

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

NCBI Gene: 5332ENSG00000101333UniProt: Q15147

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]

Primary Disease Associations & Inheritance

Auriculocondylar syndrome 2AMIM #614669
AD
Auriculocondylar syndrome 2BMIM #620458
AR
397
ClinVar variants
57
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PLCB4
🧬
Gene-Disease Validity (ClinGen)
auriculocondylar syndrome 2 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
📋
ClinVar Variants
57 Pathogenic / Likely Pathogenic· 194 VUS of 397 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
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.
0.45LOEUF
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?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.
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?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.0.32 (0.23–0.45)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.60 (0.55–0.65)
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.0.99
0≤1.21.6
LoF obs/exp: 25 / 77.8Missense obs/exp: 382 / 635.4Syn Z: 0.13

ClinVar Variant Classifications

397 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43
Likely Pathogenic14
VUS194
Likely Benign47
Benign90
Conflicting9
43
Pathogenic
14
Likely Pathogenic
194
VUS
47
Likely Benign
90
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
11
28
0
43
Likely Pathogenic
4
7
3
0
14
VUS
3
134
54
3
194
Likely Benign
0
10
16
21
47
Benign
0
8
73
9
90
Conflicting
—9
Total1117017433397

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

View in ClinVar →

Protein Context — Lollipop Plot

PLCB4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

PLCB4-related auriculocondylar syndrome

strong
ADUndeterminedAltered Gene Product Structure
Dev. DisordersSkeletal
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Auriculocondylar syndrome 2A

MIM #614669

Molecular basis of disorder known

Autosomal dominant

Auriculocondylar syndrome 2B

MIM #620458

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Auriculocondylar syndrome 2 caused by a novel PLCB4 variant in a male Chinese neonate: A case report and review of the literature.
Zhang Y et al.·Mol Genet Genomic Med
2024Review
Oncogenic signaling in uveal melanoma.
Park JJ et al.·Pigment Cell Melanoma Res
2018Review
Auriculocondylar syndrome: Pathogenesis, clinical manifestations and surgical therapies.
Li Q et al.·J Formos Med Assoc
2023Review
Respiratory and gastrointestinal dysfunctions associated with auriculo-condylar syndrome and a homozygous PLCB4 loss-of-function mutation.
Leoni C et al.·Am J Med Genet A
2016Case report
Beyond CHD7 gene: unveiling genetic diversity in clinically suspected CHARGE syndrome.
Kim D et al.·J Hum Genet
2025
Bilateral choanal stenosis in auriculocondylar syndrome caused by a PLCB4 variant.
Peart LS et al.·Am J Med Genet A
2022Case report
Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants.
Kanai SM et al.·Dis Model Mech
2022
Two Chinese Patients of Auriculocondylar Syndrome 2: A Novel PLCB4 Splicing Variant and 5-Year Follow-up.
Lin Y et al.·Cleft Palate Craniofac J
2025Case report
A homozygous missense variant in the PLCB4 gene causes severe phenotype of auriculocondylar syndrome type 2.
El Fizazi K et al.·Am J Med Genet A
2023Case report
Pathogenic Germline Variants in Uveal Melanoma Driver and BAP1-Associated Genes in Finnish Patients with Uveal Melanoma.
Repo PE et al.·Pigment Cell Melanoma Res
2025Cohort
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools