PPP3CC

Chr 8

protein phosphatase 3 catalytic subunit gamma

Also known as: CALNA3, CNA3, PP2Bgamma

NCBI Gene: 5533ENSG00000120910UniProt: P48454

Calcineurin regulatory subunit gamma encodes a regulatory subunit of calcineurin, a calcium-dependent, calmodulin-stimulated protein phosphatase that dephosphorylates key transcription factors including NFATC1 and ELK1 in calcium-mediated signaling pathways. Mutations cause autosomal recessive severe intellectual disability with progressive spastic paraplegia, affecting both cognitive development and motor function. The gene shows high constraint against loss-of-function variants (LOEUF 0.44), indicating intolerance to protein-disrupting mutations.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
4
Pubs (1 yr)
82
P/LP submissions
0%
P/LP missense
0.44
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— PPP3CC
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.
📋
ClinVar Variants
82 unique Pathogenic / Likely Pathogenic· 69 VUS of 184 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.44LOEUF
pLI 0.264
Z-score 3.86
OE 0.24 (0.13–0.44)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
1.32Z-score
OE missense 0.78 (0.70–0.87)
222 obs / 284.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.24 (0.13–0.44)
0≤0.351.4
Missense OE0.78 (0.70–0.87)
0≤0.61.4
Synonymous OE0.84
0≤1.21.6
LoF obs/exp: 7 / 29.7Missense obs/exp: 222 / 284.4Syn Z: 1.31
DN
0.6647th %ile
GOF
0.6444th %ile
LOF
0.3843th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative 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
GOFprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

184 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic78
Likely Pathogenic4
VUS69
Likely Benign6
Benign2
78
Pathogenic
4
Likely Pathogenic
69
VUS
6
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
78
0
78
Likely Pathogenic
0
0
4
0
4
VUS
0
59
10
0
69
Likely Benign
0
2
4
0
6
Benign
0
0
2
0
2
Total061980159

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

View in ClinVar →

Protein Context — Lollipop Plot

PPP3CC · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
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Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Identifying Potential Effective Diagnostic and Prognostic Biomarkers in Sepsis by Bioinformatics Analysis and Validation
Huang X et al.·Int J Gen Med
2022
Exploration of common molecular mechanisms of psoriatic arthritis and aging based on integrated bioinformatics and single-cell RNA-seq analysis.
Liu S et al.·Biochim Biophys Acta Mol Basis Dis
2025Functional
SPATA33 localizes calcineurin to the mitochondria and regulates sperm motility in mice
Miyata H et al.·Proc Natl Acad Sci U S A
2021
FK506 binding protein 12.6-mediated inhibition of sperm-specific calcineurin is essential for FK506-induced male infertility by disturbing the homeostasis of calcium and mitochondria
Xiao YF et al.·Mol Biomed
2025
Cataloging recent advances in epigenetic alterations in major mental disorders and autism.
Abdolmaleky HM et al.·Epigenomics
2021
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients