PLSCR3

Chr 17

phospholipid scramblase 3

NCBI Gene: 57048ENSG00000187838UniProt: Q9NRY6OMIM: 607611

This protein catalyzes calcium-dependent phospholipid scrambling between mitochondrial membranes and regulates cardiolipin metabolism, which is essential for mitochondrial respiratory function and morphology. Mutations in PLSCR3 cause autosomal recessive mitochondrial complex IV deficiency, nuclear type 19, presenting as a mitochondrial disorder affecting cellular respiration. The gene shows tolerance to loss-of-function variants in the general population.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 0.82
Clinical Summary— PLSCR3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
28 unique Pathogenic / Likely Pathogenic· 12 VUS of 41 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.82LOEUF
pLI 0.006
Z-score 2.05
OE 0.42 (0.23–0.82)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.83Z-score
OE missense 0.82 (0.71–0.94)
136 obs / 166.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.42 (0.23–0.82)
0≤0.351.4
Missense OE0.82 (0.71–0.94)
0≤0.61.4
Synonymous OE0.99
0≤1.21.6
LoF obs/exp: 6 / 14.4Missense obs/exp: 136 / 166.0Syn Z: 0.06
DN
0.6648th %ile
GOF
0.77top 25%
LOF
0.3258th %ile

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

GOFprediction above median
DNprediction 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

41 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic3
VUS12
Benign1
25
Pathogenic
3
Likely Pathogenic
12
VUS
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
25
0
25
Likely Pathogenic
0
0
3
0
3
VUS
0
6
6
0
12
Likely Benign
0
0
0
0
0
Benign
0
0
0
1
1
Total0634141

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

View in ClinVar →

Protein Context — Lollipop Plot

PLSCR3 · 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
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 1 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
TGFB signaling induces mitophagy via PLSCR3-mediated cardiolipin externalization in conjunction with a BNIP3L/NIX-, BNIP3-, and FUNDC1-dependent mechanism.
Yan J et al.·Autophagy
2025Functional
ALCAT1-Mediated Pathological Cardiolipin Remodeling and PLSCR3-Mediated Cardiolipin Transferring Contribute to LPS-Induced Myocardial Injury.
Han D et al.·Biomedicines
2024Open AccessFunctional
Tubby-like protein superfamily member PLSCR3 functions as a negative regulator of adipogenesis in mouse 3T3-L1 preadipocytes by suppressing induction of late differentiation stage transcription factors.
Inokawa A et al.·Biosci Rep
2015Open AccessFunctional
ALG-2-interacting Tubby-like protein superfamily member PLSCR3 is secreted by an exosomal pathway and taken up by recipient cultured cells.
Inuzuka T et al.·Biosci Rep
2013Open Access
Mobilization of pro-inflammatory lipids in obese Plscr3-deficient mice.
Mutch DM et al.·Genome Biol
2007Open Access
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