PLSCR3

Chr 17

phospholipid scramblase 3

NCBI Gene: 57048 ENSG00000187838 UniProt: Q9NRY6 OMIM: 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.

OMIM ResearchSummary from RefSeq, UniProt

Enables calcium-dependent protein binding activity; metal ion binding activity; and phospholipid scramblase activity. Involved in several processes, including apoptotic process; mitochondrial membrane organization; and regulation of release of cytochrome c from mitochondria. Located in cytosol; mitochondrion; and plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.82

Clinical Summary— PLSCR3

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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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 OE?0.42 (0.23–0.82)

0≤0.351.4

Missense OE?0.82 (0.71–0.94)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 6 / 14.4Missense obs/exp: 136 / 166.0Syn Z: 0.06

This gene — mechanism propensity

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.