PLSCR2

Summary

PLSCR2 (phospholipid scramblase 2, HGNC:16494) is a protein-coding gene on chromosome 3q24, encoding Phospholipid scramblase 2 (Q9NRY7). May catalyze calcium-induced ATP-independent rapid bidirectional and non-specific movement of phospholipids (lipid scrambling or lipid flip-flop) between the inner and outer leaflet of the plasma membrane.

This gene encodes a member of the phospholipid scramblase family. Phospholipid scramblases are membrane proteins that mediate calcium-dependent, non-specific movement of plasma membrane phospholipids and phosphatidylserine exposure. The encoded protein contains a low affinity calcium binding motif and may play a role in blood coagulation and apoptosis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 57047 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 45 total
• MANE Select transcript: NM_001395437

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16494
Approved symbol	PLSCR2
Name	phospholipid scramblase 2
Location	3q24
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000163746
Ensembl biotype	protein_coding
OMIM	607610
Entrez	57047

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000336685, ENST00000463633, ENST00000474418, ENST00000489015, ENST00000497985, ENST00000610787, ENST00000613069, ENST00000696113, ENST00000696119, ENST00000696120, ENST00000941950

RefSeq mRNA: 7 — MANE Select: NM_001395437 NM_001199978, NM_001199979, NM_001395437, NM_001395438, NM_001395439, NM_001395440, NM_020359

CCDS: CCDS3134, CCDS56284, CCDS75029

Canonical transcript exons

ENST00000696113 — 8 exons

Exon	Start	End
ENSE00001077881	146441758	146441821
ENSE00001342057	146433288	146433517
ENSE00002353302	146458411	146458453
ENSE00002356654	146455239	146455459
ENSE00002385967	146449206	146449367
ENSE00003684914	146459848	146460083
ENSE00003789677	146454002	146454163
ENSE00003966039	146469495	146469561

Expression profiles

Bgee: expression breadth ubiquitous, 159 present calls, max score 98.87.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1088 / max 13.0498, expressed in 41 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44927	0.0588	25
44926	0.0500	17

Top tissues by expression

278 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	98.87	gold quality
male germ cell	CL:0000015	95.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.84	gold quality
left testis	UBERON:0004533	79.24	gold quality
right testis	UBERON:0004534	77.76	gold quality
testis	UBERON:0000473	77.37	gold quality
buccal mucosa cell	CL:0002336	71.99	silver quality
granulocyte	CL:0000094	68.91	gold quality
monocyte	CL:0000576	68.16	gold quality
mononuclear cell	CL:0000842	67.99	gold quality
islet of Langerhans	UBERON:0000006	67.10	gold quality
leukocyte	CL:0000738	66.05	gold quality
body of pancreas	UBERON:0001150	64.96	gold quality
pancreas	UBERON:0001264	64.39	gold quality
secondary oocyte	CL:0000655	63.09	gold quality
adult organism	UBERON:0007023	62.99	gold quality
metanephros cortex	UBERON:0010533	62.49	gold quality
pancreatic ductal cell	CL:0002079	61.19	silver quality
gall bladder	UBERON:0002110	60.17	gold quality
rectum	UBERON:0001052	58.89	gold quality
mucosa of transverse colon	UBERON:0004991	58.83	gold quality
left uterine tube	UBERON:0001303	57.75	gold quality
adult mammalian kidney	UBERON:0000082	57.70	gold quality
right uterine tube	UBERON:0001302	57.38	gold quality
vermiform appendix	UBERON:0001154	57.27	gold quality
transverse colon	UBERON:0001157	57.14	gold quality
blood	UBERON:0000178	55.95	gold quality
minor salivary gland	UBERON:0001830	55.64	gold quality
fallopian tube	UBERON:0003889	54.93	gold quality
metanephros	UBERON:0000081	54.85	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.91

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA2

miRNA regulators (miRDB)

18 targeting PLSCR2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-4452	99.50	68.45	1493
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-6074	98.89	69.64	2187
HSA-MIR-936	98.87	70.51	1124
HSA-MIR-502-5P	98.77	66.51	906
HSA-MIR-648	98.64	66.13	553
HSA-MIR-6841-3P	98.08	66.54	604
HSA-MIR-301A-5P	96.88	68.07	931
HSA-MIR-301B-5P	96.88	67.75	946
HSA-MIR-217-3P	95.67	68.42	1000

Literature-anchored findings (GeneRIF, showing 2)

• Results show that binding affinities of the peptides are in the order hPLSCR1>hPLSCR3>hPLSCR2>hPLSCR4 for Ca2+ and in the order hPLSCR1>hPLSCR2>hPLSCR3>hPLSCR4 for Mg2+. (PMID:19540310)
• hPLSCR1 and PRD-hPLSCR2 showed Ca(2+)-dependent aggregation and scrambling activity (PMID:24648509)

Cross-species orthologs

17 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-71m22.1	ENSDARG00000058638
danio_rerio	plscr3b	ENSDARG00000069432
danio_rerio	si:ch73-206p6.1	ENSDARG00000077468
danio_rerio	si:ch211-71m22.3	ENSDARG00000079075
danio_rerio	si:ch211-71m22.5	ENSDARG00000091266
danio_rerio	si:dkey-62k3.6	ENSDARG00000091614
danio_rerio	plscr3a	ENSDARG00000093078
danio_rerio		ENSDARG00000100828
danio_rerio	si:ch73-170d6.4	ENSDARG00000102460
caenorhabditis_elegans	scrm-4	WBGENE00008681
caenorhabditis_elegans	scrm-6	WBGENE00009753
caenorhabditis_elegans	scrm-1	WBGENE00011935
caenorhabditis_elegans		WBGENE00013052
caenorhabditis_elegans	scrm-2	WBGENE00014200
caenorhabditis_elegans		WBGENE00015437
caenorhabditis_elegans		WBGENE00019530
caenorhabditis_elegans		WBGENE00019531

Paralogs (4): PLSCR4 (ENSG00000114698), PLSCR3 (ENSG00000187838), PLSCR1 (ENSG00000188313), PLSCR5 (ENSG00000231213)

Protein

Protein identifiers

Phospholipid scramblase 2 — Q9NRY7 (reviewed: Q9NRY7)

Alternative names: Ca(2+)-dependent phospholipid scramblase 2

All UniProt accessions (3): C9J636, Q9NRY7, F8WEZ1

UniProt curated annotations — full annotation on UniProt →

Function. May catalyze calcium-induced ATP-independent rapid bidirectional and non-specific movement of phospholipids (lipid scrambling or lipid flip-flop) between the inner and outer leaflet of the plasma membrane. Has no phospholipid scramblase activity, due to the lack of a N-terminal proline-rich domain.

Subcellular location. Membrane Nucleus.

Tissue specificity. Expression of isoform 1 seems restricted to testis.

Domain organisation. The N-terminal proline-rich domain (PRD) is required for phospholipid scramblase activity.

Similarity. Belongs to the phospholipid scramblase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NRY7-2	2	yes
Q9NRY7-1	1
Q9NRY7-3	3

RefSeq proteins (7): NP_001186907, NP_001186908, NP_001382366, NP_001382367, NP_001382368, NP_001382369, NP_065092 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005552	Scramblase	Family

Pfam: PF03803

Enzyme classification (BRENDA):

• EC 7.6.2.1 — P-type phospholipid transporter (BRENDA: 22 organisms, 260 substrates, 62 inhibitors, 53 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.016–2.215	41
P-NITROPHENYL PHOSPHATE	1.17–1.46	3
ACETYL PHOSPHATE	1.03–1.31	2
1-PALMITOYL-2-OLEOYL-SN-GLYCERO-3-PHOSPHO-L-SERI	0.111	1

Catalyzed reactions (Rhea), 1 shown:

• a 1,2-diacyl-sn-glycero-3-phosphocholine(in) = a 1,2-diacyl-sn-glycero-3-phosphocholine(out) (RHEA:38571)

UniProt features (14 total): lipid moiety-binding region 5, topological domain 2, splice variant 2, chain 1, sequence conflict 1, transmembrane region 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRY7-F1	70.24	0.38

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (6): 177, 149, 172, 173, 174, 176

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 73 (showing top): chr3q24, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_PLASMA_MEMBRANE_ORGANIZATION, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_REGULATION_OF_MEMBRANE_LIPID_DISTRIBUTION, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, OCT1_06, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS

GO Biological Process (1): plasma membrane phospholipid scrambling (GO:0017121)

GO Molecular Function (4): calcium ion binding (GO:0005509), phospholipid scramblase activity (GO:0017128), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
plasma membrane organization	1
phospholipid translocation	1
metal ion binding	1
plasma membrane phospholipid scrambling	1
intramembrane lipid carrier activity	1
binding	1
cation binding	1
nuclear lumen	1
cytoplasm	1
endomembrane system	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

318 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLSCR2	DEPDC4	Q8N2C3	395
PLSCR2	MED1	Q15648	370
PLSCR2	MS4A13	Q5J8X5	336
PLSCR2	HEATR4	Q86WZ0	325
PLSCR2	C1QL1	O75973	311
PLSCR2	ANO6	Q4KMQ2	302
PLSCR2	SH3TC1	Q8TE82	300
PLSCR2	ZNF461	Q8TAF7	290
PLSCR2	NPEPL1	Q8NDH3	275
PLSCR2	MAMDC4	Q6UXC1	271
PLSCR2	COL28A1	Q2UY09	271
PLSCR2	ZFP30	Q9Y2G7	269
PLSCR2	PCED1B	Q96HM7	266
PLSCR2	LRRC47	Q8N1G4	263
PLSCR2	WIF1	Q9Y5W5	249

IntAct

43 interactions, top by confidence:

A	B	Type	Score
FAM221B	PLSCR2	psi-mi:“MI:0915”(physical association)	0.560
POU4F2	PLSCR2	psi-mi:“MI:0915”(physical association)	0.560
LCE3E	PLSCR2	psi-mi:“MI:0915”(physical association)	0.560
PLSCR2	LCE1A	psi-mi:“MI:0915”(physical association)	0.560
OTX1	PLSCR2	psi-mi:“MI:0915”(physical association)	0.560
LCE5A	PLSCR2	psi-mi:“MI:0915”(physical association)	0.560
HOXA1	PLSCR2	psi-mi:“MI:0915”(physical association)	0.560
LYPD1	PLSCR2	psi-mi:“MI:0915”(physical association)	0.560
COQ9	PLSCR2	psi-mi:“MI:0915”(physical association)	0.560
PLSCR2	GNG13	psi-mi:“MI:0915”(physical association)	0.560
BSND	PLSCR2	psi-mi:“MI:0915”(physical association)	0.560
LCE3A	PLSCR2	psi-mi:“MI:0915”(physical association)	0.560
AQP1	PLSCR2	psi-mi:“MI:0915”(physical association)	0.560
PLSCR2	EP300	psi-mi:“MI:0915”(physical association)	0.370
FAM221B	PLSCR2	psi-mi:“MI:0915”(physical association)	0.000
POU4F2	PLSCR2	psi-mi:“MI:0915”(physical association)	0.000
LCE3E	PLSCR2	psi-mi:“MI:0915”(physical association)	0.000
LCE1A	PLSCR2	psi-mi:“MI:0915”(physical association)	0.000
OTX1	PLSCR2	psi-mi:“MI:0915”(physical association)	0.000
LCE5A	PLSCR2	psi-mi:“MI:0915”(physical association)	0.000
GNG13	PLSCR2	psi-mi:“MI:0915”(physical association)	0.000
HOXA1	PLSCR2	psi-mi:“MI:0915”(physical association)	0.000
PLSCR2	LYPD1	psi-mi:“MI:0915”(physical association)	0.000
PLSCR2	COQ9	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (15): PLSCR2 (Two-hybrid), PLSCR2 (Two-hybrid), PLSCR2 (Two-hybrid), PLSCR2 (Two-hybrid), PLSCR2 (Two-hybrid), PLSCR2 (Two-hybrid), PLSCR2 (Two-hybrid), LCE3A (Two-hybrid), LCE3E (Two-hybrid), LCE5A (Two-hybrid), LCE1A (Two-hybrid), FAM221B (Two-hybrid), AQP1 (Two-hybrid), PLSCR2 (Two-hybrid), PLSCR2 (Two-hybrid)

ESM2 similar proteins: A0PG75, A2A3N6, A7T1N0, A8XKF2, B3H5L1, D4A2Z8, E9PU17, E9PX95, F1S5L4, F4IM84, O08619, O15162, O42857, O75386, P00488, P34751, P41879, P47140, P58195, P58196, P97564, Q05187, Q05B79, Q09306, Q0KHU5, Q28C60, Q3UW68, Q3ZBG9, Q5GJ77, Q5XI69, Q69RI8, Q6DCK1, Q6DNF3, Q6QBQ4, Q6S5G3, Q84M24, Q8IJH8, Q8VHK9, Q9DCW2, Q9FHK8

Diamond homologs: A0PG75, O15162, P58195, P58196, Q3ZBG9, Q6QBQ4, Q9DCW2, Q9JIZ9, Q9JJ00, Q9NRQ2, Q9NRY6, Q9NRY7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

45 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1057 predictions. Top by Δscore:

Variant	Effect	Δscore
3:146433517:CCTA:C	acceptor_gain	0.9900
3:146449204:A:AC	donor_gain	0.9900
3:146449205:C:CC	donor_gain	0.9900
3:146459843:ATTAC:A	donor_loss	0.9900
3:146459844:TTA:T	donor_loss	0.9900
3:146459845:TA:T	donor_loss	0.9900
3:146459846:AC:A	donor_loss	0.9900
3:146459847:CCTGA:C	donor_gain	0.9900
3:146460084:C:CC	acceptor_gain	0.9900
3:146433515:ATCC:A	acceptor_loss	0.9800
3:146433517:CCTAT:C	acceptor_loss	0.9800
3:146433519:T:A	acceptor_loss	0.9800
3:146459841:AAATT:A	donor_loss	0.9800
3:146459842:AATT:A	donor_loss	0.9800
3:146460080:GGTC:G	acceptor_gain	0.9800
3:146460080:GGTCC:G	acceptor_loss	0.9800
3:146460082:TC:T	acceptor_gain	0.9800
3:146460082:TCCT:T	acceptor_loss	0.9800
3:146460083:CC:C	acceptor_gain	0.9800
3:146460083:CCTG:C	acceptor_loss	0.9800
3:146460084:CT:C	acceptor_loss	0.9800
3:146460085:T:G	acceptor_loss	0.9800
3:146461832:A:AC	donor_gain	0.9800
3:146461833:C:CC	donor_gain	0.9800
3:146458450:CTAT:C	acceptor_gain	0.9700
3:146459455:CTGG:C	donor_gain	0.9700
3:146433516:TC:T	acceptor_gain	0.9600
3:146433520:A:C	acceptor_gain	0.9600
3:146459848:C:A	donor_loss	0.9600
3:146459924:C:CT	donor_gain	0.9600

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000008046 (3:146426129 C>G), RS1000020408 (3:146436023 A>G), RS1000078391 (3:146411924 C>A,T), RS1000090602 (3:146440432 G>C), RS1000092130 (3:146434816 C>A,T), RS1000106260 (3:146496972 G>A), RS1000142835 (3:146440116 G>C), RS1000172180 (3:146475200 C>T), RS1000189877 (3:146489061 C>G), RS1000196165 (3:146411580 A>T), RS1000201968 (3:146474925 G>T), RS1000218583 (3:146429227 T>C), RS1000257838 (3:146447048 TGTG>T), RS1000264856 (3:146442975 A>C), RS1000314368 (3:146453914 A>G,T)

Disease associations

OMIM: gene MIM:607610 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008162_104	Hip circumference	6.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
sodium arsenite	affects methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, affects response to substance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	1
Tretinoin	increases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.