SLC8A3

Summary

SLC8A3 (solute carrier family 8 member A3, HGNC:11070) is a protein-coding gene on chromosome 14q24.2, encoding Sodium/calcium exchanger 3 (P57103). Mediates the electrogenic exchange of Ca(2+) against Na(+) ions across the cell membrane, and thereby contributes to the regulation of cytoplasmic Ca(2+) levels and Ca(2+)-dependent cellular processes.

This gene encodes a member of the sodium/calcium exchanger integral membrane protein family. Na+/Ca2+ exchange proteins are involved in maintaining Ca2+ homeostasis in a wide variety of cell types. The protein is regulated by intracellular calcium ions and is found in both the plasma membrane and intracellular organellar membranes, where exchange of Na+ for Ca2+ occurs in an electrogenic manner. Alternative splicing has been observed for this gene and multiple variants have been described.

Source: NCBI Gene 6547 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 137 total
• MANE Select transcript: NM_182932

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11070
Approved symbol	SLC8A3
Name	solute carrier family 8 member A3
Location	14q24.2
Locus type	gene with protein product
Status	Approved
Aliases	NCX3
Ensembl gene	ENSG00000100678
Ensembl biotype	protein_coding
OMIM	607991
Entrez	6547

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000216568, ENST00000356921, ENST00000381269, ENST00000394330, ENST00000494208, ENST00000528359, ENST00000533541, ENST00000533899, ENST00000534137, ENST00000705391, ENST00000966025, ENST00000966026, ENST00000966027, ENST00000966028

RefSeq mRNA: 6 — MANE Select: NM_182932 NM_001130417, NM_033262, NM_058240, NM_182932, NM_182936, NM_183002

CCDS: CCDS35498, CCDS41967, CCDS45131, CCDS53904, CCDS9799, CCDS9800

Canonical transcript exons

ENST00000356921 — 7 exons

Exon	Start	End
ENSE00000000121	70188379	70188951
ENSE00000000122	70044215	70046323
ENSE00002232316	70166639	70168484
ENSE00003480989	70048767	70049042
ENSE00003490374	70051008	70051107
ENSE00003538125	70060836	70060939
ENSE00003690329	70051990	70052114

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 91.49.

FANTOM5 (CAGE): breadth broad, TPM avg 2.5531 / max 278.9293, expressed in 384 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143904	1.0112	203
143905	0.3872	112
143901	0.3806	77
143907	0.2333	66
143898	0.1789	49
143903	0.1673	84
143902	0.0690	37
143908	0.0438	20
143906	0.0390	20
143900	0.0228	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	91.49	gold quality
gastrocnemius	UBERON:0001388	87.69	gold quality
cortical plate	UBERON:0005343	87.63	gold quality
muscle of leg	UBERON:0001383	86.11	gold quality
skeletal muscle organ	UBERON:0014892	84.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.88	gold quality
lateral nuclear group of thalamus	UBERON:0002736	82.60	gold quality
prefrontal cortex	UBERON:0000451	82.12	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	79.98	gold quality
skeletal muscle tissue	UBERON:0001134	79.55	gold quality
deltoid	UBERON:0001476	79.46	gold quality
Brodmann (1909) area 23	UBERON:0013554	79.46	gold quality
frontal cortex	UBERON:0001870	79.37	gold quality
frontal lobe	UBERON:0016525	79.37	gold quality
neocortex	UBERON:0001950	78.81	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	78.29	gold quality
quadriceps femoris	UBERON:0001377	78.27	gold quality
Brodmann (1909) area 9	UBERON:0013540	78.22	gold quality
middle temporal gyrus	UBERON:0002771	78.12	gold quality
anterior cingulate cortex	UBERON:0009835	78.04	gold quality
vastus lateralis	UBERON:0001379	77.83	gold quality
cerebral cortex	UBERON:0000956	77.58	gold quality
primary visual cortex	UBERON:0002436	77.45	gold quality
right frontal lobe	UBERON:0002810	77.30	gold quality
hypothalamus	UBERON:0001898	77.25	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.21	gold quality
superior frontal gyrus	UBERON:0002661	76.95	gold quality
muscle tissue	UBERON:0002385	76.49	gold quality
Brodmann (1909) area 46	UBERON:0006483	76.39	gold quality
biceps brachii	UBERON:0001507	76.24	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	156.38
E-ANND-3	yes	4.53

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): APP, ESR1, KCNIP3, TLX2

miRNA regulators (miRDB)

117 targeting SLC8A3, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-4271	99.88	68.32	2244

Literature-anchored findings (GeneRIF, showing 21)

• The gene promoter of the human isoform of this protein is controlled by cAMP and calcium. (PMID:12502570)
• This review examines the regulatory features and expression pattern of the SLC8A3 gene which suggest that NCX3 activity could be crucial in neuronal functions such as memory formation and sensory processing. (PMID:15247490)
• Studies show that both alternatively spliced variants can be translated into protein. (PMID:15777725)
• The downregulation of the regulator of Ca2+ homeostasis NCX3 by Ca2+-regulated DREAM is a striking example of the autoregulatory property of the Ca2+ signal in neurons. (PMID:16306395)
• plasma membrane Na+/Ca2+ exchangers have inhibitory interactions with the 14-3-3 proteins (PMID:16679322)
• Results demonstrate a selective regulation of NCX1, NCX2 and NCX3 isoforms in Alzheimer’s disease cortex, specifically in terminals containing amyloid-beta. (PMID:21382638)
• Human platelets express K(+) -independent Na(+) /Ca(2+) exchangers NCX1.3, NCX3.2 and NCX3.4. (PMID:21790537)
• Data suggest that NCX-mediated Ca(2+) fluxes normally exist in human ASM (potentially contributing to rapid Ca(2+) fluxes), and contribute to enhanced Ca(2+) regulation in airway inflammation. (PMID:21858195)
• calcium signaling mediated by NCX3 has a crucial role in oligodendrocyte maturation and myelin formation. (PMID:21959935)
• NCX1 and NCX3 -represent two promising druggable targets for setting on new strategies in stroke therapy. (PMID:23224883)
• NCX isoforms (NCX2, NCX3) contribute to mitochondrial Na(+)/Ca(2+) exchange in human DAergic neurons and may act downstream of PINK1 in the prevention of neurodegeneration by m[Ca(2+)] accumulation. (PMID:23224884)
• the large cytosolic loop of NCX1, NCX2, and NCX3 is involved in acquisition of immunosuppressive drug specificity (PMID:23224887)
• Functional studies, as well as mRNA and protein expression analyses, revealed that NCX1 and NCX3, but not NCX2, were divergently modulated during OPC differentiation into oligodendrocyte. (PMID:23224890)
• human macrophages and monocytes express NCX1 and NCX3 that operate in a bidirectional manner to restore Ca(2+) to generate Ca(2+) signals and to induce TNF-alpha production. (PMID:23224891)
• Ayloid beta mediates calpain cleavage of NCX3 in Alzheimer’s disease brain. (PMID:23919677)
• In the discovery phase, 60 loci not previously associated with rheumatoid arthritis risk showed evidence for association and were tested for replication in the validation cohort. A total of 12 loci were replicated at the nominal level. When combining the discovery and validation cohorts, an intronic SNP in SLC8A3 was found to be associated with ACPA-positive rheumatoid arthritis at a genome-wide level of significance. (PMID:26983453)
• stimulation of NCX3 by PKA occurred through residue S524. This effect may well participate in the fight-or-flight response in skeletal muscle and the long-term potentiation in hippocampus. (PMID:28233567)
• These results…suggest that cells can use a dynamic Ca(2+) signaling toolkit in which the NCX3 sub-cellular localization changes in synchrony with the cell cycle (PMID:29526322)
• Structure-Dynamic Coupling Through Ca(2+)-Binding Regulatory Domains of Mammalian NCX Isoform/Splice Variants (PMID:29594857)
• The downregulation of NCXs is positively correlated with the prognosis of stage II-IV colon cancer. (PMID:34127021)
• Sodium-calcium exchanger-3 regulates pain ““wind-up””: From human psychophysics to spinal mechanisms. (PMID:35705078)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc8a3	ENSDARG00000004931
mus_musculus	Slc8a3	ENSMUSG00000079055
rattus_norvegicus	Slc8a3	ENSRNOG00000029871

Paralogs (7): SLC8A2 (ENSG00000118160), FRAS1 (ENSG00000138759), FREM2 (ENSG00000150893), ADGRV1 (ENSG00000164199), FREM1 (ENSG00000164946), SLC8A1 (ENSG00000183023), FREM3 (ENSG00000183090)

Protein

Protein identifiers

Sodium/calcium exchanger 3 — P57103 (reviewed: P57103)

Alternative names: Na(+)/Ca(2+)-exchange protein 3, Solute carrier family 8 member 3

All UniProt accessions (2): P57103, F2Z391

UniProt curated annotations — full annotation on UniProt →

Function. Mediates the electrogenic exchange of Ca(2+) against Na(+) ions across the cell membrane, and thereby contributes to the regulation of cytoplasmic Ca(2+) levels and Ca(2+)-dependent cellular processes. Contributes to cellular Ca(2+) homeostasis in excitable cells, both in muscle and in brain. In a first phase, voltage-gated channels mediate the rapid increase of cytoplasmic Ca(2+) levels due to release of Ca(2+) stores from the endoplasmic reticulum. SLC8A3 mediates the export of Ca(2+) from the cell during the next phase, so that cytoplasmic Ca(2+) levels rapidly return to baseline. Contributes to Ca(2+) transport during excitation-contraction coupling in muscle. In neurons, contributes to the rapid decrease of cytoplasmic Ca(2+) levels back to baseline after neuronal activation, and thereby contributes to modulate synaptic plasticity, learning and memory. Required for normal oligodendrocyte differentiation and for normal myelination. Mediates Ca(2+) efflux from mitochondria and contributes to mitochondrial Ca(2+) ion homeostasis.

Subunit / interactions. Interacts with AKAP1.

Subcellular location. Cell membrane. Perikaryon. Cell projection. Dendrite. Dendritic spine. Sarcolemma. Cytoplasm. Sarcoplasm. Cell junction. Mitochondrion outer membrane. Perinuclear region. Endoplasmic reticulum membrane.

Tissue specificity. Isoform 2 is expressed in brain and skeletal muscle. Isoform 3 is expressed in excitable cells of brain, retina and skeletal muscle. Isoform 4 is expressed in skeletal muscle.

Activity regulation. Calcium transport is down-regulated by Na(+) and stimulated by Ca(2+).

Domain organisation. The cytoplasmic Calx-beta domains bind the regulatory Ca(2+). The first Calx-beta domain can bind up to four Ca(2+) ions. The second domain can bind another two Ca(2+) ions that are essential for calcium-regulated ion exchange.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Expressed in fetal brain. Expressed in fetal brain.

Similarity. Belongs to the Ca(2+):cation antiporter (CaCA) (TC 2.A.19) family. SLC8 subfamily.

Isoforms (7)

UniProt ID	Names	Canonical?
P57103-1	3, NCX3.3	yes
P57103-2	2, NCX3.2
P57103-3	4, NCX3.4
P57103-4	5, NCX3-tN.1
P57103-5	6, NCX3-tN.2
P57103-6	7
P57103-7	8

RefSeq proteins (6): NP_001123889, NP_150287, NP_489479, NP_891977, NP_891981, NP_892114 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003644	Calx_beta	Domain
IPR004836	Na_Ca_Ex	Family
IPR004837	NaCa_Exmemb	Domain
IPR032452	Na_Ca_Ex_C-exten	Domain
IPR038081	CalX-like_sf	Homologous_superfamily
IPR044880	NCX_ion-bd_dom_sf	Homologous_superfamily
IPR051171	CaCA	Family

Pfam: PF01699, PF03160, PF16494

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(in) + 3 Na(+)(out) = Ca(2+)(out) + 3 Na(+)(in) (RHEA:69955)

UniProt features (65 total): binding site 25, topological domain 12, transmembrane region 11, splice variant 7, repeat 2, domain 2, glycosylation site 2, signal peptide 1, chain 1, region of interest 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P57103-F1	76.87	0.35

Functional residue map

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

Ligand- & substrate-binding residues (25): 409; 409; 409; 445; 445; 470; 471; 471; 471; 471; 473; 475 …

Glycosylation sites (2): 45, 823

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-418359	Reduction of cytosolic Ca++ levels
R-HSA-425561	Sodium/Calcium exchangers
R-HSA-5578775	Ion homeostasis
R-HSA-8949215	Mitochondrial calcium ion transport
R-HSA-109582	Hemostasis
R-HSA-382551	Transport of small molecules
R-HSA-397014	Muscle contraction
R-HSA-418346	Platelet homeostasis
R-HSA-418360	Platelet calcium homeostasis
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5576891	Cardiac conduction

MSigDB gene sets: 251 (showing top): GGGACCA_MIR133A_MIR133B, GOBP_MEMORY, RNGTGGGC_UNKNOWN, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_CIRCULATORY_SYSTEM_PROCESS, RORA1_01, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GCANCTGNY_MYOD_Q6, GOBP_NEUROGENESIS, GOBP_MULTICELLULAR_ORGANISMAL_MOVEMENT, MEF2_02, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (30): hematopoietic progenitor cell differentiation (GO:0002244), monoatomic ion transport (GO:0006811), mitochondrial calcium ion transmembrane transport (GO:0006851), intracellular calcium ion homeostasis (GO:0006874), cell communication (GO:0007154), learning or memory (GO:0007611), learning (GO:0007612), memory (GO:0007613), regulation of skeletal muscle contraction (GO:0014819), telencephalon development (GO:0021537), sodium ion transmembrane transport (GO:0035725), myelination (GO:0042552), oligodendrocyte differentiation (GO:0048709), synapse organization (GO:0050808), mitochondrial calcium ion homeostasis (GO:0051560), long-term synaptic potentiation (GO:0060291), calcium ion transport into cytosol (GO:0060402), calcium ion transmembrane transport (GO:0070588), cellular response to cAMP (GO:0071320), cellular response to hypoxia (GO:0071456), calcium ion import across plasma membrane (GO:0098703), modulation of excitatory postsynaptic potential (GO:0098815), negative regulation of intracellular signal transduction (GO:1902532), regulation of cardiac conduction (GO:1903779), calcium ion export across plasma membrane (GO:1990034), sodium ion transport (GO:0006814), calcium ion transport (GO:0006816), metal ion transport (GO:0030001), transmembrane transport (GO:0055085), regulation of postsynaptic cytosolic calcium ion concentration (GO:0099566)

GO Molecular Function (7): calcium:sodium antiporter activity (GO:0005432), calmodulin binding (GO:0005516), metal ion binding (GO:0046872), calcium:monoatomic cation antiporter activity involved in regulation of postsynaptic cytosolic calcium ion concentration (GO:1905060), protein binding (GO:0005515), antiporter activity (GO:0015297), calcium:monoatomic cation antiporter activity (GO:0015368)

GO Cellular Component (30): acrosomal vesicle (GO:0001669), nucleoplasm (GO:0005654), mitochondrial outer membrane (GO:0005741), endoplasmic reticulum membrane (GO:0005789), centrosome (GO:0005813), cytosol (GO:0005829), microtubule (GO:0005874), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), microtubule cytoskeleton (GO:0015630), sarcoplasm (GO:0016528), axon (GO:0030424), dendrite (GO:0030425), neuromuscular junction (GO:0031594), sarcolemma (GO:0042383), neuronal cell body (GO:0043025), dendritic spine (GO:0043197), perikaryon (GO:0043204), axon terminus (GO:0043679), synapse (GO:0045202), postsynaptic membrane (GO:0045211), perinuclear region of cytoplasm (GO:0048471), anchoring junction (GO:0070161), sperm end piece (GO:0097229), postsynapse (GO:0098794), cytoplasm (GO:0005737), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Transport of small molecules	2
Platelet calcium homeostasis	1
Metal ion SLC transporters	1
Cardiac conduction	1
Hemostasis	1
Platelet homeostasis	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
learning or memory	2
monoatomic cation transmembrane transport	2
calcium:monoatomic cation antiporter activity	2
cytoplasm	2
neuron projection	2
hemopoiesis	1
cell differentiation	1
transport	1
calcium ion transmembrane transport	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
cellular process	1
behavior	1
cognition	1
skeletal muscle contraction	1
regulation of striated muscle contraction	1
forebrain development	1
anatomical structure development	1
sodium ion transport	1
axon ensheathment	1
central nervous system development	1
glial cell differentiation	1
cell junction organization	1
mitochondrion	1
intracellular calcium ion homeostasis	1
regulation of synaptic plasticity	1
positive regulation of synaptic transmission	1
positive regulation of cytosolic calcium ion concentration	1
calcium ion transmembrane import into cytosol	1
calcium ion transport	1
response to cAMP	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
sodium ion transmembrane transporter activity	1
protein binding	1
cation binding	1

Protein interactions and networks

STRING

1014 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC8A3	SLC8B1	Q6J4K2	653
SLC8A3	ATL1	Q8WXF7	649
SLC8A3	GPHN	Q9NQX3	550
SLC8A3	ATP2B1	P20020	530
SLC8A3	ZFYVE26	Q68DK2	469
SLC8A3	BDNF	P23560	458
SLC8A3	ATP2B3	Q16720	457
SLC8A3	ATP2B4	P23634	444
SLC8A3	ATP2B2	Q01814	428
SLC8A3	ATP2A1	O14983	425
SLC8A3	GATA2	P23769	423
SLC8A3	KCNIP3	Q9Y2W7	417
SLC8A3	CREB1	P16220	410
SLC8A3	POM121L2	Q96KW2	404
SLC8A3	SPG11	Q96JI7	390

IntAct

5 interactions, top by confidence:

A	B	Type	Score
SLC8A3	APOD	psi-mi:“MI:0915”(physical association)	0.400
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC8A3	GPD2	psi-mi:“MI:0914”(association)	0.350
SLC8A3	EXTL3	psi-mi:“MI:0914”(association)	0.350

BioGRID (38): SPPL2B (Affinity Capture-MS), GPD2 (Affinity Capture-MS), CSGALNACT2 (Affinity Capture-MS), PDE3B (Affinity Capture-MS), TMEM43 (Affinity Capture-MS), EMC7 (Affinity Capture-MS), SLC8A2 (Affinity Capture-MS), REEP4 (Affinity Capture-MS), GPD2 (Affinity Capture-MS), REEP4 (Affinity Capture-MS), SLC8A2 (Affinity Capture-MS), CSGALNACT2 (Affinity Capture-MS), SPPL2B (Affinity Capture-MS), GJA8 (Two-hybrid), SLC8A3 (Affinity Capture-RNA)

ESM2 similar proteins: A0A0R4IQZ2, A0A125YSC7, A0A125YZH9, A0A1D3TGZ2, A0A1G4GWI6, A0A384J983, A0A384JSZ0, A0A679KXN5, A2WV32, C4LWU5, C8ZJM1, G4YM00, G4Z2L3, G5EBM5, O76819, P0CD92, P14773, P16393, P20715, P21441, P48768, P54960, P57103, P70549, P84737, Q0IWF3, Q28614, Q4P333, Q5JN63, Q6WNG7, Q6ZXT3, Q76L34, Q7EYH7, Q8K596, Q8S9F2, Q8VIH3, Q93Z13, Q9AT74, Q9ATN0, Q9ERH8

Diamond homologs: B8K1V7, O22252, O54701, P23685, P32418, P48765, P48766, P48767, P48768, P57103, P70414, P70549, Q01728, Q2R041, Q6H641, Q8BUN9, Q8CGQ8, Q8K596, Q8NFF2, Q99PD7, Q9EPQ0, Q9HC58, Q9UI40, Q9UPR5, Q9VDG5, Q9VN12, S4R2P9, O60721, Q49SH1, Q6JAN0, Q71RS6, Q80T14, Q8C261, Q8TPA6, Q8VHN7, Q9IAL7, Q9U6A0, Q0ZAI3, Q28139, Q8WXG9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	119
Likely benign	5
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

2277 predictions. Top by Δscore:

Variant	Effect	Δscore
14:70046319:CGTAT:C	acceptor_gain	1.0000
14:70046320:GTAT:G	acceptor_gain	1.0000
14:70046321:TAT:T	acceptor_gain	1.0000
14:70046322:AT:A	acceptor_gain	1.0000
14:70046323:TC:T	acceptor_loss	1.0000
14:70046324:C:CA	acceptor_loss	1.0000
14:70046324:C:CC	acceptor_gain	1.0000
14:70048817:TTGAG:T	donor_gain	1.0000
14:70049038:CCCTG:C	acceptor_gain	1.0000
14:70049039:CCTGC:C	acceptor_gain	1.0000
14:70049040:CTG:C	acceptor_gain	1.0000
14:70049043:C:CC	acceptor_gain	1.0000
14:70049051:A:T	acceptor_gain	1.0000
14:70051104:TAGT:T	acceptor_gain	1.0000
14:70051105:AGTC:A	acceptor_loss	1.0000
14:70051107:TCT:T	acceptor_loss	1.0000
14:70051108:C:CA	acceptor_loss	1.0000
14:70051108:C:CC	acceptor_gain	1.0000
14:70051109:T:A	acceptor_loss	1.0000
14:70051976:A:AC	donor_gain	1.0000
14:70051977:C:CC	donor_gain	1.0000
14:70051988:AC:A	donor_loss	1.0000
14:70052021:T:TA	donor_gain	1.0000
14:70052110:CACAT:C	acceptor_gain	1.0000
14:70052111:ACAT:A	acceptor_gain	1.0000
14:70052112:CAT:C	acceptor_gain	1.0000
14:70052112:CATC:C	acceptor_gain	1.0000
14:70052114:TCTG:T	acceptor_loss	1.0000
14:70052115:C:CC	acceptor_gain	1.0000
14:70052115:CTGCA:C	acceptor_loss	1.0000

AlphaMissense

6087 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:70046213:A:G	W840R	1.000
14:70046213:A:T	W840R	1.000
14:70048772:A:T	V801D	1.000
14:70048943:G:T	A744D	1.000
14:70048959:A:G	W739R	1.000
14:70048959:A:T	W739R	1.000
14:70051034:A:G	F702S	1.000
14:70051047:A:G	W698R	1.000
14:70051047:A:T	W698R	1.000
14:70051091:A:G	L683P	1.000
14:70166657:A:G	F589S	1.000
14:70166738:A:T	V562D	1.000
14:70166753:C:T	G557D	1.000
14:70166762:C:G	R554P	1.000
14:70166768:A:T	V552D	1.000
14:70166834:C:T	G530D	1.000
14:70166835:C:G	G530R	1.000
14:70166842:G:C	D527E	1.000
14:70166842:G:T	D527E	1.000
14:70166843:T:A	D527V	1.000
14:70166843:T:C	D527G	1.000
14:70166843:T:G	D527A	1.000
14:70166844:C:G	D527H	1.000
14:70166846:T:A	D526V	1.000
14:70166846:T:G	D526A	1.000
14:70166847:C:G	D526H	1.000
14:70166849:T:A	D525V	1.000
14:70166849:T:G	D525A	1.000
14:70166850:C:G	D525H	1.000
14:70166855:A:C	I523S	1.000

dbSNP variants (sampled 300 via entrez): RS1000010568 (14:70138581 G>A), RS1000011775 (14:70096951 C>T), RS1000041480 (14:70178112 T>G), RS1000074180 (14:70178434 T>C), RS1000081139 (14:70050951 T>C), RS1000130456 (14:70188796 GGC>G), RS1000134190 (14:70172996 T>C), RS1000146320 (14:70050874 C>T), RS1000154672 (14:70090309 T>C), RS1000164829 (14:70103158 TAA>T), RS1000244647 (14:70166780 A>G,T), RS1000252591 (14:70155607 A>G), RS1000269793 (14:70145102 T>C), RS1000288960 (14:70116195 C>T), RS1000294077 (14:70172498 C>T)

Disease associations

OMIM: gene MIM:607991 | disease phenotypes: MIM:145600

GenCC curated gene-disease

Mondo (2): prostate cancer (MONDO:0008315), malignant hyperthermia, susceptibility to, 1 (MONDO:0007783)

Orphanet (2): Familial prostate cancer (Orphanet:1331), Malignant hyperthermia of anesthesia (Orphanet:423)

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001077_4	Cystic fibrosis severity	8.000000e-06
GCST001680_2	Corneal curvature	4.000000e-06
GCST003518_91	Daytime sleep phenotypes	2.000000e-06
GCST008103_136	Bipolar disorder	2.000000e-06
GCST009391_1789	Metabolite levels	6.000000e-06
GCST009391_973	Metabolite levels	6.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004345	corneal topography
EFO:0007828	daytime rest measurement
EFO:0004468	glucose measurement
EFO:0010477	fructose measurement
EFO:0010481	galactose measurement
EFO:0010538	taurocholate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C535694	Malignant hyperthermia susceptibility type 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC8 family of sodium/calcium exchangers

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
YM-244769	Inhibition	7.74	pIC50
SAR296968	Inhibition	6.89	pIC50

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
Silicon Dioxide	decreases expression, increases expression	2
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
terbufos	increases methylation	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	increases expression, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
bisphenol S	decreases methylation	1
incobotulinumtoxinA	decreases expression	1
Ethanol	increases expression, increases cleavage, increases reaction, decreases reaction	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Doxorubicin	increases expression	1
Fonofos	increases methylation	1
Lead	affects expression	1
Oxygen	increases expression	1
Parathion	increases methylation	1
Sodium Chloride	increases expression, increases reaction	1
Tretinoin	increases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer