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    SLC24A4 solute carrier family 24 member 4 [ Homo sapiens (human) ]

    Gene ID: 123041, updated on 11-Apr-2024

    Summary

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    Official Symbol
    SLC24A4provided by HGNC
    Official Full Name
    solute carrier family 24 member 4provided by HGNC
    Primary source
    HGNC:HGNC:10978
    See related
    Ensembl:ENSG00000140090 MIM:609840; AllianceGenome:HGNC:10978
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    AI2A5; NCKX4; SHEP6; SLC24A2
    Summary
    This gene encodes a sodium/potassium/calcium exchange protein. The encoded antiporter transports one calcium and one potassium ion in exchange for four sodium ions and has been implicated in amelogenesis and enamel maturation. Certain variants in this gene have been associated with skin, hair, and eye pigmentation, while other variants have been identified in people with hypomaturation-type amelogenesis imperfecta. [provided by RefSeq, Nov 2023]
    Expression
    Low expression observed in reference dataset See more
    Orthologs
    mouse all
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    Genomic context

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    Location:
    14q32.12
    Exon count:
    22
    Annotation release Status Assembly Chr Location
    RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 14 NC_000014.9 (92322581..92501481)
    RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 14 NC_060938.1 (86552327..86731081)
    105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 14 NC_000014.8 (92788925..92967825)

    Chromosome 14 - NC_000014.9Genomic Context describing neighboring genes Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8929 Neighboring gene RNA, U6 small nuclear 366, pseudogene Neighboring gene uncharacterized LOC105370627 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr14:92790043-92790622 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr14:92832163-92832664 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr14:92916101-92916601 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 6033 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8930 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr14:92937002-92937866 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr14:92966603-92967104 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr14:92967105-92967604 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 6034 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 6035 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr14:92980671-92981174 Neighboring gene uncharacterized LOC124903365 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr14:92990985-92991808 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr14:92994044-92994801 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr14:92994802-92995558 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr14:92997484-92997984 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr14:92997985-92998485 Neighboring gene MPRA-validated peak2237 silencer Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8931 Neighboring gene Ras and Rab interactor 3 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8932 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8933 Neighboring gene NANOG hESC enhancer GRCh37_chr14:93039726-93040227 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8934 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8935 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8936 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8937 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8938 Neighboring gene Sharpr-MPRA regulatory region 14383 Neighboring gene MED14-independent group 3 enhancer GRCh37_chr14:93090702-93091901 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 6037 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8939 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8940 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8941 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 8942 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr14:93122369-93122870 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr14:93128149-93128650 Neighboring gene ReSE screen-validated silencer GRCh37_chr14:93131812-93131989 Neighboring gene uncharacterized LOC124903364

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. A novel nonsense variant in SLC24A4 causing a rare form of amelogenesis imperfecta in a Pakistani family. Khan SA, et al. BMC Med Genet, 2020 May 7. PMID 32380970, Free PMC Article
    2. Lack of Association Between SLC24A4 Polymorphism and Late-onset Alzheimer's Disease in Han Chinese. Lu H, et al. Curr Neurovasc Res, 2016. PMID 27215332
    3. Reduced Protein Expression of the Na(+)/Ca(2+)+K(+)-Exchanger (SLC24A4) in Apical Plasma Membranes of Maturation Ameloblasts of Fluorotic Mice. Bronckers AL, et al. Calcif Tissue Int, 2017 Jan. PMID 27752731, Free PMC Article
    4. Elevated NCX1 and NCKX4 expression in the patent postnatal ductus arteriosus of ductal-dependent congenital heart disease patients. Hong H, et al. Pediatr Cardiol, 2015 Apr. PMID 25500693
    5. Molecular cloning of a fourth member of the potassium-dependent sodium-calcium exchanger gene family, NCKX4. Li XF, et al. J Biol Chem, 2002 Dec 13. PMID 12379639

    See all (29) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Calmodulin binds and modulates K(+)-dependent Na(+)/Ca(2+)-exchanger isoform 4, NCKX4.
      Title: Calmodulin binds and modulates K(+)-dependent Na(+)/Ca(2+)-exchanger isoform 4, NCKX4.
    2. Association between brown eye colour in rs12913832:GG individuals and SNPs in TYR, TYRP1, and SLC24A4.
      Title: Association between brown eye colour in rs12913832:GG individuals and SNPs in TYR, TYRP1, and SLC24A4.
    3. This nonsense sequence variant c.1192C > T (p.Gln398*) is the sixth disease-causing variant in SLC24A4, which extends its mutation spectrum and confirms the role of this gene in the morphogenesis of human tooth enamel. The identified variant highlights the critical role of SLC24A4 in causing a rare Amelogenesis imperfecta (AI) type in humans.
      Title: A novel nonsense variant in SLC24A4 causing a rare form of amelogenesis imperfecta in a Pakistani family.
    4. no significant relation was noted between SLC24A4 rs10498633 and late-onset Alzheimer;s disease risk in neither apolipoprotein E (APOE) epsilon4 carriers nor non-carriers after adjusting for age and gender
      Title: Lack of Association Between SLC24A4 Polymorphism and Late-onset Alzheimer's Disease in Han Chinese.
    5. pigment cells express robust, functional NCKX4 activity
      Title: Identification and Characterization of K(+)-Dependent Na(+)-Ca(2+) Exchange Transport in Pigmented MEB4 Cells Mediated by NCKX4.
    6. mutations in SLC24A4 and SLC24A5 are responsible for the phenotypic defects observed in human amylogenesis imperfecta and non-syndromic oculocutaneous albinism patients.
      Title: A Functional Study of Mutations in K+-dependent Na+-Ca2+ Exchangers Associated with Amelogenesis Imperfecta and Non-syndromic Oculocutaneous Albinism.
    7. The expressions of NCX1 and NCKX4 were significantly higher in the patent ductus arteriosus group at both the protein and mRNA levels.
      Title: Elevated NCX1 and NCKX4 expression in the patent postnatal ductus arteriosus of ductal-dependent congenital heart disease patients.
    8. enamel maturation is dependent upon STIM1 and SLC24A4 function, and that there are important differences in the Ca(2+) transcellular transport systems used by secretory- and maturation-stage ameloblasts.
      Title: STIM1 and SLC24A4 Are Critical for Enamel Maturation.
    9. Brain DNA methylation in sLC24A4 was associated with pathological Alzheimer disease.
      Title: Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease.
    10. These findings support a key role for SLC24A4 in calcium transport during enamel formation.
      Title: Identification of mutations in SLC24A4, encoding a potassium-dependent sodium/calcium exchanger, as a cause of amelogenesis imperfecta.
    Submit: New GeneRIF Correction See all GeneRIFs (18)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Associated conditions

    Description Tests
    Amelogenesis imperfecta hypomaturation type 2A5
    MedGen: C4014578 OMIM: 615887 GeneReviews: Not available
    		Compare labs
    SKIN/HAIR/EYE PIGMENTATION 6, BLOND/BROWN HAIR
    MedGen: C2673866 OMIM: 210750 GeneReviews: Not available
    		Compare labs

    EBI GWAS Catalog

    Description
    A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation.
    EBI GWAS Catalog
    Genetic determinants of hair, eye and skin pigmentation in Europeans.
    EBI GWAS Catalog
    Genome-wide association scan for survival on dialysis in African-Americans with type 2 diabetes.
    EBI GWAS Catalog
    Genome-wide association studies identify several new loci associated with pigmentation traits and skin cancer risk in European Americans.
    EBI GWAS Catalog
    Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.
    EBI GWAS Catalog
    Web-based, participant-driven studies yield novel genetic associations for common traits.
    EBI GWAS Catalog

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Genotypes

    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ38852

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables calcium channel activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables calcium, potassium:sodium antiporter activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables calcium, potassium:sodium antiporter activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables calcium, potassium:sodium antiporter activity TAS
    Traceable Author Statement
    more info
    		  
    enables calcium-dependent protein binding ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    enables calmodulin binding ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    enables symporter activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    Process Evidence Code Pubs
    involved_in amelogenesis ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in calcium ion export across plasma membrane ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in calcium ion homeostasis ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in calcium ion import across plasma membrane ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in calcium ion transmembrane transport IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in calcium ion transmembrane transport IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in cellular response to high light intensity IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in cone photoresponse recovery ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in detection of chemical stimulus involved in sensory perception of smell ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    acts_upstream_of drinking behavior ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    acts_upstream_of enamel mineralization TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in intracellular calcium ion homeostasis IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    acts_upstream_of_or_within intracellular calcium ion homeostasis IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in membrane repolarization ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in monoatomic ion transport TAS
    Traceable Author Statement
    more info
    		  
    involved_in negative regulation of calcium-mediated signaling ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    acts_upstream_of olfactory nerve maturation ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    acts_upstream_of phototransduction ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in positive regulation of gene expression IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in potassium ion transmembrane transport IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    acts_upstream_of regulation of G protein-coupled receptor signaling pathway ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    acts_upstream_of regulation of eating behavior ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in response to high light intensity ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    acts_upstream_of response to melanocyte-stimulating hormone ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in response to odorant ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in sensory perception of smell IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in sensory perception of smell ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in sodium ion transmembrane transport IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Component Evidence Code Pubs
    is_active_in apical plasma membrane ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    located_in apical plasma membrane ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    located_in cone photoreceptor outer segment ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    located_in cytoplasm ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    located_in membrane ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    is_active_in plasma membrane IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in plasma membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in plasma membrane ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    located_in plasma membrane RCA
    inferred from Reviewed Computational Analysis
    more info
    		 PubMed 
    located_in plasma membrane TAS
    Traceable Author Statement
    more info
    		  
    located_in vesicle ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  

    General protein information

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    Preferred Names
    sodium/potassium/calcium exchanger 4
    Names
    Na(+)/K(+)/Ca(2+)-exchange protein 4
    Na/Ca-K exchanger 4
    solute carrier family 24 (sodium/potassium/calcium exchanger), member 4

    NCBI Reference Sequences (RefSeq)

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    NEW Try the new Transcript table

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_023408.1 RefSeqGene

      Range
      5585..183901
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001378620.1 → NP_001365549.1  sodium/potassium/calcium exchanger 4 isoform 1 precursor

      Status: REVIEWED

      Source sequence(s)
      AL118559
      Consensus CDS
      CCDS9903.2
      UniProtKB/Swiss-Prot
      B4DHE7, B9ZVY2, Q8N8U6, Q8NCX1, Q8NFF0, Q8NFF1, Q8NFF2
      Related
      ENSP00000502715.1, ENST00000676001.1
      Conserved Domains (1) summary
      TIGR00927
      Location:80 → 606
      2A1904; K+-dependent Na+/Ca+ exchanger

    2. NM_001425254.1 → NP_001412183.1  sodium/potassium/calcium exchanger 4 isoform 2

      Status: REVIEWED

      Source sequence(s)
      AL118559

    3. NM_153646.4 → NP_705932.2  sodium/potassium/calcium exchanger 4 isoform 1 precursor

      See identical proteins and their annotated locations for NP_705932.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes the longest isoform (1).
      Source sequence(s)
      AF520704, AL118559, BC050357
      Consensus CDS
      CCDS9903.2
      UniProtKB/Swiss-Prot
      B4DHE7, B9ZVY2, Q8N8U6, Q8NCX1, Q8NFF0, Q8NFF1, Q8NFF2
      Related
      ENSP00000431840.1, ENST00000532405.6
      Conserved Domains (1) summary
      TIGR00927
      Location:80 → 606
      2A1904; K+-dependent Na+/Ca+ exchanger

    4. NM_153647.4 → NP_705933.2  sodium/potassium/calcium exchanger 4 isoform 2

      See identical proteins and their annotated locations for NP_705933.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) differs in the 5' UTR and uses an alternate in-frame splice site in the 3' coding region compared to variant 1. The resulting isoform (2) is shorter compared to isoform 1.
      Source sequence(s)
      AK295059, AL118559, BC050357
      Consensus CDS
      CCDS45155.2
      UniProtKB/Swiss-Prot
      Q8NFF2
      Related
      ENSP00000433302.1, ENST00000531433.5
      Conserved Domains (1) summary
      cl27511
      Location:80 → 587
      Na_Ca_ex; Sodium/calcium exchanger protein

    5. NM_153648.4 → NP_705934.1  sodium/potassium/calcium exchanger 4 isoform 3

      See identical proteins and their annotated locations for NP_705934.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) differs in the 5' UTR, lacks a portion of the 5' coding region and initiates translation at a downstream start codon compared to variant 1. The resulting isoform (3) is shorter at the N-terminus compared to variant 1.
      Source sequence(s)
      AF520706, AL118559, BC050357
      Consensus CDS
      CCDS45156.1
      UniProtKB/Swiss-Prot
      Q8NFF2
      Related
      ENSP00000376948.2, ENST00000393265.6
      Conserved Domains (2) summary
      TIGR00367
      Location:38 → 534
      TIGR00367; K+-dependent Na+/Ca+ exchanger related-protein
      pfam01699
      Location:388 → 540
      Na_Ca_ex; Sodium/calcium exchanger protein

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000014.9 Reference GRCh38.p14 Primary Assembly

      Range
      92322581..92501481
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_011536436.3 → XP_011534738.1  sodium/potassium/calcium exchanger 4 isoform X1

      Conserved Domains (2) summary
      TIGR00367
      Location:149 → 645
      TIGR00367; K+-dependent Na+/Ca+ exchanger related-protein
      pfam01699
      Location:499 → 651
      Na_Ca_ex; Sodium/calcium exchanger protein

    2. XM_011536437.3 → XP_011534739.1  sodium/potassium/calcium exchanger 4 isoform X2

      Conserved Domains (2) summary
      TIGR00367
      Location:149 → 626
      TIGR00367; K+-dependent Na+/Ca+ exchanger related-protein
      pfam01699
      Location:480 → 632
      Na_Ca_ex; Sodium/calcium exchanger protein

    3. XM_024449478.2 → XP_024305246.1  sodium/potassium/calcium exchanger 4 isoform X3

      Conserved Domains (1) summary
      cl27511
      Location:80 → 587
      Na_Ca_ex; Sodium/calcium exchanger protein

    4. XM_005267342.2 → XP_005267399.1  sodium/potassium/calcium exchanger 4 isoform X5

      Conserved Domains (1) summary
      pfam01699
      Location:1 → 97
      Na_Ca_ex; Sodium/calcium exchanger protein

    5. XM_011536440.2 → XP_011534742.1  sodium/potassium/calcium exchanger 4 isoform X4

      UniProtKB/TrEMBL
      B4DHR5
      Conserved Domains (1) summary
      pfam01699
      Location:202 → 354
      Na_Ca_ex; Sodium/calcium exchanger protein

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060938.1 Alternate T2T-CHM13v2.0

      Range
      86552327..86731081
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054375405.1 → XP_054231380.1  sodium/potassium/calcium exchanger 4 isoform X1

    2. XM_054375406.1 → XP_054231381.1  sodium/potassium/calcium exchanger 4 isoform X2

    3. XM_054375407.1 → XP_054231382.1  sodium/potassium/calcium exchanger 4 isoform X3

    4. XM_054375409.1 → XP_054231384.1  sodium/potassium/calcium exchanger 4 isoform X5

    5. XM_054375408.1 → XP_054231383.1  sodium/potassium/calcium exchanger 4 isoform X4

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q8NFF2.2 GenPept UniProtKB/Swiss-Prot:Q8NFF2

    Gene LinkOut

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