SLC39A8

Summary

SLC39A8 (solute carrier family 39 member 8, HGNC:20862) is a protein-coding gene on chromosome 4q24, encoding Metal cation symporter ZIP8 (Q9C0K1). Electroneutral divalent metal cation:bicarbonate symporter of the plasma membrane mediating the cellular uptake of zinc and manganese, two divalent metal cations important for development, tissue homeostasis and immunity.

This gene encodes a member of the SLC39 family of solute-carrier genes, which show structural characteristics of zinc transporters. The encoded protein is glycosylated and found in the plasma membrane and mitochondria, and functions in the cellular import of zinc at the onset of inflammation. It is also thought to be the primary transporter of the toxic cation cadmium, which is found in cigarette smoke. Multiple transcript variants encoding different isoforms have been found for this gene. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known.

Source: NCBI Gene 64116 — RefSeq curated summary.

At a glance

• Gene–disease (curated): SLC39A8-CDG (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 168
• Clinical variants (ClinVar): 167 total — 2 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 51
• MANE Select transcript: NM_001135146

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20862
Approved symbol	SLC39A8
Name	solute carrier family 39 member 8
Location	4q24
Locus type	gene with protein product
Status	Approved
Aliases	BIGM103, ZIP8, ZIP-8
Ensembl gene	ENSG00000138821
Ensembl biotype	protein_coding
OMIM	608732
Entrez	64116

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 33 protein_coding, 10 nonsense_mediated_decay, 6 protein_coding_CDS_not_defined

ENST00000356736, ENST00000394833, ENST00000424970, ENST00000502903, ENST00000510255, ENST00000512337, ENST00000512657, ENST00000514000, ENST00000682227, ENST00000682243, ENST00000682549, ENST00000682932, ENST00000683173, ENST00000683221, ENST00000683401, ENST00000683412, ENST00000683462, ENST00000683634, ENST00000683706, ENST00000683916, ENST00000684289, ENST00000684386, ENST00000856285, ENST00000856286, ENST00000856287, ENST00000856288, ENST00000856289, ENST00000856290, ENST00000856291, ENST00000856292, ENST00000856293, ENST00000856294, ENST00000856295, ENST00000856296, ENST00000856297, ENST00000856298, ENST00000856299, ENST00000856300, ENST00000856301, ENST00000856302, ENST00000856303, ENST00000856304, ENST00000931468, ENST00000943556, ENST00000943557, ENST00000943558, ENST00000943559, ENST00000943560, ENST00000943561

RefSeq mRNA: 4 — MANE Select: NM_001135146 NM_001135146, NM_001135147, NM_001135148, NM_022154

CCDS: CCDS3656

Canonical transcript exons

ENST00000356736 — 9 exons

Exon	Start	End
ENSE00000801398	102304317	102304481
ENSE00000970129	102267872	102268079
ENSE00000970130	102267490	102267674
ENSE00001411230	102344444	102344915
ENSE00001519768	102261666	102263193
ENSE00002076233	102345345	102345482
ENSE00003464023	102315668	102315830
ENSE00003497152	102304989	102305111
ENSE00003504954	102307436	102307605

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 99.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.8829 / max 1083.9382, expressed in 1692 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53378	17.3972	1411
53365	3.3332	1121
53373	2.9725	1015
53366	1.3611	623
53376	0.7866	374
53369	0.6886	179
53374	0.5252	225
53375	0.4768	216
53368	0.4173	127
53370	0.3082	88

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	99.22	gold quality
lower lobe of lung	UBERON:0008949	99.05	gold quality
visceral pleura	UBERON:0002401	97.66	gold quality
germinal epithelium of ovary	UBERON:0001304	97.48	gold quality
pleura	UBERON:0000977	97.12	gold quality
upper lobe of lung	UBERON:0008948	96.83	gold quality
parietal pleura	UBERON:0002400	96.74	gold quality
upper lobe of left lung	UBERON:0008952	96.66	gold quality
right lung	UBERON:0002167	96.39	gold quality
lung	UBERON:0002048	95.83	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.55	gold quality
endometrium epithelium	UBERON:0004811	95.36	gold quality
rectum	UBERON:0001052	94.87	gold quality
colonic mucosa	UBERON:0000317	94.45	gold quality
body of pancreas	UBERON:0001150	93.99	gold quality
adult organism	UBERON:0007023	93.19	gold quality
placenta	UBERON:0001987	91.94	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.35	gold quality
saliva-secreting gland	UBERON:0001044	91.12	gold quality
tibia	UBERON:0000979	90.75	gold quality
cartilage tissue	UBERON:0002418	90.63	gold quality
right atrium auricular region	UBERON:0006631	90.41	gold quality
pancreas	UBERON:0001264	90.23	gold quality
cardiac atrium	UBERON:0002081	90.23	gold quality
vermiform appendix	UBERON:0001154	90.21	gold quality
pigmented layer of retina	UBERON:0001782	89.52	gold quality
minor salivary gland	UBERON:0001830	89.43	gold quality
hair follicle	UBERON:0002073	89.09	gold quality
bone marrow	UBERON:0002371	88.80	gold quality
pericardium	UBERON:0002407	88.69	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	97.90
E-MTAB-6701	yes	75.29
E-HCAD-6	yes	46.24
E-GEOD-125970	yes	41.03
E-CURD-112	yes	13.68
E-GEOD-130148	yes	13.57
E-MTAB-9388	yes	8.13
E-MTAB-6678	yes	6.23
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

miRNA regulators (miRDB)

126 targeting SLC39A8, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• These data are the first to characterize human SLC39A8 (Zip8) and remarkably demonstrate that upregulation of Zip8 is sufficient to protect lung epithelia against TNF-alpha-induced cytotoxicity. (PMID:18390834)
• These results demonstrate the importance of Sp1 in the regulation of ZIP8 expression. (PMID:18556457)
• ZIP8, through control of zinc transport from the lysosome, may provide a secondary level of IFN-gamma regulation in T cells. (PMID:19401385)
• findings reveal a role for brain metal homeostasis in psychosis. (PMID:22078303)
• data identify ZIP8 as an iron transport protein that may function in iron metabolism. (PMID:22898811)
• The zinc transporter SLC39A8 (ZIP8) is a transcriptional target of NF-kappaB and functions to negatively regulate proinflammatory responses through zinc-mediated down-modulation of IkappaB kinase (IKK) activity in vitro. (PMID:23403290)
• MicroRNA-488 regulates zinc transporter SLC39A8/ZIP8 during pathogenesis of osteoarthritis (PMID:23688035)
• Data indicate that the average expression level of zinc transporter Zip2 was significantly higher and zinc transporters Zip6, Zip8 mRNA levels were significantly lower in short stature children than in health controls. (PMID:23921484)
• Polymorphisms in SLC39A14 and SLC39A8 seemed to affect blood cadmium concentrations, for SLC39A14 this effect may occur via differential gene expression. (PMID:24514587)
• data provide evidence of positive selection on a schizophrenia risk SNP rs13107325 in the SLC39A8 gene, and we propose a hypothesis about the relationship among positive selection of host alleles, schizophrenia, hypertension, energy intake, and the unique history of Europeans. (PMID:26006263)
• The lead single nucleotide polymorphism (SNP) in the 4q24 locus was rs13107325 (P-value = 5.1 x 10(-11), beta = -0.77), located in an exon of SLC39A8, which encodes a protein involved in manganese and zinc transport. (PMID:26025379)
• Autosomal-recessive intellectual disability with cerebellar atrophy syndrome is caused by mutation of the manganese and zinc transporter gene SLC39A8. (PMID:26637978)
• SLC39A8 SNP (rs13107325) was associated with NT-proBNP levels in patients with acute coronary syndrome (ACS). The SLC39A8 SNP was also associated with higher risk of cardiovascular death. (PMID:26908625)
• These results indicate that the ZIP8 Ala391-to-Thr391 substitution has an effect on intracellular cadmium accumulation and cell toxicity, providing a potential mechanistic explanation for the association of this genetic variant with blood pressure. (PMID:27466201)
• We identified an association between Crohn’s Disease and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with Crohn’s Disease in 2 replication cohorts. (PMID:27492617)
• SLC39A8 deficiency can cause both a type II CDG and Leigh-like syndrome. (PMID:27995398)
• The study indicates that common single nucleotide polymorphisms in manganese transporters (SLC30A10 and SLC39A8) influence manganese homeostasis in early development. (PMID:28917719)
• The expression, localization, and function of ZIP8 and other divalent cation transporters within macrophages have important implications for TB prevention and dissemination and warrant further study. [review] (PMID:29120360)
• Increased free Zn(2+) correlates with induction of sarco(endo)plasmic reticulum stress via altered expression levels of Zn(2+) -transporters, Zip8, Zip14, and ZnT8, in heart failure. (PMID:29333637)
• a potential pathogenic mechanism of diseases that are associated with hSLC39A8 mutations (PMID:29453449)
• the results of the present study suggested that Zip8 was an important regulator of neuroblastoma cell proliferation and migration, indicating that Zip8 may be a potential anticancer therapeutic target and a promising diagnostic biomarker for human neuroblastoma. (PMID:29749445)
• a missense single nucleotide polymorphism in SLC39A8 (p.Ala391Thr, rs13107325) associated with severe idiopathic scoliosis. (PMID:30301978)
• results show that a missense mutation in gene SLC39A8 is associated with larger gray matter volume in the putamen and that this association is significantly weakened in schizophrenia. (PMID:30649180)
• Study confirms the genetic association of the missense variant [Thr]391 of SLC39A8 with Crohn’s disease but could not replicate the association in gut microbiome composition. (PMID:30703110)
• results suggest a potential role for ZIP8 in intestinal inflammation, induced by IFNgamma in the intestinal epithelial compartment, and that perturbations in negative regulation of NF-kappaB by ZIP8 A391T may contribute to Crohn’s disease pathogenesis (PMID:31151823)
• Both ZIP8 and ZIP14 have roles in manganese metabolism of alveolar epithelial cells. (PMID:31261654)
• A novel coding variant of SLC39A8 is found to be significantly associated with adolescent Idiopathic Scoliosis in a Chinese Han population. (PMID:31513097)
• SLC39A8 encodes a protein named ZIP8, which is responsible for the transport of the essential metals including ferrum (Fe2+), manganese (Mn2+) and zinc (Zn2+), and the nonessential neurotoxic metal cadmium (Cd2+). (PMID:31533672)
• solute carriers ZIP8 and ZIP14 regulate manganese accumulation in brain microvascular endothelial cells and control brain manganese levels (PMID:31699897)
• Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis. (PMID:32247823)
• The Functions of ZIP8, ZIP14, and ZnT10 in the Regulation of Systemic Manganese Homeostasis. (PMID:32392784)
• The schizophrenia risk locus in SLC39A8 alters brain metal transport and plasma glycosylation. (PMID:32753748)
• Genetic markers and continuity of healthy metabolic status: Tehran cardio-metabolic genetic study (TCGS). (PMID:32788640)
• N-glycome analysis detects dysglycosylation missed by conventional methods in SLC39A8 deficiency. (PMID:32852845)
• Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease. (PMID:32897876)
• A missense variant in SLC39A8 confers risk for Crohn’s disease by disrupting manganese homeostasis and intestinal barrier integrity. (PMID:33139556)
• Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling. (PMID:33608496)
• ZIP8 exacerbates collagen-induced arthritis by increasing pathogenic T cell responses. (PMID:33795795)
• HIF-1alpha Dependent Upregulation of ZIP8, ZIP14, and TRPA1 Modify Intracellular Zn(2+) Accumulation in Inflammatory Synoviocytes. (PMID:34198528)
• C Deletion at the re74650330 Locus of the SLC39A8 Gene (rs74650330) Increases the Risk of Coronary Artery Disease in Individuals with Low-Density Lipoprotein Cholesterol Levels. (PMID:34672770)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc39a8	ENSDARG00000056757
danio_rerio		ENSDARG00000113547
mus_musculus	Slc39a8	ENSMUSG00000053897
rattus_norvegicus	Slc39a8	ENSRNOG00000012508
caenorhabditis_elegans		WBGENE00021936

Paralogs (6): SLC39A14 (ENSG00000104635), SLC39A5 (ENSG00000139540), SLC39A6 (ENSG00000141424), SLC39A4 (ENSG00000147804), SLC39A12 (ENSG00000148482), SLC39A10 (ENSG00000196950)

Protein

Protein identifiers

Metal cation symporter ZIP8 — Q9C0K1 (reviewed: Q9C0K1)

Alternative names: BCG-induced integral membrane protein in monocyte clone 103 protein, LIV-1 subfamily of ZIP zinc transporter 6, Solute carrier family 39 member 8, Zrt- and Irt-like protein 8

All UniProt accessions (7): Q9C0K1, A0A804HHS9, A0A804HHT0, A0A804HJR0, A0A804HKQ9, A0A804HKW0, A0A804HKX2

UniProt curated annotations — full annotation on UniProt →

Function. Electroneutral divalent metal cation:bicarbonate symporter of the plasma membrane mediating the cellular uptake of zinc and manganese, two divalent metal cations important for development, tissue homeostasis and immunity. Transports an electroneutral complex composed of a divalent metal cation and two bicarbonate anions or alternatively a bicarbonate and a selenite anion. Thereby, it also contributes to the cellular uptake of selenium, an essential trace metal and micronutrient. Also imports cadmium a non-essential metal which is cytotoxic and carcinogenic. May also transport iron and cobalt through membranes. Through zinc import, indirectly regulates the metal-dependent transcription factor MTF1 and the expression of some metalloproteases involved in cartilage catabolism and also probably heart development. Also indirectly regulates the expression of proteins involved in cell morphology and cytoskeleton organization. Indirectly controls innate immune function and inflammatory response by regulating zinc cellular uptake which in turn modulates the expression of genes specific of these processes. Protects, for instance, cells from injury and death at the onset of inflammation. By regulating zinc influx into monocytes also directly modulates their adhesion to endothelial cells and arteries. Reclaims manganese from the bile at the apical membrane of hepatocytes, thereby regulating the activity of the manganese-dependent enzymes through the systemic levels of the nutrient. Also participates in manganese reabsorption in the proximal tubule of the kidney. By mediating the extracellular uptake of manganese by cells of the blood-brain barrier, may also play a role in the transport of the micronutrient to the brain. With manganese cellular uptake also participates in mitochondrial proper function. Finally, also probably functions intracellularly, translocating zinc from lysosome to cytosol to indirectly enhance the expression of specific genes during TCR-mediated T cell activation.

Subunit / interactions. Homodimer.

Subcellular location. Cell membrane. Lysosome membrane. Apical cell membrane. Basolateral cell membrane.

Tissue specificity. Ubiquitously expressed. Expressed in thymus, placenta, lung, liver, pancreas, salivary gland and, to a lower extent, in spleen, testis, ovary, small intestine, colon, leukocyte, heart. Highest expression is observed in pancreas. Expressed by macrophages (at protein level). Expressed by microvascular capillary endothelial cells that constitute the blood-brain barrier (at protein level).

Post-translational modifications. N-glycosylated. N-glycosylation is not required for proper iron and zinc transport.

Disease relevance. Congenital disorder of glycosylation 2N (CDG2N) [MIM:616721] A form of congenital disorder of glycosylation, a genetically heterogeneous group of autosomal recessive, multisystem disorders caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. The disease is caused by variants affecting the gene represented in this entry. Rare variants in SLC39A8 may be a cause of Leigh-like mitochondrial syndrome characterized by profound developmental delay, dystonia, seizures and failure to thrive.

Induction. Up-regulated by manganese. Up-regulated by lipopolysaccharides (at protein level). Up-regulated by inflammatory cytokines like TNF. Down-regulated following phorbol ester treatment. Up-regulated by zinc and T-cell activation. (Microbial infection) Up-regulated by live and heat-killed Mycobacterium bovis bacterial cell wall.

Similarity. Belongs to the ZIP transporter (TC 2.A.5) family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9C0K1-1	1	yes
Q9C0K1-2	2
Q9C0K1-3	3

RefSeq proteins (4): NP_001128618, NP_001128619, NP_001128620, NP_071437 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003689	ZIP	Family
IPR050799	ZIP_Transporter	Family

Pfam: PF02535

Catalyzed reactions (Rhea), 6 shown:

• Zn(2+)(out) + 2 hydrogencarbonate(out) = Zn(2+)(in) + 2 hydrogencarbonate(in) (RHEA:62252)
• Cd(2+)(out) + 2 hydrogencarbonate(out) = Cd(2+)(in) + 2 hydrogencarbonate(in) (RHEA:62256)
• Mn(2+)(out) + 2 hydrogencarbonate(out) = Mn(2+)(in) + 2 hydrogencarbonate(in) (RHEA:62260)
• selenite(out) + Zn(2+)(out) + hydrogencarbonate(out) = selenite(in) + Zn(2+)(in) + hydrogencarbonate(in) (RHEA:62264)
• Fe(2+)(out) + 2 hydrogencarbonate(out) = Fe(2+)(in) + 2 hydrogencarbonate(in) (RHEA:62368)
• Co(2+)(out) + 2 hydrogencarbonate(out) = Co(2+)(in) + 2 hydrogencarbonate(in) (RHEA:73491)

UniProt features (29 total): topological domain 7, sequence variant 7, transmembrane region 6, splice variant 3, glycosylation site 2, signal peptide 1, chain 1, short sequence motif 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9C0K1-F1	73.46	0.26

Functional residue map

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

Glycosylation sites (2): 40, 88

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-442380	Zinc influx into cells by the SLC39 gene family
R-HSA-382551	Transport of small molecules
R-HSA-425366
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-425410	Metal ion SLC transporters
R-HSA-435354	Zinc transporters

MSigDB gene sets: 518 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, HNF3ALPHA_Q6, chr4q24, LU_IL4_SIGNALING, GOBP_INFLAMMATORY_RESPONSE, GOCC_VACUOLAR_MEMBRANE, GOBP_TRANSITION_METAL_ION_TRANSPORT, PEREZ_TP63_TARGETS, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOZGIT_ESR1_TARGETS_DN, GOBP_CELLULAR_RESPONSE_TO_CADMIUM_ION, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS

GO Biological Process (28): DNA-templated transcription (GO:0006351), regulation of DNA-templated transcription (GO:0006355), protein N-linked glycosylation (GO:0006487), arginine metabolic process (GO:0006525), cobalt ion transport (GO:0006824), zinc ion transport (GO:0006829), intracellular zinc ion homeostasis (GO:0006882), mercury ion transport (GO:0015694), bicarbonate transport (GO:0015701), intracellular monoatomic cation homeostasis (GO:0030003), intracellular manganese ion homeostasis (GO:0030026), extracellular matrix organization (GO:0030198), regulation of membrane potential (GO:0042391), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), negative regulation of inflammatory response (GO:0050728), leukocyte adhesion to arterial endothelial cell (GO:0061757), cadmium ion transmembrane transport (GO:0070574), manganese ion transmembrane transport (GO:0071421), zinc ion transmembrane transport (GO:0071577), zinc ion import across plasma membrane (GO:0071578), plasma membrane selenite transport (GO:0097080), iron ion import across plasma membrane (GO:0098711), cellular detoxification of cadmium ion (GO:0098849), cartilage homeostasis (GO:1990079), mitochondrial manganese ion transmembrane transport (GO:1990540), monoatomic ion transport (GO:0006811), metal ion transport (GO:0030001), transmembrane transport (GO:0055085)

GO Molecular Function (5): zinc ion transmembrane transporter activity (GO:0005385), monoatomic cation:bicarbonate symporter activity (GO:0140410), zinc:bicarbonate symporter activity (GO:0140412), symporter activity (GO:0015293), metal ion transmembrane transporter activity (GO:0046873)

GO Cellular Component (7): lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), organelle membrane (GO:0031090), lysosome (GO:0005764), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Zinc transporters	1
Transport of small molecules	1
SLC-mediated transmembrane transport	1
Metal ion SLC transporters	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic cation transmembrane transport	5
transition metal ion transport	3
intracellular monoatomic cation homeostasis	2
zinc ion transmembrane transport	2
membrane	2
plasma membrane region	2
gene expression	1
RNA biosynthetic process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
glycoprotein biosynthetic process	1
amino acid metabolic process	1
carboxylic acid metabolic process	1
inorganic ion homeostasis	1
detoxification of mercury ion	1
transport	1
intracellular monoatomic ion homeostasis	1
monoatomic cation homeostasis	1
manganese ion homeostasis	1
extracellular structure organization	1
external encapsulating structure organization	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
leukocyte adhesion to vascular endothelial cell	1
cadmium ion transport	1
manganese ion transport	1
zinc ion transport	1
inorganic cation import across plasma membrane	1
transition metal ion transmembrane transporter activity	1
bicarbonate transmembrane transporter activity	1
solute:monoatomic cation symporter activity	1
zinc ion transmembrane transporter activity	1

Protein interactions and networks

STRING

1190 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC39A8	SLC11A2	P49281	761
SLC39A8	SLC30A10	Q6XR72	758
SLC39A8	SLC39A9	Q9NUM3	751
SLC39A8	SLC30A1	Q9Y6M5	748
SLC39A8	SLC39A1	Q9NY26	727
SLC39A8	SLC30A7	Q8NEW0	725
SLC39A8	SLC39A11	Q8N1S5	715
SLC39A8	SLC30A4	O14863	711
SLC39A8	SLC30A5	Q8TAD4	699
SLC39A8	SLC30A6	Q6NXT4	686
SLC39A8	SLC30A2	Q9BRI3	684
SLC39A8	SLC30A9	Q6PML9	647
SLC39A8	SLC30A3	Q99726	644
SLC39A8	SLC39A3	Q9BRY0	611
SLC39A8	SLC39A2	Q9NP94	608

IntAct

7 interactions, top by confidence:

A	B	Type	Score
SLC39A8	PTGER4	psi-mi:“MI:0915”(physical association)	0.370
P		psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
STX7	SCAMP1	psi-mi:“MI:0914”(association)	0.350
SLC39A8	GOLIM4	psi-mi:“MI:0914”(association)	0.350
SLC39A8	CEBPZOS	psi-mi:“MI:0914”(association)	0.350

BioGRID (167): TAOK2 (Affinity Capture-MS), GPD2 (Affinity Capture-MS), RMDN2 (Affinity Capture-MS), SLC9A6 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), C1GALT1C1 (Affinity Capture-MS), C1orf43 (Affinity Capture-MS), ERGIC2 (Affinity Capture-MS), ZDHHC17 (Affinity Capture-MS), EXTL2 (Affinity Capture-MS), VAPB (Affinity Capture-MS), EDA (Affinity Capture-MS), ST7L (Affinity Capture-MS), SGPP1 (Affinity Capture-MS), MGAT5 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2KQY6, A0A6I8PMZ8, A0JPN2, A4IGY6, A5D7L5, A7T1N0, B3DHU2, O43868, O75899, O88871, O94402, P04919, P0DX17, P23562, P26432, P26433, P48764, P55205, Q08E40, Q0DHJ5, Q0DWA9, Q0VCH8, Q15043, Q28C60, Q4VAE3, Q504Y0, Q5FVQ0, Q5FWH7, Q5RAB7, Q5Z413, Q6DCK1, Q6L8F3, Q6PI78, Q75N73, Q78IQ7, Q80T41, Q8K596, Q8VIH3, Q8W469, Q91W10

Diamond homologs: A0A0G2KQY6, A0A6I8PMZ8, A4IGY6, A5D7H1, A5D7L5, A8WMY3, A8X482, L5KLU7, P0DX17, Q06916, Q15043, Q1KZG0, Q29175, Q2M1K6, Q31125, Q504Y0, Q5FVQ0, Q5FWH7, Q5R6I6, Q5RAB7, Q5RFD5, Q5TJF6, Q6L8F3, Q6MGB4, Q6P5F6, Q6PEH9, Q75N73, Q78IQ7, Q8AW42, Q8BZH0, Q91W10, Q92504, Q96H72, Q9C0K1, Q9M647, Q9PUB8, Q9ULF5, Q9UT11, Q9V3A4, Q9XTQ7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	4
Uncertain significance	70
Likely benign	38
Benign	35

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1210340	NM_001135146.2(SLC39A8):c.218dup (p.Cys74fs)	Pathogenic
1686211	NM_001135146.2(SLC39A8):c.1283C>T (p.Thr428Ile)	Pathogenic
1030798	NM_001135146.2(SLC39A8):c.316C>T (p.Gln106Ter)	Likely pathogenic
1304789	NM_001135146.2(SLC39A8):c.611G>T (p.Gly204Val)	Likely pathogenic
218896	NM_001135146.2(SLC39A8):c.1019T>A (p.Ile340Asn)	Likely pathogenic
869411	NM_001135146.2(SLC39A8):c.338G>C (p.Cys113Ser)	Likely pathogenic

SpliceAI

1675 predictions. Top by Δscore:

Variant	Effect	Δscore
4:102267672:CTC:C	acceptor_gain	1.0000
4:102267676:T:C	acceptor_loss	1.0000
4:102304316:C:CT	donor_loss	1.0000
4:102304328:C:CT	donor_gain	1.0000
4:102304363:G:C	donor_gain	1.0000
4:102304477:CCATT:C	acceptor_gain	1.0000
4:102304478:CATT:C	acceptor_gain	1.0000
4:102304478:CATTC:C	acceptor_gain	1.0000
4:102304479:ATT:A	acceptor_gain	1.0000
4:102304480:TT:T	acceptor_gain	1.0000
4:102304480:TTC:T	acceptor_loss	1.0000
4:102304482:C:A	acceptor_loss	1.0000
4:102304482:C:CC	acceptor_gain	1.0000
4:102304483:T:A	acceptor_loss	1.0000
4:102304484:A:AC	acceptor_gain	1.0000
4:102304484:A:C	acceptor_gain	1.0000
4:102304486:A:AC	acceptor_gain	1.0000
4:102304486:A:C	acceptor_gain	1.0000
4:102304493:C:CT	acceptor_gain	1.0000
4:102304494:A:T	acceptor_gain	1.0000
4:102304500:C:CT	acceptor_gain	1.0000
4:102304984:TTTA:T	donor_loss	1.0000
4:102304985:TTA:T	donor_loss	1.0000
4:102304986:TA:T	donor_loss	1.0000
4:102304987:A:AG	donor_loss	1.0000
4:102304988:C:CG	donor_loss	1.0000
4:102305109:TGCCT:T	acceptor_loss	1.0000
4:102305111:CCT:C	acceptor_loss	1.0000
4:102305112:CT:C	acceptor_loss	1.0000
4:102305113:T:G	acceptor_loss	1.0000

AlphaMissense

3009 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:102263099:C:T	G443E	0.999
4:102267514:G:C	F403L	0.999
4:102267514:G:T	F403L	0.999
4:102267516:A:G	F403L	0.999
4:102267961:A:G	L320P	0.999
4:102307446:A:G	L181P	0.999
4:102307477:C:A	G171W	0.999
4:102263100:C:G	G443R	0.998
4:102263100:C:T	G443R	0.998
4:102267964:C:A	G319V	0.998
4:102267964:C:T	G319D	0.998
4:102267965:C:G	G319R	0.998
4:102267966:A:C	D318E	0.998
4:102267966:A:T	D318E	0.998
4:102307459:C:G	A177P	0.998
4:102307476:C:T	G171E	0.998
4:102307477:C:G	G171R	0.998
4:102307477:C:T	G171R	0.998
4:102267512:A:G	L404P	0.997
4:102267515:A:G	F403S	0.997
4:102267522:C:G	G401R	0.997
4:102267539:A:T	I395K	0.997
4:102267595:G:C	C376W	0.997
4:102267659:A:G	L355P	0.997
4:102267896:A:G	C342R	0.997
4:102267904:G:T	A339E	0.997
4:102267967:T:A	D318V	0.997
4:102267967:T:G	D318A	0.997
4:102307485:A:G	L168P	0.997
4:102263111:C:T	G439E	0.996

dbSNP variants (sampled 300 via entrez): RS1000051252 (4:102327397 T>A), RS1000066158 (4:102316277 A>G), RS1000170349 (4:102329273 T>A), RS1000177081 (4:102320982 T>C), RS1000227244 (4:102332640 T>C), RS1000242944 (4:102273813 G>A), RS1000249293 (4:102320754 G>GAAAA), RS1000268614 (4:102276372 A>C), RS1000381029 (4:102341204 G>A,T), RS1000431961 (4:102289479 T>C), RS1000434379 (4:102282387 C>T), RS1000471466 (4:102327668 G>A), RS1000576544 (4:102306484 T>C), RS1000609232 (4:102274813 A>G), RS1000628800 (4:102306159 T>C)

Disease associations

OMIM: gene MIM:608732 | disease phenotypes: MIM:616721

GenCC curated gene-disease

Disease	Classification	Inheritance
SLC39A8-CDG	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Leigh syndrome	Limited	AR

Mondo (1): SLC39A8-CDG (MONDO:0014746)

Orphanet (1): SLC39A8-CDG (Orphanet:468699)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000540	Hypermetropia
HP:0000639	Nystagmus
HP:0000938	Osteopenia
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001363	Craniosynostosis
HP:0001382	Joint hypermobility
HP:0001392	Abnormality of the liver
HP:0001531	Failure to thrive in infancy
HP:0002059	Cerebral atrophy
HP:0002119	Ventriculomegaly
HP:0002120	Cerebral cortical atrophy
HP:0002187	Profound intellectual disability
HP:0002421	Poor head control
HP:0002465	Poor speech
HP:0002490	Increased CSF lactate
HP:0002521	Hypsarrhythmia
HP:0002540	Inability to walk
HP:0002719	Recurrent infections
HP:0002882	Sudden episodic apnea

GWAS associations

168 associations (top):

Study	Trait	p-value
GCST000755_6	HDL cholesterol	7.000000e-11
GCST000830_8	Body mass index	2.000000e-13
GCST001227_9	Systolic blood pressure	3.000000e-14
GCST001228_17	Diastolic blood pressure	2.000000e-17
GCST001236_13	Blood pressure	1.000000e-10
GCST001238_8	Hypertension	5.000000e-07
GCST002223_53	HDL cholesterol	1.000000e-15
GCST002539_53	Schizophrenia	8.000000e-15
GCST002783_100	Body mass index	3.000000e-09
GCST002783_25	Body mass index	3.000000e-07
GCST002783_375	Body mass index	1.000000e-12
GCST002783_508	Body mass index	2.000000e-12
GCST002899_8	HDL cholesterol	3.000000e-13
GCST002932_21	Manganese levels	5.000000e-11
GCST002938_19	Copper levels	2.000000e-06
GCST003177_12	Childhood body mass index	4.000000e-07
GCST003298_2	NT-proBNP levels in acute coronary syndrome	6.000000e-10
GCST003448_3	Erythrocyte cadmium concentration in never smokers	3.000000e-07
GCST004131_126	Inflammatory bowel disease	4.000000e-06
GCST004132_34	Crohn’s disease	4.000000e-08
GCST004495_101	BMI (adjusted for smoking behaviour)	3.000000e-10
GCST004495_102	BMI (adjusted for smoking behaviour)	4.000000e-09
GCST004497_43	Body mass index (joint analysis main effects and smoking interaction)	2.000000e-10
GCST004497_44	Body mass index (joint analysis main effects and smoking interaction)	1.000000e-08
GCST004499_103	BMI in non-smokers	1.000000e-07
GCST004499_104	BMI in non-smokers	7.000000e-07
GCST004521_11	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004557_131	Body mass index	5.000000e-10
GCST004557_165	Body mass index	2.000000e-10
GCST004557_184	Body mass index	1.000000e-09

EFO canonical traits (41, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004340	body mass index
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0006340	mean arterial pressure
EFO:0005278	cardiovascular disease biomarker measurement
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0007984	platelet component distribution width
EFO:0008434	initial pursuit acceleration
EFO:0004337	intelligence
EFO:0006941	grip strength measurement
EFO:0004329	alcohol drinking
EFO:0004574	total cholesterol measurement
EFO:0009458	alcohol use disorder measurement
EFO:0007835	alcohol dependence measurement
EFO:0007041	obese body mass index status
EFO:0008579	risk-taking behaviour
EFO:0004346	neuroimaging measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0007645	longitudinal alcohol consumption measurement
EFO:0010100	multisite chronic pain
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0004784	self reported educational attainment
EFO:0000195	metabolic syndrome
EFO:0004530	triglyceride measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004614	apolipoprotein A 1 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs13135092	Toxicity	3	ethanol	Alcohol abuse

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs13135092	SLC39A8	3	1.50	1	ethanol

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC39 family of metal ion transporters

CTD chemical–gene interactions

67 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	8
Cadmium	increases phosphorylation, decreases expression, decreases reaction, increases uptake, decreases uptake (+7 more)	7
Cadmium Chloride	affects response to substance, decreases uptake, increases response to substance, increases uptake, decreases expression (+3 more)	6
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases expression	3
Estradiol	affects cotreatment, increases expression	3
mercuric bromide	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	increases expression, affects cotreatment	2
Manganese	affects transport	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	decreases expression	2
Zinc	increases transport, increases expression, increases import	2
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
lead acetate	decreases expression	1
quercitrin	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
cadmium sulfate	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
3-(4-methylphenylsulfonyl)-2-propenenitrile	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
(+)-JQ1 compound	decreases expression	1

Cellosaurus cell lines

10 cell lines: 10 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2G6	Abcam HeLa SLC39A8 KO	Cancer cell line	Female
CVCL_D4NR	HCT116-SLC39A8-KO-c6	Cancer cell line	Male
CVCL_D4NS	HCT116-SLC39A8-KO-c9	Cancer cell line	Male
CVCL_D8AI	Ubigene A-549 SLC39A8 KO	Cancer cell line	Male
CVCL_D8FD	Ubigene Caco-2 SLC39A8 KO	Cancer cell line	Male
CVCL_E0WS	Ubigene K-562 SLC39A8 KO	Cancer cell line	Female
CVCL_E1DD	Ubigene THP-1 SLC39A8 KO	Cancer cell line	Male
CVCL_TN59	HAP1 SLC39A8 (-) 1	Cancer cell line	Male
CVCL_TN60	HAP1 SLC39A8 (-) 2	Cancer cell line	Male
CVCL_TN61	HAP1 SLC39A8 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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