SLC30A8

Summary

SLC30A8 (solute carrier family 30 member 8, HGNC:20303) is a protein-coding gene on chromosome 8q24.11, encoding Proton-coupled zinc antiporter SLC30A8 (Q8IWU4). Proton-coupled zinc ion antiporter mediating the entry of zinc into the lumen of pancreatic beta cell secretory granules, thereby regulating insulin secretion.

The protein encoded by this gene is a zinc efflux transporter involved in the accumulation of zinc in intracellular vesicles. This gene is expressed at a high level only in the pancreas, particularly in islets of Langerhans. The encoded protein colocalizes with insulin in the secretory pathway granules of the insulin-secreting INS-1 cells. Allelic variants of this gene exist that confer susceptibility to diabetes mellitus, noninsulin-dependent (NIDDM). Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 169026 — RefSeq curated summary.

At a glance

• Gene–disease (curated): type 2 diabetes mellitus (Limited, GenCC)
• GWAS associations: 65
• Clinical variants (ClinVar): 76 total — 1 pathogenic
• Phenotypes (HPO): 5
• MANE Select transcript: NM_173851

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20303
Approved symbol	SLC30A8
Name	solute carrier family 30 member 8
Location	8q24.11
Locus type	gene with protein product
Status	Approved
Aliases	ZnT-8, ZNT8
Ensembl gene	ENSG00000164756
Ensembl biotype	protein_coding
OMIM	611145
Entrez	169026

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000427715, ENST00000456015, ENST00000518396, ENST00000518521, ENST00000519688, ENST00000520469, ENST00000521035, ENST00000521243, ENST00000524274

RefSeq mRNA: 5 — MANE Select: NM_173851 NM_001172811, NM_001172813, NM_001172814, NM_001172815, NM_173851

CCDS: CCDS55272, CCDS6322

Canonical transcript exons

ENST00000456015 — 8 exons

Exon	Start	End
ENSE00001087202	117171034	117171168
ENSE00001087212	117161738	117161888
ENSE00001087215	117152944	117153090
ENSE00001087217	117163425	117163530
ENSE00001158919	117157691	117157844
ENSE00001196217	117172536	117176714
ENSE00002129519	117134995	117135398
ENSE00003597845	117146954	117147153

Expression profiles

Bgee: expression breadth ubiquitous, 117 present calls, max score 99.55.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4849 / max 764.9451, expressed in 8 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
90337	0.3536	6
90338	0.0654	4
90340	0.0325	2
90339	0.0211	3
90330	0.0123	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	99.55	gold quality
pancreas	UBERON:0001264	88.48	gold quality
epithelial cell of pancreas	CL:0000083	85.91	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.66	gold quality
body of pancreas	UBERON:0001150	84.00	gold quality
secondary oocyte	CL:0000655	71.48	silver quality
tibialis anterior	UBERON:0001385	69.15	silver quality
kidney epithelium	UBERON:0004819	67.59	gold quality
pancreatic ductal cell	CL:0002079	64.68	silver quality
ileal mucosa	UBERON:0000331	63.20	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	60.45	gold quality
testis	UBERON:0000473	59.75	gold quality
right testis	UBERON:0004534	59.32	gold quality
left testis	UBERON:0004533	58.76	gold quality
deltoid	UBERON:0001476	57.25	silver quality
skin of hip	UBERON:0001554	55.83	silver quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
kidney	UBERON:0002113	52.90	gold quality
adult mammalian kidney	UBERON:0000082	52.59	gold quality
cerebellar vermis	UBERON:0004720	51.89	gold quality
fundus of stomach	UBERON:0001160	51.04	gold quality
myocardium	UBERON:0002349	50.25	gold quality
duodenum	UBERON:0002114	50.17	gold quality
smooth muscle tissue	UBERON:0001135	50.06	gold quality
gall bladder	UBERON:0002110	49.99	gold quality
cortical plate	UBERON:0005343	49.72	gold quality
buccal mucosa cell	CL:0002336	49.34	gold quality
rectum	UBERON:0001052	49.01	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	2933.03
E-MTAB-5061	yes	26.25
E-ENAD-27	yes	12.83
E-GEOD-83139	yes	11.98
E-ANND-3	yes	8.32
E-HCAD-31	no	19.66

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PDX1

miRNA regulators (miRDB)

147 targeting SLC30A8, 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-4776-3P	100.00	68.73	1340
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805

Literature-anchored findings (GeneRIF, showing 40)

• identified the full-length sequences of SLC30A8, extending the SLC30 family to ten members; used an expressed sequence tag (EST) data mining strategy to determine the pattern of ZnT genes expression in tissues (PMID:15154973)
• ZnT-8 may be a major component for providing zinc to insulin maturation and/or storage processes in insulin-secreting pancreatic beta-cells. (PMID:15331542)
• ZnT-8 is a pancreatic beta-cell-specific zinc transporter [review] (PMID:16158222)
• A non-synonymous polymorphism in SLC30A8 (rs13266634, R325W) is associated with increased risk of developing type 2 diabetes in causcasians. (PMID:17293876)
• Rare mutaations are unlikely to be responsible for maturity onset diabetes of the young or other forms of early onset type 2 diabetes. (PMID:17657472)
• The zinc transporter ZnT8 (Slc30A8), was targeted by autoantibodies in 60-80% of new-onset Type 1 diabetes (T1D) compared with <2% of controls and <3% type 2 diabetic and in up to 30% of patients with other autoimmune disorders with a T1D association. (PMID:17942684)
• For the first time, the expression of hZnT-8 is shown in peripheral blood lymphocytes. It varied strongly between individuals. (PMID:17971500)
• The association of 6 loci with type 2 diabetes risk in Japanese patients is reported. (PMID:18162508)
• SLC30A8 rs13266634 gene variation is associated with protection from the development of posttransplantation diabetes mellitus in renal allograft recipients. (PMID:18162509)
• Impaired insulin secretion is specifically present in impaired proinsulin conversion is specifically present in a variant of SLC30A8. (PMID:18264689)
• Of European non-diabetic offspring of type 2 diabetes patients, 46% are homozygous carriers of the Arg325Trp polymorphism of SLC30A8. (PMID:18324385)
• A non-synonymous variant in SLC30A8 is not associated with type 1 diabetes. (PMID:18400535)
• Little evidence of association was observed between SNPs in SLC30A8 and type 2 diabetes in African Americans. (PMID:18443202)
• Data confirmed the associations of single nucleotide polymorphisms in SLC30A8 with risk for type 2 diabetes in Asians. (PMID:18469204)
• Data show that a common nonsynonymous single nucleotide polymorphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes. (PMID:18591387)
• SLC30A8 is a susceptible locus for type 2 diabetes in Chinese population, and its variant can influence insulin secretion. (PMID:18628523)
• The results indicate that in Chinese Hans, common variants in SLC30A8 loci independently or additively contribute to type 2 diabetes risk, likely mediated through beta-cell dysfunction. (PMID:18633108)
• Study show that polymorphisms in SLC30A8 were associated with type 2 diabetes risk in the studied population. (PMID:18694974)
• variant residue at amino acid 325 is a key determinant of humoral autoreactivity to ZnT8 and that the SLC30A8 genotype is an important determinant of autoantibody specificity (PMID:18850084)
• Single nucleotide polymorphism in SLC30A8 is associated with type 2 diabetes. (PMID:18991055)
• Data show that SNPs in SLC30A8 did not confer a significant risk for type 2 diabetes in Pima Indians. (PMID:19008344)
• Type 2 diabetes susceptibility of SLC30A8 was confirmed in Japanese. (PMID:19033397)
• No statistically significant differences in genotype and allele frequencies of single nucleotide polymorphism (SNP) rs13266634 in gene SLC30A8 were found between patients with polycystic ovary syndrome (PCOS) and healthy controls. (PMID:19108828)
• The C-terminal domain of human ZnT8 contains at least two discrete epitopes, one of which is critically dependent upon the arginine residue at position 325. (PMID:19120306)
• SLC30A8 provides an important additional and independent predictive marker for T1 diabetes mellitus. (PMID:19120307)
• REVIEW: role in the autoimmune disease process of type 1 diabetes (PMID:19323954)
• ZnT8 is required for normal insulin crystallization and insulin release in vivo but not, remarkably, in vitro (PMID:19542200)
• Children who carry homozygous SLC30A8 single-nucleoetide polymorphism progress to diabetes faster than heterozygote carriers. (PMID:19590848)
• findings suggest for a dual role of SLC30A8 in diabetes, which is consisted in conferring genetic susceptibility to T2D and being a major islet self-antigen in T1D as well[review] (PMID:19655390)
• ZnT8As are detectable in a proportion of patients with adult-onset autoimmune diabetes and seem to be a valuable marker to differentiate clinical phenotypes. (PMID:19808923)
• there is an association between PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 and type 2 diabetes in the Chinese population (PMID:19862325)
• Report a chimeric assay providing an efficient and economical technique to screen for islet autoantibodies reacting with IA-2 and ZnT8 in type 1 diabetes mellitus. (PMID:20035758)
• insulinoma-associated protein 2 beta (IA-2beta) and zinc transporter-8 may have a role in rapid progression of type 1 diabetes (PMID:20091020)
• SLC30A8 rs13266634 polymorphism is among most replicated genetic markers of type 2 diabetes in Europeans and East Asians; risk C-allele does not affect ex-vivo insulin secretion and SLC30A8 expression, which correlates with that of insulin and glucagon (PMID:20138556)
• SLC30A8 (rs13266634) C allele carriers could elevate the risk of type 2 diabetes, especially in Europeans and Asians. (PMID:20167458)
• ZnT8 autoantibodies determination may be useful measure of therapeutic efficacy in the context of immune-based clinical interventions for type 1 diabetes. (PMID:20610599)
• HHEX, IDE and SLC30A8 showed strongest tissue-specific mRNA expression bias and are associated with increased risk of type 2 diabete. (PMID:20703447)
• rs12255372 and rs13266634 markers are independent genetic type 2 diabetes risk factors in a Russian population. (PMID:20873210)
• Studies indicate that T1DM can be detected by determining four autoantibodies, namely those antibodies against insulin, glutamic acid decarboxylase 65, insulinoma antigen (IA)-2 (ICA512) and the zinc transporter ZnT8. (PMID:21073664)
• This transporter represents an exciting therapeutic target for intervention in type 2 diabetes. (PMID:21099294)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc30a8	ENSDARG00000100917
mus_musculus	Slc30a8	ENSMUSG00000022315
rattus_norvegicus	Slc30a8	ENSRNOG00000004747
drosophila_melanogaster	ZnT63C	FBGN0035432

Paralogs (8): SLC30A4 (ENSG00000104154), SLC30A3 (ENSG00000115194), SLC30A5 (ENSG00000145740), SLC30A6 (ENSG00000152683), SLC30A2 (ENSG00000158014), SLC30A7 (ENSG00000162695), SLC30A1 (ENSG00000170385), SLC30A10 (ENSG00000196660)

Protein

Protein identifiers

Proton-coupled zinc antiporter SLC30A8 — Q8IWU4 (reviewed: Q8IWU4)

Alternative names: Solute carrier family 30 member 8, Zinc transporter 8

All UniProt accessions (4): A0A096LNR0, A0A096LPF3, E5RG87, Q8IWU4

UniProt curated annotations — full annotation on UniProt →

Function. Proton-coupled zinc ion antiporter mediating the entry of zinc into the lumen of pancreatic beta cell secretory granules, thereby regulating insulin secretion.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle membrane. Cell membrane.

Tissue specificity. In the endocrine pancreas, expressed in insulin-producing beta cells. Expressed at relatively high levels in subcutaneous fat tissue from lean persons; much lower levels in visceral fat, whether from lean or obese individuals, and in subcutaneous fat tissue from obese individuals. Expressed in peripheral blood mononuclear cells, including T-cells and B-cells, with great variation among individuals ranging from negative to strongly positive.

Polymorphism. Variant Trp-325 is a risk factor that confers susceptibility to type 2 diabetes mellitus (T2D) [MIM:125853].

Miscellaneous. Each subunit of the homodimer independently transports zinc ions in a pH-dependent manner. The cytosolic pH promotes binding of zinc ions to the transporter binding site. Upon change into the organelle-facing conformation, the two histidines of the zinc-binding site get protonated at lumenal lower pH, triggering zinc release into the organelle. The transporter then moves back to the cytosolic-facing conformation where the two histidines get deprotonated at higher pH, resulting in a net antiport of 2 protons.

Similarity. Belongs to the cation diffusion facilitator (CDF) transporter (TC 2.A.4) family. SLC30A subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IWU4-1	1	yes
Q8IWU4-2	2

RefSeq proteins (5): NP_001166282, NP_001166284, NP_001166285, NP_001166286, NP_776250* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002524	Cation_efflux	Family
IPR027469	Cation_efflux_TMD_sf	Homologous_superfamily
IPR027470	Cation_efflux_CTD	Domain
IPR036837	Cation_efflux_CTD_sf	Homologous_superfamily
IPR050681	CDF/SLC30A	Family
IPR058533	Cation_efflux_TM	Domain

Pfam: PF01545, PF16916

Catalyzed reactions (Rhea), 1 shown:

• Zn(2+)(in) + 2 H(+)(out) = Zn(2+)(out) + 2 H(+)(in) (RHEA:72627)

UniProt features (45 total): binding site 14, topological domain 7, mutagenesis site 7, transmembrane region 6, sequence conflict 4, sequence variant 2, chain 1, region of interest 1, short sequence motif 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6XPD	ELECTRON MICROSCOPY	3.8
6XPE	ELECTRON MICROSCOPY	4.1
6XPF	ELECTRON MICROSCOPY	5.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IWU4-F1	81.75	0.59

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 (14): 52 (in chain a); 53 (in chain a); 54 (in chain a); 106; 110; 137; 220; 224; 301 (in chain b); 318 (in chain b); 345; 352 (in chain b) …

Mutagenesis-validated functional residues (7):

Position	Phenotype
52–54	decreased zinc ion transmembrane transport.
106	decreased zinc ion transmembrane transport; when associated with a-220.
110	loss of transported zinc binding and decreased zinc ion transmembrane transport; when associated with n-224.
137	decreased zinc ion transmembrane transport; when associated with a-345.
220	decreased zinc ion transmembrane transport; when associated with a-106.
224	loss of transported zinc binding and decreased zinc ion transmembrane transport; when associated with n-110.
345	decreased zinc ion transmembrane transport; when associated with a-137.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-264876	Insulin processing
R-HSA-435368	Zinc efflux and compartmentalization by the SLC30 family

MSigDB gene sets: 172 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GOBP_RESPONSE_TO_ZINC_ION, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOBP_INSULIN_SECRETION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, CAGCTG_AP4_Q5, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, ATGTTAA_MIR302C, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (16): zinc ion transport (GO:0006829), intracellular zinc ion homeostasis (GO:0006882), response to glucose (GO:0009749), response to zinc ion (GO:0010043), insulin processing (GO:0030070), insulin secretion (GO:0030073), positive regulation of insulin secretion (GO:0032024), response to type II interferon (GO:0034341), regulation of vesicle-mediated transport (GO:0060627), zinc ion import into organelle (GO:0062111), response to interleukin-1 (GO:0070555), zinc ion transmembrane transport (GO:0071577), zinc ion import across plasma membrane (GO:0071578), monoatomic ion transport (GO:0006811), monoatomic cation transport (GO:0006812), transmembrane transport (GO:0055085)

GO Molecular Function (8): zinc ion transmembrane transporter activity (GO:0005385), zinc ion binding (GO:0008270), protein homodimerization activity (GO:0042803), zinc:proton antiporter activity (GO:0140826), protein binding (GO:0005515), monoatomic cation transmembrane transporter activity (GO:0008324), antiporter activity (GO:0015297), metal ion binding (GO:0046872)

GO Cellular Component (7): Golgi membrane (GO:0000139), plasma membrane (GO:0005886), secretory granule (GO:0030141), transport vesicle membrane (GO:0030658), secretory granule membrane (GO:0030667), cytoplasmic vesicle (GO:0031410), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Peptide hormone metabolism	1
Zinc transporters	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
zinc ion transmembrane transport	3
bounding membrane of organelle	3
response to cytokine	2
monoatomic cation transmembrane transport	2
transport	2
cytoplasmic vesicle membrane	2
transition metal ion transport	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
response to hexose	1
response to metal ion	1
peptide hormone processing	1
insulin metabolic process	1
protein secretion	1
peptide hormone secretion	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
innate immune response	1
vesicle-mediated transport	1
regulation of cellular process	1
regulation of transport	1
zinc ion transport	1
inorganic cation import across plasma membrane	1
monoatomic ion transport	1
cellular process	1
transition metal ion transmembrane transporter activity	1
transition metal ion binding	1
identical protein binding	1
protein dimerization activity	1
zinc ion transmembrane transporter activity	1
metal cation:proton antiporter activity	1
binding	1
monoatomic ion transmembrane transporter activity	1
secondary active transmembrane transporter activity	1
cation binding	1
Golgi apparatus	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1258 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC30A8	PTPRN	Q16849	965
SLC30A8	HHEX	Q03014	934
SLC30A8	CDKAL1	Q5VV42	927
SLC30A8	INS	P01308	906
SLC30A8	TCF7L2	Q9NQB0	890
SLC30A8	GAD2	Q05329	889
SLC30A8	IGF2BP2	Q9Y6M1	863
SLC30A8	KCNJ11	Q14654	840
SLC30A8	FTO	Q9C0B1	814
SLC30A8	KIF11	P52732	791
SLC30A8	EXT2	Q93063	768
SLC30A8	MTNR1B	P49286	763
SLC30A8	INSM2	Q96T92	763
SLC30A8	TSPAN8	P19075	756
SLC30A8	KCNQ1	P51787	755

IntAct

244 interactions, top by confidence:

A	B	Type	Score
CREB3L1	SLC30A8	psi-mi:“MI:0915”(physical association)	0.810
SLC30A8	CREB3L1	psi-mi:“MI:0915”(physical association)	0.810
SLC30A8	HMG20A	psi-mi:“MI:0915”(physical association)	0.560
BIK	SLC30A8	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	SPAG4	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	BIK	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	EBP	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	CLDN6	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	SSMEM1	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	FNDC9	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	SAR1A	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	MUC1	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	SCN3B	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	CGRRF1	psi-mi:“MI:0915”(physical association)	0.560
PLN	SLC30A8	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (205): SLC30A8 (Two-hybrid), CREB3L1 (Two-hybrid), SLC30A8 (Two-hybrid), SLC30A8 (Two-hybrid), SLC30A8 (Two-hybrid), SLC30A8 (Two-hybrid), SLC30A8 (Two-hybrid), SLC30A8 (Two-hybrid), SLC30A8 (Two-hybrid), SLC30A8 (Two-hybrid), SLC30A8 (Two-hybrid), SLC30A8 (Two-hybrid), SLC30A8 (Two-hybrid), SLC30A8 (Two-hybrid), SLC30A8 (Two-hybrid)

ESM2 similar proteins: A0A0G2KQY6, A0A3Q7ZPG5, A4IFD7, A4IIC5, A5PMX1, A8WMY3, O13918, O14863, O35149, O45923, O55174, O59758, O80632, P0CE46, P20107, P32798, P40544, P97441, Q28CE7, Q2HJ10, Q3KR82, Q52KD7, Q5BJM8, Q5I020, Q5MNV6, Q5NA18, Q5XHB4, Q5ZIU9, Q62941, Q6DBM8, Q6DG36, Q6NRI1, Q6NTL1, Q6P3N9, Q6QIX3, Q8BFU1, Q8BGG0, Q8H329, Q8IWU4, Q8LE59

Diamond homologs: A7Z1S6, O07084, O45923, P0CE46, P13512, P30540, P55237, P75757, P94178, Q03455, Q2HJ10, Q3UVU3, Q54QU8, Q54T06, Q5I020, Q5XHB4, Q66D85, Q6D7E5, Q83SA2, Q8BGG0, Q8IWU4, Q8R4H9, Q8TAD4, Q8X400, Q8Z8B6, Q8ZGY6, Q8ZQT3, Q9SI03, O14863, O35149, O55174, P97441, Q08E25, Q5R617, Q62941, Q6DBM8, Q6P0D1, Q6QIX3, Q99726, Q9BRI3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	55
Likely benign	7
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
442200	GRCh37/hg19 8p23.3-q24.3(chr8:158049-146295771)	Pathogenic

SpliceAI

1208 predictions. Top by Δscore:

Variant	Effect	Δscore
8:117146952:A:AG	acceptor_gain	1.0000
8:117146953:G:GG	acceptor_gain	1.0000
8:117146953:GT:G	acceptor_gain	1.0000
8:117157840:ATTGT:A	donor_gain	1.0000
8:117157841:TTGT:T	donor_gain	1.0000
8:117157843:GT:G	donor_gain	1.0000
8:117157844:TGTAA:T	donor_loss	1.0000
8:117157845:G:GC	donor_loss	1.0000
8:117157845:G:GG	donor_gain	1.0000
8:117157846:TAA:T	donor_loss	1.0000
8:117161736:A:AG	acceptor_gain	1.0000
8:117161737:G:GG	acceptor_gain	1.0000
8:117161737:GACTA:G	acceptor_gain	1.0000
8:117161784:G:GT	donor_gain	1.0000
8:117161846:GA:G	donor_gain	1.0000
8:117161850:ATC:A	donor_gain	1.0000
8:117161886:AAG:A	donor_loss	1.0000
8:117161889:GT:G	donor_loss	1.0000
8:117161890:T:A	donor_loss	1.0000
8:117163423:A:AG	acceptor_gain	1.0000
8:117163424:G:GG	acceptor_gain	1.0000
8:117163424:GCCA:G	acceptor_gain	1.0000
8:117146946:A:AG	acceptor_gain	0.9900
8:117146947:T:G	acceptor_gain	0.9900
8:117146952:AGTGT:A	acceptor_gain	0.9900
8:117146953:GTGT:G	acceptor_gain	0.9900
8:117146953:GTGTG:G	acceptor_gain	0.9900
8:117147154:G:GG	donor_gain	0.9900
8:117157685:TCCTA:T	acceptor_loss	0.9900
8:117157686:CCTA:C	acceptor_loss	0.9900

AlphaMissense

2422 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:117161865:A:C	S234R	0.989
8:117161867:T:A	S234R	0.989
8:117161867:T:G	S234R	0.989
8:117152961:A:C	S97R	0.985
8:117152963:T:A	S97R	0.985
8:117152963:T:G	S97R	0.985
8:117161847:A:C	S228R	0.984
8:117161849:T:A	S228R	0.984
8:117161849:T:G	S228R	0.984
8:117153021:A:C	S117R	0.979
8:117153023:T:A	S117R	0.979
8:117153023:T:G	S117R	0.979
8:117153009:A:C	S113R	0.978
8:117153011:T:A	S113R	0.978
8:117153011:T:G	S113R	0.978
8:117161853:A:C	S230R	0.972
8:117161855:T:A	S230R	0.972
8:117161855:T:G	S230R	0.972
8:117153072:T:C	F134L	0.966
8:117153074:T:A	F134L	0.966
8:117153074:T:G	F134L	0.966
8:117157726:T:A	W152R	0.965
8:117157726:T:C	W152R	0.965
8:117152968:C:A	A99D	0.956
8:117163464:T:C	F255L	0.956
8:117163466:T:A	F255L	0.956
8:117163466:T:G	F255L	0.956
8:117152982:G:C	A104P	0.952
8:117163485:A:C	S262R	0.952
8:117163487:C:A	S262R	0.952

dbSNP variants (sampled 300 via entrez): RS1000008555 (8:117117267 T>C,G), RS1000020917 (8:117160853 A>G), RS1000021597 (8:117065148 A>G), RS1000025104 (8:117169227 G>C), RS1000026854 (8:117072811 A>C,G), RS1000033806 (8:117108392 A>G), RS1000068671 (8:117032457 C>T), RS1000100971 (8:117142295 C>A), RS1000117282 (8:117124554 T>C), RS1000136319 (8:117152837 C>G), RS1000142118 (8:117071273 T>C), RS1000153864 (8:117143072 G>A), RS1000160356 (8:117080432 A>ACGATTGACTCTCTTAC), RS1000164909 (8:117142827 C>T), RS1000173608 (8:116962694 A>G)

Disease associations

OMIM: gene MIM:611145 | disease phenotypes: MIM:125853

GenCC curated gene-disease

Disease	Classification	Inheritance
type 2 diabetes mellitus	Limited	Autosomal dominant

Mondo (1): type 2 diabetes mellitus (MONDO:0005148)

Orphanet (0):

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000855	Insulin resistance
HP:0003584	Late onset
HP:0005978	Type II diabetes mellitus
HP:0031819	Increased waist to hip ratio

GWAS associations

65 associations (top):

Study	Trait	p-value
GCST000012_1	Type 2 diabetes	6.000000e-08
GCST000024_10	Type 2 diabetes	5.000000e-08
GCST000025_10	Type 2 diabetes	5.000000e-08
GCST000027_2	Type 2 diabetes	3.000000e-06
GCST000028_1	Type 2 diabetes	5.000000e-08
GCST000277_6	Type 2 diabetes	7.000000e-06
GCST000303_2	Glycated hemoglobin levels	5.000000e-08
GCST000383_4	Type 2 diabetes	2.000000e-14
GCST000478_6	Type 2 diabetes	8.000000e-08
GCST000568_3	Fasting blood glucose	3.000000e-11
GCST000712_24	Type 2 diabetes	1.000000e-08
GCST001172_1	Asthma	5.000000e-13
GCST001212_5	Proinsulin levels	3.000000e-18
GCST001527_19	Fasting blood glucose (BMI interaction)	3.000000e-20
GCST001550_4	Type 2 diabetes	4.000000e-08
GCST001762_573	Obesity-related traits	8.000000e-06
GCST002128_5	Type 2 diabetes	5.000000e-07
GCST002168_5	Intraocular pressure	2.000000e-06
GCST002352_38	Type 2 diabetes	2.000000e-18
GCST002390_12	Glycated hemoglobin levels	2.000000e-07
GCST002586_10	Fasting plasma glucose	5.000000e-12
GCST003069_1	Left superior temporal gyrus thickness (schizophrenia interaction)	2.000000e-07
GCST003400_42	Type 2 diabetes	9.000000e-13
GCST003619_4	Type 2 diabetes	1.000000e-11
GCST003775_3	Lung cancer	3.000000e-06
GCST004206_13	Fasting plasma glucose	5.000000e-13
GCST004206_4	Fasting plasma glucose	4.000000e-11
GCST004894_145	Type 2 diabetes	4.000000e-42
GCST004894_29	Type 2 diabetes	2.000000e-07
GCST004894_67	Type 2 diabetes	2.000000e-22

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004541	HbA1c measurement
EFO:0004467	insulin measurement
EFO:0004340	body mass index
EFO:0004736	aspartate aminotransferase measurement
EFO:0004695	intraocular pressure measurement
EFO:0004468	glucose measurement
EFO:0004530	triglyceride measurement
EFO:0009924	Drugs used in diabetes use measurement
EFO:0004469	HOMA-B
EFO:0010501	indole-3-propionate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs13266634	Efficacy	3	repaglinide	Diabetes Mellitus;Type 2
rs13266634	Efficacy	3	insulin recombinant;zinc acetate

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs13266634	SLC30A8	3	2.75	2	repaglinide;insulin recombinant;zinc acetate
rs16889462	SLC30A8		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC30 zinc transporter family

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Zinc	affects localization, increases abundance, increases transport, increases uptake	3
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Valproic Acid	affects expression, decreases methylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
bisphenol A	decreases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
3-iodothyronamine	affects uptake	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	increases methylation	1
Cadmium	increases abundance, increases expression	1
Copper	affects cotreatment, decreases expression	1
Glucose	increases reaction, increases secretion	1
Triclosan	decreases expression	1
Cadmium Chloride	increases abundance, increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_YB10	EndoC-betaH1 SLC30A8-KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus