SLC39A6

Summary

SLC39A6 (solute carrier family 39 member 6, HGNC:18607) is a protein-coding gene on chromosome 18q12.2, encoding Zinc transporter ZIP6 (Q13433). Zinc-influx transporter which plays a role in zinc homeostasis and in the induction of epithelial-to-mesenchymal transition (EMT).

Zinc is an essential cofactor for hundreds of enzymes. It is involved in protein, nucleic acid, carbohydrate, and lipid metabolism, as well as in the control of gene transcription, growth, development, and differentiation. SLC39A6 belongs to a subfamily of proteins that show structural characteristics of zinc transporters (Taylor and Nicholson, 2003 [PubMed 12659941]).

Source: NCBI Gene 25800 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 100 total
• Druggable target: yes
• MANE Select transcript: NM_012319

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18607
Approved symbol	SLC39A6
Name	solute carrier family 39 member 6
Location	18q12.2
Locus type	gene with protein product
Status	Approved
Aliases	LIV-1, ZIP6
Ensembl gene	ENSG00000141424
Ensembl biotype	protein_coding
OMIM	608731
Entrez	25800

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000269187, ENST00000440549, ENST00000586829, ENST00000590986

RefSeq mRNA: 2 — MANE Select: NM_012319 NM_001099406, NM_012319

CCDS: CCDS42428, CCDS45854

Canonical transcript exons

ENST00000269187 — 10 exons

Exon	Start	End
ENSE00000948458	36126219	36127016
ENSE00000948460	36123495	36123664
ENSE00000948461	36122052	36122270
ENSE00000948462	36116674	36116779
ENSE00000948463	36114097	36114474
ENSE00000948464	36112501	36112581
ENSE00000948465	36111059	36111249
ENSE00001162199	36108531	36109745
ENSE00002945678	36129114	36129340
ENSE00003540413	36124520	36124700

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 68.5898 / max 802.1530, expressed in 1800 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171683	61.9957	1796
171678	3.4547	287
171679	1.7391	290
171684	0.5578	262
171682	0.3297	175
171680	0.3196	140
171681	0.1933	99

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.81	gold quality
choroid plexus epithelium	UBERON:0003911	99.50	gold quality
pigmented layer of retina	UBERON:0001782	99.36	gold quality
hair follicle	UBERON:0002073	99.21	gold quality
tibia	UBERON:0000979	99.19	gold quality
seminal vesicle	UBERON:0000998	99.17	gold quality
gingival epithelium	UBERON:0001949	99.14	gold quality
caput epididymis	UBERON:0004358	99.04	gold quality
epithelium of mammary gland	UBERON:0003244	99.00	gold quality
oocyte	CL:0000023	98.98	gold quality
mammary duct	UBERON:0001765	98.95	gold quality
corpus epididymis	UBERON:0004359	98.94	gold quality
upper leg skin	UBERON:0004262	98.93	gold quality
gingiva	UBERON:0001828	98.80	gold quality
endometrium epithelium	UBERON:0004811	98.76	gold quality
eye	UBERON:0000970	98.62	gold quality
cartilage tissue	UBERON:0002418	98.45	gold quality
palpebral conjunctiva	UBERON:0001812	98.44	gold quality
parietal pleura	UBERON:0002400	98.35	gold quality
skin of hip	UBERON:0001554	98.34	gold quality
germinal epithelium of ovary	UBERON:0001304	98.32	gold quality
endothelial cell	CL:0000115	98.31	gold quality
decidua	UBERON:0002450	98.24	gold quality
pleura	UBERON:0000977	98.22	gold quality
cortical plate	UBERON:0005343	98.08	gold quality
visceral pleura	UBERON:0002401	98.07	gold quality
ventricular zone	UBERON:0003053	97.84	gold quality
stromal cell of endometrium	CL:0002255	97.79	gold quality
upper arm skin	UBERON:0004263	97.79	gold quality
endometrium	UBERON:0001295	97.75	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-10885	yes	954.19
E-MTAB-9841	yes	665.49
E-MTAB-10287	yes	109.86
E-MTAB-7008	no	127.73
E-HCAD-13	no	3.47
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

Literature-anchored findings (GeneRIF, showing 36)

• LIV-1 co-clusters with estrogen receptor alpha in microarray analysis of breast cancer biopsies. (PMID:11911440)
• Review of LIV-1 and other LZT proteins. (PMID:12659941)
• LIV-1, a member of the ZIP family of zinc transporters, is an integral plasma membrane protein that transports zinc into cells. (PMID:12839489)
• Structure-function analysis of LIV-1. (PMID:12839489)
• LIV-1 is coregulated with estrogen receptor in some breast cancers. (PMID:12960427)
• data suggest that LIV-1 protein is a promising candidate for a novel marker for breast cancer patients with better outcome (PMID:15986450)
• regulation of LIV-1 protein in human breast cancer xenografts (PMID:17786585)
• Hence, our data provide the first evidence that LIV-1 mRNA is overexpressed in cervical cancer in situ and is involved in invasion of cervical cancer cells through targeting MAPK-mediated Snail and Slug expression. (PMID:17825787)
• LIV-1 mRNA upregulation is associated with the progression of cervical cancer but not with the development of endometrial carcinoma. (PMID:17959546)
• LIV-1 may be a regulator of E-cadherin (PMID:18330719)
• Single nucleotide polymorphism in SLC39A6 gene is associated with acute lymphoblastic leukemia. (PMID:19066393)
• LIV-1 enhances the aggressive phenotype through the induction of epithelial to mesenchymal transition in human pancreatic carcinoma cells. (PMID:19724917)
• Zip6 over-expression is not an underlying mechanism initiating breast cancer, but in fact may play a “tumor-constraining” role. (PMID:19852955)
• The present study identifies LIV1 as a critical mediator responsible for HDACi-induced apoptosis. The effect of LIV1 is, at least in part, mediated by affecting intracellular zinc homeostasis. (PMID:19887557)
• LIV-1 is involved in prostate cancer progression as an intracellular target of growth factor receptor signaling which promoted EMT and cancer metastasis (PMID:22110740)
• The results of this study showed evidence for a positive correlation between LIV1 and ZnT6 insuperior temporal, occipital, and frontal gyri in patient with alzheimer disease. (PMID:22349685)
• Some studies correlate LIV-1 expression with a more aggressive cancer phenotype and increased likelihood for metastasis to lymph nodes. In contrast, other evidence suggests this transporter is associated with a more favorable prognosis. [review] (PMID:22852056)
• Down-regulated LIV-1 cells showed significant inhibition of proliferation in vitro and reduction of tumor growth in vivo. Furthermore, E-cadherin expression increased in LIV-1 siRNA expressing Hep-G2. (PMID:23437163)
• SLC39A6 has an important role in the prognosis of esophageal squamous-cell carcinoma and may be a potential therapeutic target. (PMID:23644492)
• a causative role for ZIP6 in cell motility and migration (PMID:23919497)
• Zinc and its transporters, ZIP6 and ZIP10, are required for the breast cancer cells motility stimulated with high glucose level, such as in diabetes. (PMID:24587242)
• drug resistance of ovarian cancer cells to trichostatin A may be related to expression of the LIV1 gene (PMID:25420545)
• Knock-down of ZIP6 but not ZIP7 in MIN6 beta cells impaired the protective effects of GLP-1 on fatty acid-induced cell apoptosis, possibly via reduced activation of the p-ERK pathway (PMID:25969539)
• SLC39A6 may have a tumor promoting role in esophageal carcinoma (PMID:26444413)
• Upregulation of SLC39A6 is associated with hepatocellular carcinoma. (PMID:26684241)
• SLC39A6 promotes aggressiveness of esophageal carcinoma cells by increasing intracellular levels of zinc, activating phosphatidylinositol 3-kinase signaling, and up-regulating genes that regulate metastasis. (PMID:28209530)
• ZIP6 deficiency disturbs intracellular Zn2+ homeostasis, leading to increased cell survival in hypoxia and reduced E-cadherin expression, indicating that decreased ZIP6 expression is strongly associated with resistance to hypoxia. (PMID:28833062)
• ZIP10 is predominantly expressed in the interfollicular epidermis, epidermal appendages and hair follicles. ZIP10 depletion resulted in epidermal malformations in a reconstituted human skin model via downregulation of the epigenetic enzyme histone acetyltransferase (HAT). Decreased HAT activity, resulting from either ZIP10 depletion or treatment with the zinc chelator TPEN, was readily restored by zinc supplementation. (PMID:30339739)
• this work shows that zinc entry into activated lymphocytes depends on Zip6 and that this transporter is essential for the correct function of the cellular activation machinery (PMID:30552163)
• These data demonstrate that LIV-1-GRPEL1 axis dually regulates mitotic exit as well as apoptosis by interacting with PP2A B55alpha and AIF. (PMID:31636012)
• SLC39A6 is involved in gastric adenocarcinoma, and genotype at SLC39A6 rs1050631 can predict post-resection prognosis of gastric adenocarcinoma patients, at least in a population in an area with high gastric adenocarcinoma incidence. (PMID:31703635)
• The ZIP6/ZIP10 heteromer is essential for the zinc-mediated trigger of mitosis. (PMID:32797246)
• Zap70 Regulates TCR-Mediated Zip6 Activation at the Immunological Synapse. (PMID:34394081)
• Oestrogen-regulated protein SLC39A6: a biomarker of good prognosis in luminal breast cancer. (PMID:34453638)
• Suppression of SLC39A6-CREB1 axis in liver cancer causes PCK1-mediated mitochondrial dysfunction. (PMID:37435980)
• Expression of cell surface zinc transporter LIV1 in triple negative breast cancer is an indicator of poor prognosis and therapy failure. (PMID:38345361)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc39a6	ENSDARG00000068143
mus_musculus	Slc39a6	ENSMUSG00000024270
rattus_norvegicus	Slc39a6	ENSRNOG00000028703
caenorhabditis_elegans		WBGENE00021936

Paralogs (6): SLC39A14 (ENSG00000104635), SLC39A8 (ENSG00000138821), SLC39A5 (ENSG00000139540), SLC39A4 (ENSG00000147804), SLC39A12 (ENSG00000148482), SLC39A10 (ENSG00000196950)

Protein

Protein identifiers

Zinc transporter ZIP6 — Q13433 (reviewed: Q13433)

Alternative names: Estrogen-regulated protein LIV-1, Solute carrier family 39 member 6, Zrt- and Irt-like protein 6

All UniProt accessions (2): Q13433, K7EQ91

UniProt curated annotations — full annotation on UniProt →

Function. Zinc-influx transporter which plays a role in zinc homeostasis and in the induction of epithelial-to-mesenchymal transition (EMT). When associated with SLC39A10, the heterodimer formed by SLC39A10 and SLC39A6 mediates cellular zinc uptake to trigger cells to undergo epithelial- to-mesenchymal transition (EMT). The SLC39A10-SLC39A6 heterodimer also controls NCAM1 phosphorylation and its integration into focal adhesion complexes during EMT. Zinc influx inactivates GSK3B, enabling unphosphorylated SNAI1 in the nucleus to down-regulate adherence genes such as CDH1, causing loss of cell adherence. In addition, the SLC39A10-SLC39A6 heterodimer plays an essentiel role in initiating mitosis by importing zinc into cells to initiate a pathway resulting in the onset of mitosis. Participates in the T-cell receptor signaling regulation by mediating cellular zinc uptake into activated lymphocytes. Regulates the zinc influx necessary for proper meiotic progression to metaphase II (MII) that allows the oocyte-to-egg transition.

Subunit / interactions. Interacts with SLC39A10; which triggers cells to undergo EMT and mitosis. Found in a complex with SLC39A6, SLC39A10 and with the ‘Ser-727’ phosphorylated form of STAT3 throughout mitosis. Found in a complex with SLC39A6, SLC39A10 and with NCAM1; this complex controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-to-mesenchymal transition (EMT). Found in a complex with SLC39A6, SLC39A10 and with GSK3B that controls NCAM1 phosphorylation.

Subcellular location. Cell membrane. Cell projection. Lamellipodium membrane. Membrane raft. Apical cell membrane.

Tissue specificity. Highly expressed in the breast, prostate, placenta, kidney, pituitary and corpus callosum. Weakly expressed in heart and intestine. Also highly expressed in cells derived from an adenocarcinoma of the cervix and lung carcinoma.

Post-translational modifications. Cleaved on the N-terminus before locating to the plasma membrane. N-glycosylated. Phosphorylated by ZAP70 in response to TCR stimulation leading to its activation.

Induction. Up-regulated by estrogen in breast cancer cells lines. Decreased protein level in response to zinc treatment. Increased upon T cell activation. Induced by STAT3.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q13433-1	1	yes
Q13433-2	2

RefSeq proteins (2): NP_001092876, NP_036451* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003689	ZIP	Family
IPR050799	ZIP_Transporter	Family

Pfam: PF02535

Catalyzed reactions (Rhea), 1 shown:

• Zn(2+)(in) = Zn(2+)(out) (RHEA:29351)

UniProt features (35 total): topological domain 7, transmembrane region 6, compositionally biased region 5, glycosylation site 5, splice variant 3, region of interest 2, modified residue 2, signal peptide 1, chain 1, coiled-coil region 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13433-F1	60.04	0.08

Functional residue map

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

Post-translational modifications (2): 471, 478

Glycosylation sites (5): 67, 241, 266, 283, 684

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: 268 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, MODULE_52, ZHAN_LATE_DIFFERENTIATION_GENES_UP, YANG_BREAST_CANCER_ESR1_BULK_UP, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOZGIT_ESR1_TARGETS_DN, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, MODULE_16, GGGTGGRR_PAX4_03, GOBP_MONOATOMIC_CATION_TRANSPORT, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, MODULE_66, WEI_MYCN_TARGETS_WITH_E_BOX

GO Biological Process (12): epithelial to mesenchymal transition (GO:0001837), intracellular zinc ion homeostasis (GO:0006882), intracellular monoatomic cation homeostasis (GO:0030003), lymphocyte activation (GO:0046649), T cell receptor signaling pathway (GO:0050852), zinc ion transmembrane transport (GO:0071577), zinc ion import across plasma membrane (GO:0071578), monoatomic ion transport (GO:0006811), zinc ion transport (GO:0006829), bicarbonate transport (GO:0015701), metal ion transport (GO:0030001), transmembrane transport (GO:0055085)

GO Molecular Function (4): zinc ion transmembrane transporter activity (GO:0005385), monoatomic cation:bicarbonate symporter activity (GO:0140410), protein binding (GO:0005515), metal ion transmembrane transporter activity (GO:0046873)

GO Cellular Component (8): endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), cell surface (GO:0009986), apical plasma membrane (GO:0016324), lamellipodium membrane (GO:0031258), membrane raft (GO:0045121), membrane (GO:0016020), cell projection (GO:0042995)

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
transport	3
cellular anatomical structure	3
zinc ion transmembrane transport	2
mesenchymal cell differentiation	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
intracellular monoatomic ion homeostasis	1
monoatomic cation homeostasis	1
leukocyte activation	1
antigen receptor-mediated signaling pathway	1
zinc ion transport	1
monoatomic cation transmembrane transport	1
inorganic cation import across plasma membrane	1
transition metal ion transport	1
monoatomic cation transport	1
cellular process	1
transition metal ion transmembrane transporter activity	1
bicarbonate transmembrane transporter activity	1
solute:monoatomic cation symporter activity	1
binding	1
monoatomic cation transmembrane transporter activity	1
metal ion transport	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
lamellipodium	1
cell projection membrane	1
leading edge membrane	1
membrane microdomain	1

Protein interactions and networks

STRING

860 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC39A6	SLC39A9	Q9NUM3	808
SLC39A6	SLC30A1	Q9Y6M5	797
SLC39A6	SLC39A1	Q9NY26	795
SLC39A6	SLC30A5	Q8TAD4	789
SLC39A6	SLC39A11	Q8N1S5	768
SLC39A6	SLC30A6	Q6NXT4	753
SLC39A6	SLC30A4	O14863	747
SLC39A6	SLC30A7	Q8NEW0	734
SLC39A6	SLC30A9	Q6PML9	720
SLC39A6	SLC30A2	Q9BRI3	715
SLC39A6	SLC39A10	Q9ULF5	684
SLC39A6	SNAI1	O95863	681
SLC39A6	SLC30A3	Q99726	666
SLC39A6	SLC30A10	Q6XR72	660
SLC39A6	STAT3	P40763	626

IntAct

75 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
GPR156	PLD2	psi-mi:“MI:0914”(association)	0.640
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
SLC39A5	TMEM223	psi-mi:“MI:0914”(association)	0.530
SPINT2	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
PCDHAC2	TMEM223	psi-mi:“MI:0914”(association)	0.530
HTR2C	KLRG2	psi-mi:“MI:0914”(association)	0.530
CCR6	PODXL	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
TNFRSF13B	TNFRSF10B	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
SLC39A6		psi-mi:“MI:0915”(physical association)	0.370
CD81	STX3	psi-mi:“MI:0914”(association)	0.350
CD81	PVR	psi-mi:“MI:0914”(association)	0.350
M	TM9SF1	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
TMEM106A	QSOX1	psi-mi:“MI:0914”(association)	0.350
P2RY10	POTEF	psi-mi:“MI:0914”(association)	0.350
DGCR2	CCDC85C	psi-mi:“MI:0914”(association)	0.350
HCRTR2	FADS1	psi-mi:“MI:0914”(association)	0.350
LPCAT2	ADGRL1	psi-mi:“MI:0914”(association)	0.350
CDH16	EGFR	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
PCDHB3	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (154): SLC39A6 (Affinity Capture-MS), SLC39A6 (Affinity Capture-MS), SLC39A6 (Affinity Capture-MS), SLC39A6 (Affinity Capture-MS), SLC39A6 (Affinity Capture-MS), SLC39A6 (Affinity Capture-MS), SLC39A6 (Affinity Capture-MS), SLC39A6 (Affinity Capture-MS), SLC39A6 (Affinity Capture-MS), SLC39A6 (Proximity Label-MS), SLC39A6 (Proximity Label-MS), SLC39A6 (Proximity Label-MS), SLC39A6 (Affinity Capture-MS), SLC39A6 (Affinity Capture-MS), SLC39A6 (Two-hybrid)

ESM2 similar proteins: A0A0G2KQY6, A0A6I8PMZ8, A0JPN2, A4IGY6, A5D7L5, E9PU17, E9PX95, F1QYC4, F1S5L4, O35119, O60353, O62852, O94402, O95477, P0DX17, P41233, Q08E40, Q13433, Q15043, Q3SZN3, Q3TT99, Q4V887, Q504Y0, Q5FVQ0, Q5FWH7, Q5GJ77, Q5R9M9, Q5RAB7, Q5RCN4, Q61089, Q61586, Q6L8F3, Q6P5F6, Q6PEH9, Q6R5J1, Q6W3E5, Q75N73, Q84M24, Q8C145, Q8WMU5

Diamond homologs: A0A0G2KQY6, A0A6I8PMZ8, A0JPN2, A4IGY6, A5D7L5, A8WMY3, A8X482, L5KLU7, P0DX17, P40544, Q06916, Q08E40, Q13433, Q15043, Q1KZG0, Q29175, Q2M1K6, Q31125, Q4V887, Q504Y0, Q5FVQ0, Q5FWH7, Q5R6I6, Q5R9M9, Q5RAB7, Q5RFD5, Q5TJF6, Q6L8F3, Q6MGB4, Q6P5F6, Q6P5W5, Q6PEH9, Q75N73, Q8AW42, Q8BZH0, Q8C145, Q91W10, Q92504, Q95KA5, Q96H72

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ZAP70	“up-regulates activity”	SLC39A6	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 108 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Lysosphingolipid and LPA receptors	6	68.2×	5e-08
Class A/1 (Rhodopsin-like receptors)	10	11.1×	3e-06
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	7	9.1×	2e-04
GPCR ligand binding	9	8.6×	5e-05
G alpha (q) signalling events	8	6.8×	3e-04
Signaling by GPCR	9	5.4×	4e-04
GPCR downstream signalling	8	5.2×	1e-03
G alpha (i) signalling events	8	4.7×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	6	13.5×	2e-03
positive regulation of cytosolic calcium ion concentration	7	8.4×	5e-03
G protein-coupled receptor signaling pathway	15	5.6×	5e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	86
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1518 predictions. Top by Δscore:

Variant	Effect	Δscore
18:36111149:T:TA	donor_gain	1.0000
18:36111246:TCAC:T	acceptor_gain	1.0000
18:36111247:CAC:C	acceptor_gain	1.0000
18:36111247:CACC:C	acceptor_gain	1.0000
18:36111249:CC:C	acceptor_loss	1.0000
18:36111249:CCTT:C	acceptor_gain	1.0000
18:36111250:C:CA	acceptor_loss	1.0000
18:36111250:C:CC	acceptor_gain	1.0000
18:36111251:T:C	acceptor_gain	1.0000
18:36111252:T:C	acceptor_gain	1.0000
18:36111252:T:TC	acceptor_gain	1.0000
18:36111256:C:CT	acceptor_gain	1.0000
18:36111257:A:T	acceptor_gain	1.0000
18:36114092:TATA:T	donor_loss	1.0000
18:36114094:TACC:T	donor_loss	1.0000
18:36114095:A:AC	donor_gain	1.0000
18:36114095:A:AT	donor_loss	1.0000
18:36114096:C:CC	donor_gain	1.0000
18:36114363:T:TA	donor_gain	1.0000
18:36114475:C:CC	acceptor_gain	1.0000
18:36114481:A:AC	acceptor_gain	1.0000
18:36116672:A:AC	donor_gain	1.0000
18:36116672:ACGAT:A	donor_gain	1.0000
18:36116673:C:CA	donor_gain	1.0000
18:36116673:CG:C	donor_gain	1.0000
18:36116673:CGAT:C	donor_gain	1.0000
18:36116673:CGATC:C	donor_gain	1.0000
18:36116692:T:A	donor_gain	1.0000
18:36116775:TGATT:T	acceptor_gain	1.0000
18:36116776:GATT:G	acceptor_gain	1.0000

AlphaMissense

5061 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:36111083:G:C	F697L	1.000
18:36111083:G:T	F697L	1.000
18:36111085:A:G	F697L	1.000
18:36111150:C:T	G675E	1.000
18:36111151:C:G	G675R	1.000
18:36111151:C:T	G675R	1.000
18:36111163:C:G	G671R	1.000
18:36111163:C:T	G671R	1.000
18:36112533:G:T	A631D	1.000
18:36112551:C:T	G625D	1.000
18:36112581:C:T	G615D	1.000
18:36114097:C:G	G615R	1.000
18:36114108:C:T	G611D	1.000
18:36114109:C:G	G611R	1.000
18:36114119:A:C	N607K	1.000
18:36114119:A:T	N607K	1.000
18:36123505:A:G	L377P	1.000
18:36123627:A:C	S336R	1.000
18:36123627:A:T	S336R	1.000
18:36123629:T:G	S336R	1.000
18:36109657:C:T	G735D	0.999
18:36109658:C:G	G735R	0.999
18:36109670:C:A	G731W	0.999
18:36111084:A:G	F697S	0.999
18:36111085:A:T	F697I	0.999
18:36111090:C:T	G695D	0.999
18:36111091:C:G	G695R	0.999
18:36111093:G:T	A694D	0.999
18:36111094:C:G	A694P	0.999
18:36111112:A:G	W688R	0.999

dbSNP variants (sampled 300 via entrez): RS1000097196 (18:36121737 C>T), RS1000101292 (18:36112244 A>G,T), RS1000312054 (18:36118011 A>G,T), RS1000317584 (18:36108908 T>C), RS1000343919 (18:36124852 C>T), RS1000370038 (18:36109218 C>T), RS1000696276 (18:36110969 C>A,G,T), RS1000858099 (18:36113180 A>T), RS1001348424 (18:36128780 C>A,G), RS1001457719 (18:36131234 C>A,T), RS1001668369 (18:36125808 T>C), RS1001765879 (18:36119161 A>G), RS1002014548 (18:36125506 G>A), RS1002319386 (18:36114787 A>G), RS1002492463 (18:36120795 G>A,C)

Disease associations

OMIM: gene MIM:608731 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002010_1	Esophageal squamous cell cancer (length of survival)	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0000714	survival time

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523581 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC39 family of metal ion transporters

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, affects cotreatment, decreases expression	7
trichostatin A	affects cotreatment, decreases expression, decreases reaction, increases cleavage, increases expression (+1 more)	4
Zinc	decreases response to substance, affects uptake, increases transport, increases uptake, decreases expression (+3 more)	4
Tobacco Smoke Pollution	increases expression	2
Aflatoxin B1	increases methylation, affects expression, increases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	decreases expression	1
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
methotrexate polyglutamate	affects abundance	1
arsenite	increases methylation	1
afimoxifene	decreases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
zinc chromate	increases abundance, increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ochratoxin A	decreases expression	1
gallium nitrate	decreases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases reaction, increases cleavage, increases expression, decreases response to substance, decreases expression	1
chromium hexavalent ion	increases abundance, increases expression	1
CGP 52608	affects binding, increases reaction	1
apicidin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
torcetrapib	increases expression	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Fulvestrant	decreases expression	1
Vorinostat	decreases response to substance	1
Panobinostat	decreases expression	1

Cellosaurus cell lines

9 cell lines: 7 cancer cell line, 1 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4NM	HCT116-SLC39A6-KO-c12	Cancer cell line	Male
CVCL_D4NN	HCT116-SLC39A6-KO-c8	Cancer cell line	Male
CVCL_D8AH	Ubigene A-549 SLC39A6 KO	Cancer cell line	Male
CVCL_E5FJ	Jurkat Zip6KO	Cancer cell line	Male
CVCL_E6RV	Genomeditech CHO-K1 H_SLC39A6	Spontaneously immortalized cell line	Female
CVCL_E6UY	Genomeditech HEK-293 H_SLC39A6	Transformed cell line	Female
CVCL_E6W9	Genomeditech LLC1 H_SLC39A6	Cancer cell line
CVCL_E8JE	BxPC-3 human SLC39A6	Cancer cell line	Female
CVCL_TN58	HAP1 SLC39A6 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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