SLC39A2

Summary

SLC39A2 (solute carrier family 39 member 2, HGNC:17127) is a protein-coding gene on chromosome 14q11.2, encoding Zinc transporter ZIP2 (Q9NP94). Transporter for the divalent cation Zn(2+).

This gene encodes a member of the ZIP family of metal ion transporters. The encoded protein functions as a zinc transporter. Mutations in this gene may be associated with susceptibility to carotid artery disease. Multiple transcript variants have been described.

Source: NCBI Gene 29986 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 39 total
• MANE Select transcript: NM_014579

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17127
Approved symbol	SLC39A2
Name	solute carrier family 39 member 2
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	ZIP2
Ensembl gene	ENSG00000165794
Ensembl biotype	protein_coding
OMIM	612166
Entrez	29986

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000298681, ENST00000554128, ENST00000554422

RefSeq mRNA: 2 — MANE Select: NM_014579 NM_001256588, NM_014579

CCDS: CCDS58303, CCDS9563

Canonical transcript exons

ENST00000298681 — 4 exons

Exon	Start	End
ENSE00001096609	21000947	21001871
ENSE00001096611	20999293	20999561
ENSE00001096614	21000116	21000166
ENSE00001137055	20999742	20999872

Expression profiles

Bgee: expression breadth ubiquitous, 142 present calls, max score 92.92.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6512 / max 86.7677, expressed in 118 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138492	0.6512	118

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tongue squamous epithelium	UBERON:0006919	92.92	silver quality
skin of abdomen	UBERON:0001416	88.87	gold quality
skin of leg	UBERON:0001511	88.25	gold quality
epithelium of esophagus	UBERON:0001976	87.67	gold quality
esophagus squamous epithelium	UBERON:0006920	87.28	gold quality
zone of skin	UBERON:0000014	86.76	gold quality
squamous epithelium	UBERON:0006914	85.96	gold quality
gingival epithelium	UBERON:0001949	84.20	gold quality
esophagus mucosa	UBERON:0002469	83.87	gold quality
gingiva	UBERON:0001828	83.42	gold quality
mammalian vulva	UBERON:0000997	83.15	gold quality
cervix epithelium	UBERON:0004801	81.49	silver quality
lower esophagus mucosa	UBERON:0035834	81.37	gold quality
upper arm skin	UBERON:0004263	80.35	silver quality
cervix squamous epithelium	UBERON:0006922	79.89	gold quality
seminal vesicle	UBERON:0000998	78.28	gold quality
vagina	UBERON:0000996	77.96	gold quality
palpebral conjunctiva	UBERON:0001812	77.54	gold quality
upper leg skin	UBERON:0004262	76.76	gold quality
sperm	CL:0000019	73.52	silver quality
choroid plexus epithelium	UBERON:0003911	72.83	gold quality
skin of hip	UBERON:0001554	72.58	gold quality
ectocervix	UBERON:0012249	71.73	gold quality
male germ cell	CL:0000015	71.64	silver quality
mucosa of transverse colon	UBERON:0004991	71.10	gold quality
uterine cervix	UBERON:0000002	69.69	gold quality
oral cavity	UBERON:0000167	69.36	silver quality
penis	UBERON:0000989	67.58	gold quality
oviduct epithelium	UBERON:0004804	66.91	silver quality
pancreatic ductal cell	CL:0002079	64.68	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.17

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting SLC39A2, 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-8485	100.00	77.57	4731
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-5009-3P	99.45	69.43	1341
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-654-3P	98.38	67.61	905
HSA-MIR-676-3P	97.86	65.70	668
HSA-MIR-4714-3P	96.53	67.44	452

Literature-anchored findings (GeneRIF, showing 13)

• ZiP2 and Zip3 are down regulated in malignant cells (PMID:17550612)
• regulation of ZIP2 protein in human breast cancer xenografts (PMID:17786585)
• Gene expression regulation of ZIPs after zinc supplementation. (PMID:18279033)
• Zip2 Gln/Arg/Leu polymorphism plays a role in the susceptibility to carotid artery disease. (PMID:18328005)
• Expression of two Zn2+ influx transporters, ZIP2 and ZIP4, is reduced as a function of retinal pigment epithelium age. (PMID:21603979)
• Increased expression of Zip2 gene is closely associated with immunity of pulmonary tuberculosis patients, suggesting that the Zip2 gene may play a key role in initial infection control. (PMID:23686108)
• 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)
• results of this study suggest that ZIP2, a zinc transporter expressed specifically in the epidermis, and zinc taken up by ZIP2 are necessary for the differentiation of keratinocytes (PMID:24936057)
• ZIP2 Gln/Arg/Leu polymorphism involve in proinflammatory mediation and zinc homeostasis in elderly population with a more pronounced anti-inflammatory effect of zinc supplementation in subjects carrying ZIP2 Leu- (Arg43Arg) genotype (PMID:26643924)
• Results showed decreased expression of Zn uptake transporters ZIP2 and ZIP4 on mRNA and protein level correlating with SHANK3 expression levels, and found reduced levels of ZIP4 protein co-localizing with SHANK3 at the plasma membrane. ZIP4 exists in a complex with SHANK3. Further results confirmed a link between enterocytic SHANK3, ZIP2 and ZIP4. (PMID:28345660)
• the splice switch to DeltaC-ZIP2 as well as decreased expression of other ZIPs caused zinc deficiency, which is sufficient for induction of MUC5AC. (PMID:29289532)
• Reassessment of the Transport Mechanism of the Human Zinc Transporter SLC39A2. (PMID:29791142)
• results provide the first structural evidence for the previously observed pH and voltage modulation of ZIP2-mediated metal transport, identify the substrate-binding site, and suggest a structure-based transport mechanism for the ZIP2 transporter. (PMID:30914478)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Slc39a2	ENSMUSG00000072572
rattus_norvegicus	Slc39a2	ENSRNOG00000010375
caenorhabditis_elegans		WBGENE00014669
caenorhabditis_elegans		WBGENE00017936

Paralogs (2): SLC39A3 (ENSG00000141873), SLC39A1 (ENSG00000143570)

Protein

Protein identifiers

Zinc transporter ZIP2 — Q9NP94 (reviewed: Q9NP94)

Alternative names: 6A1, Eti-1, Solute carrier family 39 member 2, Zrt- and Irt-like protein 2

All UniProt accessions (1): Q9NP94

UniProt curated annotations — full annotation on UniProt →

Function. Transporter for the divalent cation Zn(2+). Mediates the influx of Zn(2+) into cells from extracellular space. The Zn(2+) uniporter activity is independent of H(+)-driving force, but is modulated by extracellular pH and membrane potential. Also transports other divalent cations Zn(2+), Cd2(+), Cu2(+), Co2(+) in the order of decreasing affinity, respectively. In the skin, aids in the differentiation of keratinocytes in the epidermis.

Subcellular location. Cell membrane.

Tissue specificity. Expressed only in prostate and uterine epithelial cells.

Activity regulation. Activity is increased at acidic pH (6.5). Inhibited in the presence of high extracellular K(+).

Induction. Shows a dramatic induction in normal epithelial cells contact inhibition.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NP94-1	1	yes
Q9NP94-2	2

RefSeq proteins (2): NP_001243517, NP_055394* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003689	ZIP	Family

Pfam: PF02535

Catalyzed reactions (Rhea), 2 shown:

• Cd(2+)(in) = Cd(2+)(out) (RHEA:28707)
• Zn(2+)(in) = Zn(2+)(out) (RHEA:29351)

UniProt features (52 total): mutagenesis site 20, topological domain 8, transmembrane region 8, sequence variant 5, binding site 4, sequence conflict 3, splice variant 2, chain 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NP94-F1	82.55	0.55

Functional residue map

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

Catalytic / active sites (1): 63 (critical for the ph sensitivity)

Ligand- & substrate-binding residues (4): 175; 179; 202; 276

Mutagenesis-validated functional residues (20):

Position	Phenotype
63	decreased of about 60% in transport activity. loss of ph dependence for transport activity.
67	decreased of about 35% in transport activity. alters the ph and voltage modulation of the transporter.
70	increased of about 65% in transport activity. does not change h(+) affinity.
71	does not affect ph sensitivity.
106	decreased of about 30% in transport activity.
106	increased of about 35% in transport activity.
120	does not affect ph sensitivity.
175	abolishes transport activity.
176	does not alter the substrate selectivity of slc39a2.
179	decreased of about 60% in transport activity. does not alter the substrate selectivity of slc39a2.
179	abolishes transport activity.
202	abolishes transport activity.
202	does not affect transport kinetics parameters. exhibits a broader substrate selectivity.
203	decreased of about 78% in transport activity.
203	abolishes transport activity.
203	decreases of about 72% in transport activity.
269	exhibits a broader substrate selectivity.
276	abolishes transport activity.
276	does not affect transport activity. reduces affinity for h(+).

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: 96 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_TRANSITION_METAL_ION_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_EPIDERMIS_DEVELOPMENT, TCCAGAT_MIR5165P, GOBP_SKIN_DEVELOPMENT, RICKMAN_HEAD_AND_NECK_CANCER_C, GOBP_TRANSMEMBRANE_TRANSPORT, PITX2_Q2, AP4_01, PAX2_02, GOMF_METAL_ION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY

GO Biological Process (7): zinc ion transport (GO:0006829), keratinocyte differentiation (GO:0030216), cadmium ion transmembrane transport (GO:0070574), zinc ion transmembrane transport (GO:0071577), monoatomic ion transport (GO:0006811), metal ion transport (GO:0030001), transmembrane transport (GO:0055085)

GO Molecular Function (3): zinc ion transmembrane transporter activity (GO:0005385), metal ion transmembrane transporter activity (GO:0046873), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), cytoplasmic vesicle (GO:0031410), cytoplasmic ribonucleoprotein granule (GO:0036464), 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	2
transport	2
cytoplasm	2
transition metal ion transport	1
epidermal cell differentiation	1
skin development	1
cadmium ion transport	1
zinc ion transport	1
monoatomic cation transport	1
cellular process	1
transition metal ion transmembrane transporter activity	1
zinc ion transmembrane transport	1
monoatomic cation transmembrane transporter activity	1
metal ion transport	1
binding	1
membrane	1
cell periphery	1
intracellular vesicle	1
ribonucleoprotein granule	1
cellular anatomical structure	1

Protein interactions and networks

STRING

676 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC39A2	SLC39A11	Q8N1S5	716
SLC39A2	SLC39A4	Q6P5W5	706
SLC39A2	SLC39A12	Q504Y0	697
SLC39A2	SLC39A9	Q9NUM3	693
SLC39A2	SLC39A7	Q92504	673
SLC39A2	SLC39A13	Q96H72	652
SLC39A2	SLC39A5	Q6ZMH5	647
SLC39A2	SLC30A6	Q6NXT4	647
SLC39A2	SLC30A1	Q9Y6M5	646
SLC39A2	SLC39A6	Q13433	621
SLC39A2	SLC39A14	Q15043	621
SLC39A2	SLC39A10	Q9ULF5	617
SLC39A2	SLC39A8	Q9C0K1	608
SLC39A2	SLC30A9	Q6PML9	583
SLC39A2	SLC30A7	Q8NEW0	572

IntAct

161 interactions, top by confidence:

A	B	Type	Score
FAM3C	SLC39A2	psi-mi:“MI:0915”(physical association)	0.560
FZD7	SLC39A2	psi-mi:“MI:0915”(physical association)	0.560
UBE2J1	SLC39A2	psi-mi:“MI:0915”(physical association)	0.560
VAMP5	SLC39A2	psi-mi:“MI:0915”(physical association)	0.560
NRM	SLC39A2	psi-mi:“MI:0915”(physical association)	0.560
SLC39A2	SLC7A1	psi-mi:“MI:0915”(physical association)	0.560
SLC39A2	ARL13B	psi-mi:“MI:0915”(physical association)	0.560
SLC39A2	GPR42	psi-mi:“MI:0915”(physical association)	0.560
SLC39A2	LY6G6C	psi-mi:“MI:0915”(physical association)	0.560
SLC39A2	GJA8	psi-mi:“MI:0915”(physical association)	0.560
SLC39A2	CNR2	psi-mi:“MI:0915”(physical association)	0.560
SLC39A2	TRHR	psi-mi:“MI:0915”(physical association)	0.560
SLC39A9	SLC39A2	psi-mi:“MI:0915”(physical association)	0.560
SLC39A2	UBE2J1	psi-mi:“MI:0915”(physical association)	0.560
SLC30A8	SLC39A2	psi-mi:“MI:0915”(physical association)	0.560
TMEM60	SLC39A2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (95): SLC39A2 (Two-hybrid), SLC39A2 (Two-hybrid), SLC39A2 (Two-hybrid), SLC39A2 (Two-hybrid), SLC39A2 (Two-hybrid), SLC39A2 (Two-hybrid), SLC39A2 (Two-hybrid), SLC39A2 (Two-hybrid), SLC39A2 (Two-hybrid), SLC39A2 (Two-hybrid), SLC39A2 (Two-hybrid), SLC39A2 (Two-hybrid), SLC39A2 (Two-hybrid), SLC39A2 (Two-hybrid), SLC39A2 (Two-hybrid)

ESM2 similar proteins: A0A0G2K1Q8, A0A0G2KQY6, A0A6I8PMZ8, A0JPN2, A4IGY6, A5D7L5, B2RXE2, E9PU17, E9PX95, E9PXX9, G3X943, O00337, O43868, O88627, O94402, P02730, P04919, P0DX17, P23562, P55205, P97441, Q08E40, Q0DWA9, Q0VCH8, Q14940, Q15043, Q4VAE3, Q504Y0, Q5FVQ0, Q5FWH7, Q5RAB7, Q5Z413, Q62674, Q62773, Q6L8F3, Q6PI78, Q6TL19, Q75N73, Q78IQ7, Q8HYW2

Diamond homologs: A1AFW5, A1KRK6, A4SE48, A4WEI1, A7ZRS2, A8A4J6, A8ZVV7, A9MPX1, A9N5W7, B1HYT6, B1ISB7, B1LF36, B1XG45, B2FM90, B2UL32, B3ECE6, B3QP89, B4SPV6, B4T660, B4TI40, B4TVS2, B5BG02, B5F683, B5FV58, B5QZ27, B5REE9, B5YR85, B6I411, B7LGI2, B7LQB7, B7LZI9, B7MAB7, B7N0I9, B7ND33, B7NJQ3, B7UIV3, C0PYW1, C3PFG5, C4ZQV8, P0A8H3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

288 predictions. Top by Δscore:

Variant	Effect	Δscore
14:21000115:GAACA:G	acceptor_gain	1.0000
14:21000167:G:GG	donor_gain	1.0000
14:21000110:TCTTA:T	acceptor_loss	0.9900
14:21000111:CTTA:C	acceptor_loss	0.9900
14:21000112:TTAG:T	acceptor_loss	0.9900
14:21000113:TAG:T	acceptor_loss	0.9900
14:21000114:A:AG	acceptor_gain	0.9900
14:21000114:A:AT	acceptor_loss	0.9900
14:21000115:G:GA	acceptor_gain	0.9900
14:21000115:GA:G	acceptor_gain	0.9900
14:21000115:GAAC:G	acceptor_gain	0.9900
14:21000162:CTCAT:C	donor_gain	0.9900
14:21000164:CAT:C	donor_gain	0.9900
14:21000165:AT:A	donor_gain	0.9900
14:21000166:TG:T	donor_loss	0.9900
14:21000167:G:GA	donor_loss	0.9900
14:21000168:TA:T	donor_loss	0.9900
14:21000169:AA:A	donor_loss	0.9900
14:21000944:TAG:T	acceptor_loss	0.9900
14:21000945:A:AG	acceptor_gain	0.9900
14:21000945:AGAT:A	acceptor_gain	0.9900
14:21000946:G:GG	acceptor_gain	0.9900
14:21000946:GATG:G	acceptor_gain	0.9900
14:20999376:A:G	donor_gain	0.9800
14:20999463:G:GT	donor_gain	0.9800
14:20999559:GAG:G	donor_gain	0.9800
14:21000163:TCAT:T	donor_gain	0.9800
14:20999371:C:G	donor_gain	0.9700
14:20999557:CAGAG:C	donor_loss	0.9700
14:20999558:AGAGG:A	donor_loss	0.9700

AlphaMissense

1951 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:21001544:T:C	F299L	0.967
14:21001546:T:A	F299L	0.967
14:21001546:T:G	F299L	0.967
14:21001454:T:C	F269L	0.965
14:21001456:C:A	F269L	0.965
14:21001456:C:G	F269L	0.965
14:21001449:G:A	G267D	0.964
14:20999787:G:A	G54D	0.960
14:21001187:G:A	G180R	0.958
14:21001187:G:C	G180R	0.958
14:21001436:G:C	G263R	0.956
14:20999792:T:C	F56L	0.952
14:20999794:C:A	F56L	0.952
14:20999794:C:G	F56L	0.952
14:21000983:G:C	G112R	0.952
14:21001235:T:C	C196R	0.952
14:21001542:G:A	G298D	0.952
14:20999798:G:A	G58R	0.949
14:20999798:G:C	G58R	0.949
14:21001445:G:C	A266P	0.947
14:21001541:G:C	G298R	0.944
14:20999786:G:C	G54R	0.941
14:21001449:G:T	G267V	0.940
14:21001448:G:C	G267R	0.938
14:21000984:G:A	G112D	0.937
14:21001455:T:C	F269S	0.937
14:20999799:G:A	G58E	0.936
14:20999477:T:C	C11R	0.934
14:21000986:T:C	F113L	0.934
14:21000988:C:A	F113L	0.934

dbSNP variants (sampled 300 via entrez): RS1000347973 (14:21000695 C>T), RS1000705784 (14:20998345 A>C,T), RS1000824733 (14:21000462 TTTG>T,TTTGTTG), RS1001666340 (14:20999589 T>C), RS1002669331 (14:21000808 C>T), RS1002826557 (14:21000530 G>A), RS1003673082 (14:21002280 G>A), RS1003724684 (14:20997572 T>C), RS1003829824 (14:21001925 A>T), RS1004214960 (14:20997724 T>C), RS1004735556 (14:20997508 G>A), RS1005201816 (14:20998132 G>A), RS1006173366 (14:21000480 C>T), RS1006289180 (14:21000155 G>T), RS1006705018 (14:20998512 C>A)

Disease associations

OMIM: gene MIM:612166 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC39 family of metal ion transporters

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression, increases expression	2
Arsenic	increases response to substance, decreases expression, increases abundance	2
sodium arsenate	decreases expression, increases abundance	1
ethyl-p-hydroxybenzoate	increases expression	1
sulforaphane	increases activity, increases reaction	1
zinc chloride	increases expression, affects cotreatment, increases abundance, increases activity, increases reaction	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Calcitriol	decreases expression	1
Carbamazepine	affects expression	1
Cytarabine	decreases expression	1
Glutathione	affects cotreatment, increases abundance	1
Silicon Dioxide	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Triclosan	increases expression	1
Valproic Acid	increases methylation	1
Vitamin E	increases expression	1
Zinc	increases transport	1
Aflatoxin B1	increases methylation	1
Asbestos, Crocidolite	increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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