SLC39A7

Summary

SLC39A7 (solute carrier family 39 member 7, HGNC:4927) is a protein-coding gene on chromosome 6p21.32, encoding Zinc transporter SLC39A7 (Q92504). Transports Zn(2+) from the endoplasmic reticulum (ER)/Golgi apparatus to the cytosol, playing an essential role in the regulation of cytosolic zinc levels. It is a common-essential gene (DepMap: required in 95.7% of cancer cell lines).

The protein encoded by this gene transports zinc from the Golgi and endoplasmic reticulum to the cytoplasm. This transport may be important for activation of tyrosine kinases, some of which could be involved in cancer progression. Therefore, modulation of the encoded protein could be useful as a therapeutic agent against cancer. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 7922 — RefSeq curated summary.

At a glance

• Gene–disease (curated): agammaglobulinemia 9, autosomal recessive (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 260 total — 3 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 12
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 95.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_006979

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4927
Approved symbol	SLC39A7
Name	solute carrier family 39 member 7
Location	6p21.32
Locus type	gene with protein product
Status	Approved
Aliases	H2-KE4, D6S2244E, KE4, RING5, ZIP7
Ensembl gene	ENSG00000112473
Ensembl biotype	protein_coding
OMIM	601416
Entrez	7922

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 11 retained_intron, 7 protein_coding, 1 nonsense_mediated_decay

ENST00000374675, ENST00000374677, ENST00000444757, ENST00000698677, ENST00000698678, ENST00000698679, ENST00000698680, ENST00000698681, ENST00000698682, ENST00000698683, ENST00000698684, ENST00000698685, ENST00000698686, ENST00000698687, ENST00000698688, ENST00000698689, ENST00000698690, ENST00000899925, ENST00000947913

RefSeq mRNA: 3 — MANE Select: NM_006979 NM_001077516, NM_001288777, NM_006979

CCDS: CCDS43453

Canonical transcript exons

ENST00000374677 — 7 exons

Exon	Start	End
ENSE00001935408	33200867	33201656
ENSE00003321302	33201745	33201913
ENSE00003349240	33202072	33202125
ENSE00003843106	33203541	33204437
ENSE00003974403	33202910	33203106
ENSE00003974411	33202560	33202700
ENSE00003974421	33202263	33202427

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 98.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 57.8939 / max 265.9175, expressed in 1827 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67248	55.9219	1826
67246	0.9951	551
67247	0.7154	446
67245	0.2614	81

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	98.85	gold quality
islet of Langerhans	UBERON:0000006	98.63	gold quality
body of pancreas	UBERON:0001150	98.04	gold quality
pancreas	UBERON:0001264	98.00	gold quality
placenta	UBERON:0001987	97.91	gold quality
mucosa of transverse colon	UBERON:0004991	97.86	gold quality
pituitary gland	UBERON:0000007	97.84	gold quality
adenohypophysis	UBERON:0002196	97.75	gold quality
rectum	UBERON:0001052	97.71	gold quality
smooth muscle tissue	UBERON:0001135	97.44	gold quality
left adrenal gland	UBERON:0001234	97.34	gold quality
right lobe of thyroid gland	UBERON:0001119	97.24	gold quality
left lobe of thyroid gland	UBERON:0001120	97.22	gold quality
left adrenal gland cortex	UBERON:0035825	97.16	gold quality
body of stomach	UBERON:0001161	97.15	gold quality
right adrenal gland	UBERON:0001233	97.14	gold quality
right adrenal gland cortex	UBERON:0035827	97.03	gold quality
saliva-secreting gland	UBERON:0001044	97.00	gold quality
thyroid gland	UBERON:0002046	96.96	gold quality
apex of heart	UBERON:0002098	96.93	gold quality
minor salivary gland	UBERON:0001830	96.88	gold quality
prostate gland	UBERON:0002367	96.82	gold quality
metanephros cortex	UBERON:0010533	96.82	gold quality
adrenal gland	UBERON:0002369	96.75	gold quality
transverse colon	UBERON:0001157	96.72	gold quality
duodenum	UBERON:0002114	96.72	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.61	gold quality
upper lobe of left lung	UBERON:0008952	96.60	gold quality
right atrium auricular region	UBERON:0006631	96.50	gold quality
gall bladder	UBERON:0002110	96.42	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.66
E-CURD-10	no	11.76

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

37 targeting SLC39A7, 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-3667-3P	99.99	67.17	1636
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-3689A-5P	98.35	70.12	1049
HSA-MIR-3689B-5P	98.35	70.12	1049
HSA-MIR-3689E	98.35	70.12	1049
HSA-MIR-3689F	98.35	70.08	1052
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-4436A	98.05	64.83	1140
HSA-MIR-12127	97.93	66.67	793
HSA-MIR-3661	97.83	67.30	705
HSA-MIR-3614-3P	97.81	67.15	582
HSA-MIR-30C-1-3P	97.80	66.36	1499
HSA-MIR-30C-2-3P	97.80	66.45	1499
HSA-MIR-6788-5P	97.80	66.41	1532
HSA-MIR-1972	97.67	67.38	1172

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 95.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 19)

• Structure-function analysis of HKE4, a zinc transporter. (PMID:14525538)
• ZIP7 is a functional zinc transporter that acts by transporting zinc from the Golgi apparatus to the cytoplasm of the cell (PMID:15705588)
• ZIP7 is a critical component in the redistribution of zinc from intracellular stores to the cytoplasm and, as such, is essential for the zinc-induced inhibition of phosphatases, which leads to activation of growth factor receptors in MCF-7 cells (PMID:18583420)
• ZIP7 releases zinc from the endoplasmic reticulum and might be required for tyrosine kinase activation. (PMID:19246244)
• The connection with proliferation and migration, as well as the activation of ZIP7 by CK2, a kinase that is antiapoptotic and promotes cell division (PMID:22317921)
• 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)
• The recurrent seizures plus normal diet group showed worse performances in neurological reflex tests and reduced latencies to myoclonic seizures induced by penicillin compared with the control, which was concomitant with altered expressions of ZnT-7, MT-1, MT-2, and ZIP7. (PMID:27147436)
• These data reveal the role of ZIP7-mediated zinc release from intracellular stores in driving major pathways, such as MAPK, mTOR and PI3K-AKT, involved in providing cell survival and proliferation and often over activated in cancer. (PMID:28205653)
• Results suggest that solute carrier family 39 (zinc transporter), member 7 (SLC39A7) plays a crucial role in the proliferation and survival of colorectal cancer cells, which associates with colorectal tumorigenesis. (PMID:28981607)
• Genetic ablation of ZIP7 results in decreased levels of cytosolic zinc, increased endoplasmic reticulum zinc levels, and induction of endoplasmic reticulum stress. (PMID:29980658)
• The loss of SLC39A7 resulted in augmented ER stress and impaired receptor trafficking, thereby globally affecting downstream signaling. (PMID:30237509)
• Data indicate a form of autosomal recessive agammaglobulinemia caused by hypomorphic mutations in the endoplasmic reticulum-to-cytoplasmic zinc transporter solute carrier family 39 (zinc transporter), member 7 (ZIP7). (PMID:30718914)
• ZIP7 may be essential for the control of endoplasmic reticulum (ER) localized zinc and mechanisms that disrupt this process may lead to ER-stress and contribute to insulin resistance (IR). (PMID:30781350)
• Using the new pS(275)S(276)ZIP7 antibody which only recognises activated ZIP7 (pZIP7), this study demonstrated that the hyperactivation of ZIP7 is prevalent in tamoxifen-resistant breast cancer cells. (PMID:31483418)
• SLC39A7, regulated by miR-139-5p, induces cell proliferation, migration and inhibits apoptosis in gastric cancer via Akt/mTOR signaling pathway. (PMID:32109290)
• Zinc transporter SLC39A7 relieves zinc deficiency to suppress alternative macrophage activation and impairment of phagocytosis. (PMID:32645059)
• Evaluation of the prognostic values of solute carrier (SLC) family 39 genes for patients with lung adenocarcinoma. (PMID:33535184)
• Zinc transporter ZIP7 is a novel determinant of ferroptosis. (PMID:33608508)
• SLC39A7 upregulation links to skin fibrosis in systemic sclerosis via TGF-beta/SMAD pathway. (PMID:38217370)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc39a7	ENSDARG00000104451
mus_musculus	Slc39a7	ENSMUSG00000024327
rattus_norvegicus	Slc39a7	ENSRNOG00000000465
drosophila_melanogaster	Catsup	FBGN0002022
caenorhabditis_elegans		WBGENE00006494
caenorhabditis_elegans		WBGENE00044067

Paralogs (1): SLC39A13 (ENSG00000165915)

Protein

Protein identifiers

Zinc transporter SLC39A7 — Q92504 (reviewed: Q92504)

Alternative names: Histidine-rich membrane protein Ke4, Really interesting new gene 5 protein, Solute carrier family 39 member 7, Zrt-, Irt-like protein 7

All UniProt accessions (6): Q92504, A0A024RCX7, A0A8V8TM21, A0A8V8TM53, A0A8V8TNV9, A2AAT0

UniProt curated annotations — full annotation on UniProt →

Function. Transports Zn(2+) from the endoplasmic reticulum (ER)/Golgi apparatus to the cytosol, playing an essential role in the regulation of cytosolic zinc levels. Acts as a gatekeeper of zinc release from intracellular stores, requiring post-translational activation by phosphorylation, resulting in activation of multiple downstream pathways leading to cell growth and proliferation. Has an essential role in B cell development and is required for proper B cell receptor signaling. Plays an important role in maintaining intestinal epithelial homeostasis and skin dermis development by regulating ER function. Controls cell signaling pathways involved in glucose metabolism in skeletal muscle. Has a protective role against ER stress in different biological contexts. Mediates Zn(2+)-induced ferroptosis.

Subunit / interactions. Homodimer.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus. cis-Golgi network membrane.

Tissue specificity. Widely expressed.

Post-translational modifications. Rapidly phosphorylated by CK2 following Zn(2+) treatment. This phosphorylation is required for efficient cytosolic Zn(2+) release. Methylation at some His residue by METTL9 leads to reduced zinc-binding.

Disease relevance. Agammaglobulinemia 9, autosomal recessive (AGM9) [MIM:619693] A form of agammaglobulinemia, a primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Phosphorylation activates zinc transport activity.

Induction. Down-regulated by Zn(+2).

Similarity. Belongs to the ZIP transporter (TC 2.A.5) family. KE4/Catsup subfamily.

RefSeq proteins (3): NP_001070984, NP_001275706, NP_008910* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003689	ZIP	Family

Pfam: PF02535

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (33 total): sequence variant 10, transmembrane region 6, compositionally biased region 4, mutagenesis site 4, modified residue 3, sequence conflict 3, region of interest 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8GZE	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92504-F1	65.92	0.20

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 (3): 66, 275, 276

Mutagenesis-validated functional residues (4):

Position	Phenotype
275	loss of phosphorylation in response to zn(2+) treatment and of cytosolic zn(2+) release; when associated with a-276.
276	loss of phosphorylation in response to zn(2+) treatment and of cytosolic zn(2+) release; when associated with a-275.
293	loss of phosphorylation in response to zn(2+) treatment and of cytosolic zn(2+) release.
294	loss of phosphorylation in response to zn(2+) treatment and of cytosolic zn(2+) release.

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: 196 (showing top): TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_B_CELL_ACTIVATION, GOBP_TRANSITION_METAL_ION_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, USF_C, YY1_Q6, GGCNKCCATNK_UNKNOWN, GOBP_MONOATOMIC_CATION_TRANSPORT, NFKB_Q6, GOBP_EPIDERMIS_DEVELOPMENT, IRF_Q6, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, ELK1_01, GOBP_MONOATOMIC_ION_HOMEOSTASIS

GO Biological Process (9): intracellular zinc ion homeostasis (GO:0006882), B cell differentiation (GO:0030183), zinc ion transmembrane transport (GO:0071577), skin epidermis development (GO:0098773), regulation of ferroptosis (GO:0110075), monoatomic ion transport (GO:0006811), zinc ion transport (GO:0006829), metal ion transport (GO:0030001), transmembrane transport (GO:0055085)

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

GO Cellular Component (5): nucleoplasm (GO:0005654), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), 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
transport	2
cellular anatomical structure	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
lymphocyte differentiation	1
B cell activation	1
zinc ion transport	1
monoatomic cation transmembrane transport	1
epidermis development	1
skin development	1
epithelium development	1
regulation of programmed cell death	1
ferroptosis	1
transition metal ion transport	1
monoatomic cation transport	1
cellular process	1
transition metal ion transmembrane transporter activity	1
zinc ion transmembrane transport	1
binding	1
monoatomic cation transmembrane transporter activity	1
metal ion transport	1
nuclear lumen	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Protein interactions and networks

STRING

1128 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC39A7	PFDN6	O15212	920
SLC39A7	HSD17B8	Q92506	918
SLC39A7	RPS18	P25232	907
SLC39A7	SLC30A6	Q6NXT4	861
SLC39A7	KIFC1	Q9BW19	855
SLC39A7	SLC39A9	Q9NUM3	854
SLC39A7	SLC30A7	Q8NEW0	844
SLC39A7	SLC39A11	Q8N1S5	838
SLC39A7	SLC30A5	Q8TAD4	826
SLC39A7	SLC39A1	Q9NY26	821
SLC39A7	RGL2	O15211	811
SLC39A7	RXRB	P28702	797
SLC39A7	SLC30A9	Q6PML9	794
SLC39A7	SLC30A1	Q9Y6M5	782
SLC39A7	COL11A2	P13942	780

IntAct

158 interactions, top by confidence:

A	B	Type	Score
FAM20B	ASPHD2	psi-mi:“MI:0914”(association)	0.670
FAM174A	GAK	psi-mi:“MI:0914”(association)	0.640
SLC39A7	CSNK2A1	psi-mi:“MI:0915”(physical association)	0.590
CSNK2A1	SLC39A7	psi-mi:“MI:2364”(proximity)	0.590
CSNK2A1	SLC39A7	psi-mi:“MI:0915”(physical association)	0.590
SLC39A7	CSNK2A1	psi-mi:“MI:0403”(colocalization)	0.590
SLC39A7	GJA8	psi-mi:“MI:0915”(physical association)	0.560
SLC39A7	SHISAL1	psi-mi:“MI:0915”(physical association)	0.560
LCE2C	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
SLC39A7	KRTAP9-2	psi-mi:“MI:0915”(physical association)	0.560
SMCP	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
SPRY3	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
LCE1F	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
SLC34A2	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
SLC39A7	KCNF1	psi-mi:“MI:0915”(physical association)	0.560
LCE1A	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
KRTAP1-3	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
WFDC12	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
SLC39A7	CRCT1	psi-mi:“MI:0915”(physical association)	0.560
LCE1C	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
BIK	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
LCE5A	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
LCE4A	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
LCE2D	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
GJA8	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
UNC93A	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560
SLC39A7	TNFRSF10D	psi-mi:“MI:0915”(physical association)	0.560
AQP6	SLC39A7	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (393): SLC39A7 (Affinity Capture-MS), SLC39A7 (Affinity Capture-MS), SLC39A7 (Proximity Label-MS), SLC39A7 (Proximity Label-MS), SLC39A7 (Proximity Label-MS), SLC39A7 (Proximity Label-MS), SLC39A7 (Proximity Label-MS), SLC39A7 (Affinity Capture-MS), SLC39A7 (Affinity Capture-MS), SLC39A7 (Affinity Capture-MS), SLC39A7 (Affinity Capture-MS), SLC39A7 (Affinity Capture-MS), SLC39A7 (Affinity Capture-MS), SLC39A7 (Affinity Capture-MS), SLC39A7 (Affinity Capture-MS)

ESM2 similar proteins: A0JPN2, A2A6C4, E9PY61, F7E727, L5KLU7, P04920, P0DX17, P56183, P56722, Q13433, Q16849, Q1KZG0, Q29175, Q31125, Q3UVU3, Q49LS1, Q4R6K2, Q4V887, Q504Y0, Q5FWH7, Q5R9M9, Q5RD44, Q5RFD5, Q5TJF6, Q60673, Q60738, Q62720, Q62865, Q63259, Q6L8F3, Q6MGB4, Q6P5W5, Q6PB70, Q6PEH9, Q6ZMH5, Q76MJ5, Q78IQ7, Q7TSG2, Q80UU1, Q8C145

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.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 136 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
Formation of the cornified envelope	8	7.7×	3e-03
Keratinization	11	6.7×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
keratinization	7	15.3×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	3
Uncertain significance	126
Likely benign	108
Benign	6

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1333089	NM_006979.3(SLC39A7):c.1087G>A (p.Glu363Lys)	Pathogenic
1333090	NM_006979.3(SLC39A7):c.650T>C (p.Leu217Pro)	Pathogenic
1507871	NM_006979.3(SLC39A7):c.568C>G (p.Pro190Ala)	Pathogenic
1333091	NM_006979.3(SLC39A7):c.1114C>T (p.Gln372Ter)	Likely pathogenic
3065745	NM_006979.3(SLC39A7):c.868C>T (p.Arg290Ter)	Likely pathogenic
809917	NM_006979.3(SLC39A7):c.53G>A (p.Trp18Ter)	Likely pathogenic

SpliceAI

927 predictions. Top by Δscore:

Variant	Effect	Δscore
6:33200935:GCCG:G	donor_gain	1.0000
6:33200937:CGGT:C	donor_loss	1.0000
6:33200938:GGTGA:G	donor_loss	1.0000
6:33200939:G:GG	donor_gain	1.0000
6:33200939:G:T	donor_loss	1.0000
6:33201650:GGCT:G	donor_gain	1.0000
6:33201657:G:GG	donor_gain	1.0000
6:33202070:A:AG	acceptor_gain	1.0000
6:33202071:G:GG	acceptor_gain	1.0000
6:33202123:GTG:G	donor_gain	1.0000
6:33202131:G:GT	donor_gain	1.0000
6:33202326:T:TA	acceptor_gain	1.0000
6:33202327:G:A	acceptor_gain	1.0000
6:33202557:CAGAG:C	acceptor_gain	1.0000
6:33202558:A:AG	acceptor_gain	1.0000
6:33202558:A:C	acceptor_loss	1.0000
6:33202558:AGAGC:A	acceptor_gain	1.0000
6:33202559:G:GC	acceptor_gain	1.0000
6:33202559:GA:G	acceptor_gain	1.0000
6:33202559:GAGC:G	acceptor_gain	1.0000
6:33202559:GAGCG:G	acceptor_gain	1.0000
6:33202695:GCT:G	donor_gain	1.0000
6:33202700:GGTA:G	donor_loss	1.0000
6:33202701:G:C	donor_loss	1.0000
6:33202701:G:GG	donor_gain	1.0000
6:33202702:T:A	donor_loss	1.0000
6:33202897:T:TA	acceptor_gain	1.0000
6:33202902:T:A	acceptor_gain	1.0000
6:33202904:TACAA:T	acceptor_loss	1.0000
6:33202905:A:AG	acceptor_gain	1.0000

AlphaMissense

3035 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:33201896:T:C	L188P	0.999
6:33202316:T:C	F230L	0.999
6:33202318:T:A	F230L	0.999
6:33202318:T:G	F230L	0.999
6:33202329:A:T	E234V	0.999
6:33202959:C:A	N330K	0.999
6:33202959:C:G	N330K	0.999
6:33203066:A:C	D366A	0.999
6:33203066:A:G	D366G	0.999
6:33203066:A:T	D366V	0.999
6:33203067:C:A	D366E	0.999
6:33203067:C:G	D366E	0.999
6:33203072:C:A	A368D	0.999
6:33203677:G:A	G425D	0.999
6:33203682:T:C	F427L	0.999
6:33203684:T:A	F427L	0.999
6:33203684:T:G	F427L	0.999
6:33201853:A:C	S174R	0.998
6:33201855:T:A	S174R	0.998
6:33201855:T:G	S174R	0.998
6:33201860:C:A	A176D	0.998
6:33201866:G:A	G178D	0.998
6:33201872:T:C	L180P	0.998
6:33202304:G:A	G226R	0.998
6:33202304:G:C	G226R	0.998
6:33202305:G:A	G226E	0.998
6:33202935:T:A	N322K	0.998
6:33202935:T:G	N322K	0.998
6:33202937:T:C	L323P	0.998
6:33202968:T:A	D333E	0.998

dbSNP variants (sampled 300 via entrez): RS1000076425 (6:33204090 G>A,T), RS1000424042 (6:33204059 A>G), RS1001951266 (6:33201835 C>G), RS1002841616 (6:33200610 T>C), RS1002954205 (6:33200336 C>T), RS1004647081 (6:33203314 A>G), RS1005322811 (6:33201152 G>A,T), RS1005603478 (6:33201445 C>G), RS1006477418 (6:33200563 C>A,T), RS1006656113 (6:33200325 G>A), RS1007115600 (6:33204141 C>G), RS1007141585 (6:33200691 C>G,T), RS1008029242 (6:33199692 TAAA>T,TAA,TAAAA,TAAAAA), RS1008040895 (6:33199712 G>A,C), RS1008591978 (6:33204509 G>T)

Disease associations

OMIM: gene MIM:601416 | disease phenotypes: MIM:619693

GenCC curated gene-disease

Disease	Classification	Inheritance
agammaglobulinemia 9, autosomal recessive	Strong	Autosomal recessive
agammaglobulinemia	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
agammaglobulinemia	Moderate	AR

Mondo (2): agammaglobulinemia 9, autosomal recessive (MONDO:0030519), agammaglobulinemia (MONDO:0015977)

Orphanet (1): Agammaglobulinemia-skin involvement-failure to thrive syndrome (Orphanet:693627)

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000964	Eczematoid dermatitis
HP:0001051	Seborrheic dermatitis
HP:0001508	Failure to thrive
HP:0001873	Thrombocytopenia
HP:0002718	Recurrent bacterial infections
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0004432	Agammaglobulinemia
HP:0011463	Childhood onset
HP:0030252	Absent circulating B cells

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000361	Agammaglobulinemia	C15.378.147.142; C15.604.515.032; C20.673.088

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724589 (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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.87	Kd	13.64	nM	CHEMBL5653589
7.87	ED50	13.64	nM	CHEMBL5653589
6.89	IC50	130	nM	CHEMBL5723565

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149426: Binding affinity to human SLC39A7 incubated for 45 mins by Kinobead based pull down assay	kd	0.0136	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Zinc	increases transport, decreases expression, decreases reaction, affects binding, affects cotreatment (+3 more)	6
Benzo(a)pyrene	affects methylation, decreases expression	3
Cisplatin	affects cotreatment, affects expression, affects response to substance	2
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	increases expression	1
pyrithione	affects binding, affects cotreatment, decreases reaction, increases reaction	1
trichostatin A	affects expression	1
ochratoxin A	decreases expression	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
4,5,6,7-tetrabromobenzotriazole	affects binding, affects cotreatment, decreases reaction, increases reaction	1
2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole	affects binding, affects cotreatment, decreases reaction, increases reaction, increases phosphorylation	1
bisphenol B	increases expression	1
Grape Seed Proanthocyanidins	decreases expression	1
bisphenol AF	increases expression	1
Panobinostat	affects cotreatment, affects expression	1
Amphotericin B	decreases expression	1
Atrazine	increases expression	1
Cadmium	increases abundance, increases expression	1
Cannabidiol	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Selenium	increases expression	1
Dihydrotestosterone	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Ionomycin	affects binding, increases reaction	1
Cyclosporine	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 1 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652468	Binding	Binding affinity to human SLC39A7 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem
CHEMBL5723541	Functional	Affinity On-target Cellular interaction: (HES-LUC reporter gene assay, U2OS cells) EUB0002669a SLC39A7	Affinity On-target Cellular Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4NP	HCT116-SLC39A7-KO-c15	Cancer cell line	Male
CVCL_D4NQ	HCT116-SLC39A7-KO-c8	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00520494	PHASE4	COMPLETED	Efficacy and Safety of Vivaglobin® in Previously Untreated Patients With Primary Immunodeficiency
NCT05612607	PHASE4	UNKNOWN	Switched Memory B-cells as a Marker for Humoral Immune System Recovery in Patients With Secondary Antibody Deficiency Due to Hematological Malignancies
NCT07135427	PHASE4	RECRUITING	Genetic Variation in IgG in Alpha 1 Antitrypsin Deficiency
NCT00168012	PHASE3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IVIG-F10 in Patients With Primary Immunodeficiencies (PID)
NCT00168025	PHASE3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT00322556	PHASE3	COMPLETED	Safety and Efficacy of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT01581593	PHASE3	COMPLETED	Efficacy and Safety Study of Kedrion IVIG 10% to Treat Subjects With Primary Immunodeficiency (PID)
NCT03578341	PHASE3	UNKNOWN	Oral Colostrum and Its Effect on Immune System
NCT06954441	PHASE3	RECRUITING	V-IMMUNE: A Novel Immunoglobulin Therapy for Immunodeficiency
NCT00161993	PHASE2	COMPLETED	Safety, Pharmacokinetic and Efficacy Study of a 10% Triple Virally Reduced Intravenous Immune Globulin Solution in Patients With Primary Immunodeficiency (Hypo- or Agammaglobulinemia)
NCT05584631	PHASE1	RECRUITING	IVIG vs SCIG in CIDP
NCT00661401	Not specified	COMPLETED	Specific IgG Antibody in Patients With Primary Antibody Deficiencies Treated With Subcutaneous Immunoglobulin
NCT02972281	Not specified	COMPLETED	Systematic Search for Primary Immunodeficiency in Adults With Infections