MT4

Summary

MT4 (metallothionein 4, HGNC:18705) is a protein-coding gene on chromosome 16q13, encoding Metallothionein-4 (P47944). Seems to bind zinc and copper.

Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including cellular response to zinc ion; detoxification of copper ion; and intracellular zinc ion homeostasis. Predicted to act upstream of or within intracellular monoatomic cation homeostasis. Predicted to be active in cytoplasm and nucleus.

Source: NCBI Gene 84560 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 14 total
• MANE Select transcript: NM_032935

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18705
Approved symbol	MT4
Name	metallothionein 4
Location	16q13
Locus type	gene with protein product
Status	Approved
Aliases	MTIV
Ensembl gene	ENSG00000102891
Ensembl biotype	protein_coding
OMIM	606206
Entrez	84560

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000219162

RefSeq mRNA: 1 — MANE Select: NM_032935 NM_032935

CCDS: CCDS42165

Canonical transcript exons

ENST00000219162 — 3 exons

Exon	Start	End
ENSE00000684649	56568841	56568957
ENSE00001303400	56565073	56565159
ENSE00001327376	56567751	56567816

Expression profiles

Bgee: expression breadth ubiquitous, 108 present calls, max score 89.95.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0579 / max 77.8971, expressed in 7 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154227	0.0579	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.95	gold quality
skin of leg	UBERON:0001511	88.20	gold quality
zone of skin	UBERON:0000014	87.19	gold quality
skin of abdomen	UBERON:0001416	86.96	gold quality
epithelium of bronchus	UBERON:0002031	75.43	silver quality
dorsal plus ventral thalamus	UBERON:0001897	72.99	silver quality
trachea	UBERON:0003126	72.96	silver quality
lower esophagus mucosa	UBERON:0035834	70.69	gold quality
dorsal root ganglion	UBERON:0000044	69.75	silver quality
metanephric glomerulus	UBERON:0004736	67.59	gold quality
frontal pole	UBERON:0002795	65.81	silver quality
thymus	UBERON:0002370	65.68	silver quality
layer of synovial tissue	UBERON:0007616	65.56	gold quality
endometrium epithelium	UBERON:0004811	65.28	gold quality
esophagus mucosa	UBERON:0002469	62.44	gold quality
middle frontal gyrus	UBERON:0002702	61.97	silver quality
vagina	UBERON:0000996	60.62	gold quality
Brodmann (1909) area 10	UBERON:0013541	51.90	gold quality
granulocyte	CL:0000094	50.58	silver quality
ectocervix	UBERON:0012249	49.98	gold quality
esophagus	UBERON:0001043	46.18	gold quality
right lung	UBERON:0002167	41.44	gold quality
uterine cervix	UBERON:0000002	39.83	gold quality
right lobe of liver	UBERON:0001114	39.01	gold quality
skeletal muscle tissue	UBERON:0001134	37.22	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
caudate nucleus	UBERON:0001873	37.01	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.69

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• The association of metallothionein-4 gene polymorphism and renal function in long-term lead-exposed workers (PMID:19921116)
• MT4 expression is significantly downregulated in human masticatory mucosa during wound healing (PMID:28005267)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mt2	ENSDARG00000041623
mus_musculus	Mt4	ENSMUSG00000031757
rattus_norvegicus	Mt4	ENSRNOG00000019004

Paralogs (11): MT3 (ENSG00000087250), MT1G (ENSG00000125144), MT2A (ENSG00000125148), MT1B (ENSG00000169688), MT1E (ENSG00000169715), MT1X (ENSG00000187193), MT1F (ENSG00000198417), MT1H (ENSG00000205358), MT1A (ENSG00000205362), MT1M (ENSG00000205364), MT1HL1 (ENSG00000244020)

Protein

Protein identifiers

Metallothionein-4 — P47944 (reviewed: P47944)

Alternative names: Metallothionein-IV

All UniProt accessions (1): P47944

UniProt curated annotations — full annotation on UniProt →

Function. Seems to bind zinc and copper. Could play a special role in regulating zinc metabolism during the differentiation of stratified epithelia.

Similarity. Belongs to the metallothionein superfamily. Type 1 family.

RefSeq proteins (1): NP_116324* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000006	Metalthion_vert	Family
IPR017854	Metalthion_dom_sf	Homologous_superfamily
IPR023587	Metalthion_dom_sf_vert	Homologous_superfamily

Pfam: PF00131

UniProt features (31 total): binding site 27, sequence variant 3, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P47944-F1	68.63	0.00

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 (27): 6; 25; 27; 34; 35; 35; 37; 38; 38; 42; 45; 8 …

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5661231	Metallothioneins bind metals
R-HSA-5660526	Response to metal ions
R-HSA-8953897	Cellular responses to stimuli

MSigDB gene sets: 106 (showing top): MORF_RAGE, MORF_FLT1, GOBP_RESPONSE_TO_ZINC_ION, GOBP_CELLULAR_RESPONSE_TO_CADMIUM_ION, MORF_ATRX, GOBP_RESPONSE_TO_COPPER_ION, MORF_ESR1, EFC_Q6, GOBP_RESPONSE_TO_METAL_ION, MARTINEZ_RB1_TARGETS_DN, MORF_FANCG, GOBP_DETOXIFICATION, GOBP_CELLULAR_RESPONSE_TO_ZINC_ION, MORF_RAP1A, SANSOM_APC_TARGETS_UP

GO Biological Process (6): intracellular zinc ion homeostasis (GO:0006882), detoxification of copper ion (GO:0010273), cellular response to cadmium ion (GO:0071276), cellular response to copper ion (GO:0071280), cellular response to zinc ion (GO:0071294), intracellular monoatomic cation homeostasis (GO:0030003)

GO Molecular Function (1): metal ion binding (GO:0046872)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Response to metal ions	1
Cellular responses to stimuli	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular response to metal ion	3
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
detoxification of inorganic compound	1
stress response to copper ion	1
response to cadmium ion	1
response to copper ion	1
response to zinc ion	1
intracellular monoatomic ion homeostasis	1
monoatomic cation homeostasis	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

322 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MT4	H3BSS0	H3BSS0	820
MT4	KRT4	P19013	491
MT4	ATP7B	P35670	443
MT4	SLC30A1	Q9Y6M5	440
MT4	KRT13	P13646	424
MT4	KRT33A	O76009	414
MT4	MCIDAS	D6RGH6	406
MT4	MT3	P25713	403
MT4	ATOX1	O00244	377
MT4	MTF1	Q14872	374
MT4	CCS	O14618	353
MT4	APRT	P07741	353
MT4	LOX	P28300	353
MT4	FBN1	P35555	353
MT4	CP	P00450	352

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: O42152, O93593, P07216, P15786, P15787, P25127, P25128, P25713, P28184, P37359, P37360, P37361, P47944, P47945, P52720, P52723, P52724, P52725, P52727, P55944, P55945, P62678, P62679, P62680, P62681, P62682, P62711, P62712, P62713, P68494, P68495, P68497, P68498, P68501, P68502, P68503, P68504, P68505, Q05890, Q2MJS5

Diamond homologs: O18842, O19000, P02795, P02797, P02798, P02800, P02801, P02802, P02803, P02804, P04355, P04731, P04732, P04733, P07438, P09577, P09578, P0DM35, P11957, P13640, P14425, P17808, P18055, P47944, P47945, P49068, P55942, P55943, P58280, P67981, P67982, P67983, P68041, P68301, P68302, P68303, P68304, P79376, P79377, P79378

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	13
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

273 predictions. Top by Δscore:

Variant	Effect	Δscore
16:56565155:GTCTG:G	donor_gain	1.0000
16:56565158:TGGTG:T	donor_loss	1.0000
16:56565160:G:A	donor_loss	1.0000
16:56565160:G:GG	donor_gain	1.0000
16:56565161:T:A	donor_loss	1.0000
16:56567817:G:GG	donor_gain	1.0000
16:56565141:G:T	donor_gain	0.9900
16:56565156:TCTG:T	donor_gain	0.9900
16:56565157:CTG:C	donor_gain	0.9900
16:56565158:TG:T	donor_gain	0.9900
16:56565159:GG:G	donor_gain	0.9900
16:56567815:GA:G	donor_gain	0.9900
16:56565162:GAG:G	donor_loss	0.9800
16:56567812:GAAGA:G	donor_gain	0.9800
16:56565163:A:AG	donor_gain	0.9700
16:56565164:G:GG	donor_gain	0.9700
16:56567745:TTCTA:T	acceptor_loss	0.9700
16:56567746:TCTA:T	acceptor_loss	0.9700
16:56567747:CTA:C	acceptor_loss	0.9700
16:56567748:TA:T	acceptor_loss	0.9700
16:56567749:A:AC	acceptor_loss	0.9700
16:56567750:G:A	acceptor_loss	0.9700
16:56567814:AGA:A	donor_gain	0.9700
16:56567815:GAG:G	donor_gain	0.9700
16:56567721:C:G	acceptor_gain	0.9400
16:56567749:A:AG	acceptor_gain	0.9400
16:56567750:G:GG	acceptor_gain	0.9400
16:56567748:TAGG:T	acceptor_gain	0.9200
16:56567749:AGGA:A	acceptor_gain	0.9200
16:56567750:GGAG:G	acceptor_gain	0.9200

AlphaMissense

409 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000082211 (16:56567222 C>G), RS1000867433 (16:56566091 G>A), RS1001746466 (16:56568301 G>C,T), RS1003708720 (16:56564562 C>T), RS1004784786 (16:56567177 C>A,G,T), RS1005559681 (16:56567983 T>C), RS1006009511 (16:56568196 G>A), RS1007780631 (16:56563880 G>A), RS1008453143 (16:56566442 G>A,C), RS1010087014 (16:56567457 C>A,G), RS1010533967 (16:56567675 A>G,T), RS1010606868 (16:56564615 T>C), RS1011614248 (16:56563364 T>C), RS1011797975 (16:56568720 T>C,G), RS1012239798 (16:56565557 G>A,T)

Disease associations

OMIM: gene MIM:606206 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST009303_14	Abstraction and mental flexibility	4.000000e-06
GCST010241_3	Apolipoprotein A1 levels	1.000000e-19
GCST010242_284	HDL cholesterol levels	1.000000e-28

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009332	executive function measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	2
GSK-J4	increases expression	1
pinosylvin	increases expression	1
Lead	affects response to substance	1
Mercury	affects abundance	1
Silicon Dioxide	decreases expression	1
Silver Nitrate	increases expression	1
Thiram	increases expression	1
Zinc	increases expression	1
Ziram	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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