MTF1

Chr 1

metal regulatory transcription factor 1

Also known as: MTF-1, ZRF

NCBI Gene: 4520ENSG00000188786UniProt: Q01538

This gene encodes a transcription factor that induces expression of metallothioneins and other genes involved in metal homeostasis in response to heavy metals such as cadmium, zinc, copper, and silver. The protein is a nucleocytoplasmic shuttling protein that accumulates in the nucleus upon heavy metal exposure and binds to promoters containing a metal-responsive element (MRE). [provided by RefSeq, Jul 2008]

80
ClinVar variants
5
Pathogenic / LP
0.97
pLI score· haploinsufficient
0
Active trials
Clinical Summary— MTF1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
5 Pathogenic / Likely Pathogenic· 64 VUS of 80 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.32LOEUF
pLI 0.969
Z-score 4.50
OE 0.15 (0.08–0.32)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.54Z-score
OE missense 0.65 (0.59–0.72)
272 obs / 418.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.15 (0.08–0.32)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.65 (0.59–0.72)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 5 / 32.8Missense obs/exp: 272 / 418.2Syn Z: 0.48

ClinVar Variant Classifications

80 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic1
VUS64
Likely Benign8
Benign3
4
Pathogenic
1
Likely Pathogenic
64
VUS
8
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
4
0
4
Likely Pathogenic
0
0
1
0
1
VUS
0
60
4
0
64
Likely Benign
0
3
1
4
8
Benign
0
2
0
1
3
Total06510580

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

MTF1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

MTF1-related intellectual disability

limited
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Identification of hub cuproptosis related genes and immune cell infiltration characteristics in periodontitis.
Liu S et al.·Front Immunol
2023
Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis.
Tsuchiya H et al.·Ann Rheum Dis
2021
Cuproptosis-Related Genes MTF1 and LIPT1 as Novel Prognostic Biomarker in Acute Myeloid Leukemia.
Li Y et al.·Biochem Genet
2024
The TRPM7 chanzyme in smooth muscle cells drives abdominal aortic aneurysm in mice.
Wang X et al.·Nat Cardiovasc Res
2025
Biological characterization and clinical significance of cuproptosis-related genes in lung adenocarcinoma.
Li M et al.·BMC Pulm Med
2025
Point-of-Care Testing of the MTF1 Osteoarthritis Biomarker Using Phenolphthalein-Soaked Swabs.
Park SY et al.·Biosensors (Basel)
2023
A multi-omics prognostic model of cuproptosis affects the prognosis of stomach adenocarcinoma.
Wu Y et al.·Clin Epigenetics
2025Functional
MTF1 genetic variants are associated with lung cancer risk in the Chinese Han population.
Cheng Y et al.·BMC Cancer
2024
Osteoarthritis year in review 2015: biology.
Malfait AM·Osteoarthritis Cartilage
2016Review
The Hippo pathway promotes platinum-based chemotherapy by inhibiting MTF1-dependent heavy metal response.
Chen H et al.·BMC Cancer
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Zinc-MTF1-metallothionein axis plays critical roles in the defense against ferroptosis in human cells.
Wagatsuma T et al.·Free Radic Biol Med
2026
MTF1 attenuates ferroptosis and cuproptosis synergistic potentiation in gastric cancer.
Luan M et al.·Cell Death Differ
2025
A New Toolbox to Label Zinc-MTF1 Responsive Neuronal Populations Unravels Cellular Congruence between MTF1 Responses and T-type Calcium Channelopathies in an Experimental Model of Epilepsy.
Meconi A et al.·Mol Neurobiol
2025🔓 Open AccessFunctional
Zinc Transporters and MTF1-Notch1-P21 Signalling Axis in TPEN-Induced Cell Death in Human Skeletal Muscle (Rhabdomyosarcoma) Cells.
Alluri KK et al.·Cureus
2025🔓 Open Access
Mechanistic role of metal-responsive transcription factor-1 (MTF1) in cadmium-induced prostate carcinogenesis.
Chandrasekaran B et al.·Int J Biol Sci
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools