MITF

Chr 3ARAD

melanocyte inducing transcription factor

Also known as: CMM8, COMMAD, MI, MITF-A, WS2, WS2A, bHLHe32

NCBI Gene: 4286ENSG00000187098UniProt: O75030

The protein encoded by this gene is a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. The encoded protein regulates melanocyte development and is responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2 and Tietz syndrome. [provided by RefSeq, Aug 2017]

Primary Disease Associations & Inheritance

{Melanoma, cutaneous malignant, susceptibility to, 8}MIM #614456
COMMAD syndromeMIM #617306
AR
Tietz albinism-deafness syndromeMIM #103500
AD
Waardenburg syndrome, type 2AMIM #193510
AD
UniProtColoboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness
494
ClinVar variants
25
Pathogenic / LP
0.98
pLI score· haploinsufficient
0
Active trials
Clinical Summary— MITF
🧬
Gene-Disease Validity (ClinGen)
Waardenburg syndrome type 2 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
25 Pathogenic / Likely Pathogenic· 317 VUS of 494 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.
0.31LOEUF
pLI 0.981
Z-score 4.38
OE 0.13 (0.07–0.31)
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.
1.47Z-score
OE missense 0.77 (0.69–0.85)
243 obs / 316.5 exp
Tolerant

Mild missense constraint

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.0.13 (0.07–0.31)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.77 (0.69–0.85)
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.0.96
0≤1.21.6
LoF obs/exp: 4 / 29.8Missense obs/exp: 243 / 316.5Syn Z: 0.36

ClinVar Variant Classifications

494 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic5
VUS317
Likely Benign152
20
Pathogenic
5
Likely Pathogenic
317
VUS
152
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
1
6
0
20
Likely Pathogenic
3
2
0
0
5
VUS
5
295
14
3
317
Likely Benign
0
1
43
108
152
Benign
0
0
0
0
0
Total2129963111494

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

View in ClinVar →

Protein Context — Lollipop Plot

MITF · protein map & ClinVar variants

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

Gene2Phenotype Curations

MITF-related Waardenburg syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersEyeSkinEar
G2P ↗

MITF-related melanoma, cutaneous malignant

limited
ADGain Of FunctionAbsent Gene Product, Altered Gene Product Structure
Cancer
G2P ↗

MITF-related Tietz syndrome

definitive
ADUndeterminedUncertain
Dev. DisordersEyeSkin
G2P ↗

MITF-related coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD syndrome)

strong
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEyeSkin
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Melanoma, cutaneous malignant, susceptibility to, 8}

MIM #614456

Molecular basis of disorder known

COMMAD syndrome

MIM #617306

Molecular basis of disorder known

Autosomal recessive

Tietz albinism-deafness syndrome

MIM #103500

Molecular basis of disorder known

Autosomal dominant

Waardenburg syndrome, type 2A

MIM #193510

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — MITF
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Germline mutations predisposing to melanoma.
Toussi A et al.·J Cutan Pathol
2020Review
Renal Cell Carcinoma of Variant Histology: Biology and Therapies.
Msaouel P et al.·Hematol Oncol Clin North Am
2023Review
Review and update of mutations causing Waardenburg syndrome.
Pingault V et al.·Hum Mutat
2010Review
Association of Genetic Diagnoses for Childhood-Onset Hearing Loss With Cochlear Implant Outcomes.
Carlson RJ et al.·JAMA Otolaryngol Head Neck Surg
2023
Human Hair Graying Revisited: Principles, Misconceptions, and Key Research Frontiers.
Paus R et al.·J Invest Dermatol
2024Review
Immunohistochemistry in melanocytic lesions: Updates with a practical review for pathologists.
Saleem A et al.·Semin Diagn Pathol
2022Review
Molecular diagnose of a large hearing loss population from China by targeted genome sequencing.
Wu J et al.·J Hum Genet
2022
Novel Anti-Melanogenesis Properties of Polydeoxyribonucleotide, a Popular Wound Healing Booster.
Noh TK et al.·Int J Mol Sci
2016
O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer.
Zhang Y et al.·Nat Commun
2024
HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis.
Emmons MF et al.·Nat Commun
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Cyclin D1 demonstrates superior sensitivity and consistent nuclear expression compared with MiTF in cellular neurothekeoma.
Sanford JA et al.·Virchows Arch
2026
Utility of Next-Generation Sequencing in Renal Neoplasia, Including Tumors With Clear Cytoplasm and Rare Phenotypes (ELOC/MITF Alterations and Mismatch Repair Deficiency).
McCarthy M et al.·Mayo Clin Proc
2026
Central Role of MITF/TFE Family Transcription Factors in Diverse Clear and Granular Cell Tumors.
Davis D et al.·Am J Pathol
2026
miR-182-5p affects melanin formation in Crassostrea gigas by regulating the MITF gene.
Li Y et al.·Comp Biochem Physiol Part D Genomics Proteomics
2026
6'-O-Caffeoylarbutin: A Stable and Long-Lasting Skin-Lightening Agent Targeting Melanogenesis Through MITF Pathway Modulation.
Chen Z et al.·Chem Biodivers
2026
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