# NM_198159.2(MITF):c.(?_938)-102_*(78_?)del

https://sugi.bio/variant/mitf-c-938

## Summary

**MITF c.(?_938** is classified **Pathogenic** in MITF (ClinVar, Single submitter, 1 submitter; last evaluated 2015-08-04). Associated with Rare genetic deafness.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the MITF gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Rare genetic deafness.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MITF](https://sugi.bio/atlas/gene/MITF/) |
| Coding change (HGVS c.) | c.(?_938 |
| MANE Select transcript | [NM_001354604](https://www.ncbi.nlm.nih.gov/nuccore/NM_001354604) (variant reported on NM_198159) |
| Variant type | Deletion |
| Location | chr3:None-None (GRCh38) |
| ClinVar | [VCV228361](https://www.ncbi.nlm.nih.gov/clinvar/variation/228361/) |

**All HGVS expressions:** `NC_000003.11:g.(?_70005504)_(70014477_?)del`, `NC_000003.12:g.(?_69956353)_(69965326_?)del`

## Gene constraint & dosage {#gene-context}

**MITF** population constraint: LOEUF 0.482, pLI 0.99203, missense-Z 1.0386; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Waardenburg syndrome type 2** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 62.25, 21% of residues very-high.

**12 experimental structure(s)** (PDB): [4C7N](https://www.rcsb.org/structure/4C7N), [7D8R](https://www.rcsb.org/structure/7D8R), [7D8S](https://www.rcsb.org/structure/7D8S), [7D8T](https://www.rcsb.org/structure/7D8T), [7EOD](https://www.rcsb.org/structure/7EOD), [8E1D](https://www.rcsb.org/structure/8E1D).

## What this gene does {#gene-function}

*Describes the biological roles of MITF (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** MITF's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding.


### Pathways affected {#pathways}

MITF participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [SUMOylation of transcription factors](https://reactome.org/content/detail/R-HSA-3232118) | curated |
| [Regulation of MITF-M dependent genes involved in invasion](https://reactome.org/content/detail/R-HSA-9854909) | other |
| [Regulation of MITF-M dependent genes involved in metabolism](https://reactome.org/content/detail/R-HSA-9854907) | other |
| [Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence](https://reactome.org/content/detail/R-HSA-9825895) | other |
| [Regulation of MITF-M-dependent genes involved in apoptosis](https://reactome.org/content/detail/R-HSA-9824594) | other |
| [Regulation of MITF-M-dependent genes involved in cell cycle and proliferation](https://reactome.org/content/detail/R-HSA-9825892) | other |
| [Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition](https://reactome.org/content/detail/R-HSA-9926550) | other |
| [Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy](https://reactome.org/content/detail/R-HSA-9857377) | other |
| [Regulation of MITF-M-dependent genes involved in pigmentation](https://reactome.org/content/detail/R-HSA-9824585) | other |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, RNA polymerase II-specific, E-box binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of DNA-templated transcription, positive regulation of gene expression, negative regulation of cell migration, positive regulation of DNA-templated transcription, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2015-08-04.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2015-08-04 |

## Associated conditions {#conditions}

[Rare genetic deafness](https://sugi.bio/atlas/disease/rare-genetic-deafness/).

**Reported phenotype names (ClinVar):** Rare genetic deafness.

## Similar variants {#similar}

Related MITF variant pages (same residue, condition, or type): [MITF p.Ser235Ter](/variant/mitf-p-ser235ter), [MITF p.Trp348Ter](/variant/mitf-p-trp348ter), [MITF p.Asp225fs](/variant/mitf-p-asp225fs), [MITF p.Pro272fs](/variant/mitf-p-pro272fs), [MITF c.660_666+6del](/variant/mitf-c-660-666-plus-6del), [MITF c.880+1del](/variant/mitf-c-880-plus-1del), [MITF c.953_955+3del](/variant/mitf-c-953-955-plus-3del), [MITF p.Ala305fs](/variant/mitf-p-ala305fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 228361). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*