# NM_001354604.2(MITF):c.856C>G (p.Pro286Ala)

https://sugi.bio/variant/mitf-p-pro286ala

## Summary

**MITF p.Pro286Ala (c.856C>G)** is classified **Uncertain significance** in MITF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-16). AlphaMissense: likely benign (0.1988); Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 4 linked conditions · AlphaMissense likely benign · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the MITF gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to hereditary neoplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MITF](https://sugi.bio/atlas/gene/MITF/) |
| Protein change (HGVS p.) | p.Pro286Ala |
| Coding change (HGVS c.) | c.856C>G |
| MANE Select transcript | [NM_001354604](https://www.ncbi.nlm.nih.gov/nuccore/NM_001354604) |
| Variant type | single nucleotide variant |
| Location | chr3:69949144-69949144 (GRCh38) |
| ClinVar | [VCV3753920](https://www.ncbi.nlm.nih.gov/clinvar/variation/3753920/) |

**All HGVS expressions:** `LRG_776:g.214663C>G`, `LRG_776t1:c.535C>G`, `NC_000003.11:g.69998295C>G`, `NC_000003.12:g.69949144C>G`, `NG_011631.1:g.214663C>G`, `NM_000248.4:c.535C>G`, `NM_001184967.2:c.700C>G`, `NM_001354604.2:c.856C>G`, `NM_001354605.2:c.853C>G`, `NM_001354606.2:c.853C>G`, `NM_001354607.2:c.805C>G`, `NM_001354608.2:c.700C>G`, `NM_006722.3:c.853C>G`, `NM_198158.3:c.535C>G`, `NM_198159.3:c.856C>G`, `NM_198177.3:c.808C>G`, `NM_198178.3:c.367C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1988)
- REVEL 0.092 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.33 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.677, GERP 2.15, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.6**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.96** across the covering region of the MANE Select transcript (69,937,858–69,951,846), spanning 13,988 bp. Chi-square p 0.51. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for MITF (1,158 scored positions, the nearest 14 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,634 in the highest group · 3/1,613,464 alleles overall — very rare (popmax 0.000254%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## 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}

Residue **286** lies in the 'transactivation' region.

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. p.Pro286Ala falls in the transactivation region.


### 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-16.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2025–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-18 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-02-16 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [Tietz syndrome](https://sugi.bio/atlas/disease/tietz-syndrome/), [Waardenburg syndrome type 2A](https://sugi.bio/atlas/disease/waardenburg-syndrome-type-2a/), [melanoma, cutaneous malignant, susceptibility to, 8](https://sugi.bio/atlas/disease/melanoma-cutaneous-malignant-susceptibility-to-8/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Melanoma, cutaneous malignant, susceptibility to, 8, Tietz syndrome, Waardenburg syndrome type 2A, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary neoplastic syndrome, MELANOMA AND RENAL CELL CARCINOMA, SUSCEPTIBILITY TO, Cutaneous malignant melanoma 8.

## Similar variants {#similar}

Related MITF variant pages (same residue, condition, or type): [MITF p.Pro286Ser](/variant/mitf-p-pro286ser), [MITF p.Pro286Thr](/variant/mitf-p-pro286thr), [MITF c.1031+1G>A](/variant/mitf-c-1031-plus-1g-a), [MITF c.1179+1G>A](/variant/mitf-c-1179-plus-1g-a), [MITF c.355-1062G>C](/variant/mitf-c-355-minus-1062g-c), [MITF c.880+1G>A](/variant/mitf-c-880-plus-1g-a), [MITF c.955+1G>A](/variant/mitf-c-955-plus-1g-a), [MITF c.956-1G>A](/variant/mitf-c-956-minus-1g-a).

### 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 3753920). 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.*