# NM_001354604.2(MITF):c.881C>T (p.Ala294Val)

https://sugi.bio/variant/mitf-p-ala294val

## Summary

**MITF p.Ala294Val (c.881C>T)** is classified **Uncertain significance** in MITF (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-10). AlphaMissense: likely benign (0.192); Very rare (popmax 0.00534%, afr); Associated with Waardenburg syndrome type 2A.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs373945151 · 5 submitters · 5 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00534%, afr)

## 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 5 submitters, and is linked to Waardenburg syndrome type 2A.

*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 | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005521/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.Ala294Val |
| Coding change (HGVS c.) | c.881C>T |
| MANE Select transcript | [NM_001354604](https://www.ncbi.nlm.nih.gov/nuccore/NM_001354604) |
| dbSNP | [rs373945151](https://www.ncbi.nlm.nih.gov/snp/rs373945151/) |
| Variant type | single nucleotide variant |
| Location | chr3:69951812-69951812 (GRCh38) |
| ClinVar | [VCV1314112](https://www.ncbi.nlm.nih.gov/clinvar/variation/1314112/) |

**All HGVS expressions:** `LRG_776:g.217331C>T`, `LRG_776t1:c.560C>T`, `NC_000003.11:g.70000963C>T`, `NC_000003.12:g.69951812C>T`, `NG_011631.1:g.217331C>T`, `NM_000248.4:c.560C>T`, `NM_001184967.2:c.725-18C>T`, `NM_001354604.2:c.881C>T`, `NM_001354605.2:c.878C>T`, `NM_001354606.2:c.878-18C>T`, `NM_001354607.2:c.830-18C>T`, `NM_001354608.2:c.725-18C>T`, `NM_006722.3:c.878-18C>T`, `NM_198158.3:c.560-18C>T`, `NM_198159.3:c.881-18C>T`, `NM_198177.3:c.833-18C>T`, `NM_198178.3:c.392-18C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.192)
- REVEL 0.028 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.178 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.332, GERP 2.06, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.2**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.31 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00534%** (afr) · FAF95 0.00175% · FAF99 0.00104% · 4/74,970 in the highest group · 18/1,612,598 alleles overall — very rare (popmax 0.00534%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00534% | 18,742 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,213 |
| East Asian | 0.00223% | 44,756 |
| South Asian | 0.0022% | 45,520 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,970 |
| European (non-Finnish) | 0.000679% | 147,365 |

*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 **294** lies in a UniProt-annotated variant site (in ws2a; uncertain significance); 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.Ala294Val 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 2026-01-10.

**Submitter consensus:** unanimous (5/5 Uncertain significance).

**Submission history:** 5 submissions (2023–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-01 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-29 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-26 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-10 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Waardenburg syndrome type 2A, not provided, Melanoma, cutaneous malignant, susceptibility to, 8, Tietz syndrome, Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness, Hereditary cancer-predisposing syndrome, WAARDENBURG SYNDROME WITHOUT DYSTOPIA CANTHORUM, COMMAD syndrome, MELANOMA AND RENAL CELL CARCINOMA, SUSCEPTIBILITY TO, Cutaneous malignant melanoma 8.

## Same-residue context {#hotspot}

Residue **294** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MITF p.Ala294fs](/variant/mitf-p-ala294fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MITF variant pages (same residue, condition, or type): [MITF p.Ala294Glu](/variant/mitf-p-ala294glu), [MITF p.Ala294=](/variant/mitf-p-ala294), [MITF p.Ala294fs](/variant/mitf-p-ala294fs), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 1314112). 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.*