Melnick-Fraser syndrome: genes and variants
Melnick-Fraser syndrome is linked to 2 analyzed proteins (EYA1 and SIX1). 5 DNA variants are known to cause it; 85 more are uncertain, and 1 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to Melnick-Fraser syndrome
EYA1: Protein phosphatase EYA1
It functions as a transcriptional coactivator and phosphatase in developmental programs that form the ear, kidney, and craniofacial structures. Haploinsufficiency causes branchio-oto-renal spectrum disorders with hearing loss, branchial anomalies, and variable renal malformations.
4 disease-causing and 85 uncertain variants in EYA1 are linked to Melnick-Fraser syndrome.
SIX1: Homeobox protein SIX1
It regulates developmental programs in the ear, kidney, craniofacial structures, and skeletal muscle together with EYA-family cofactors. Heterozygous pathogenic variants cause branchio-otic or branchio-oto-renal syndrome with hearing loss and variable branchial or renal abnormalities.
1 disease-causing and 0 uncertain variants in SIX1 are linked to Melnick-Fraser syndrome.
Known disease-causing variants in Melnick-Fraser syndrome
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| EYA1 R440Q | 440 | Disease-causing (★★) | |
| EYA1 S487P | 487 | Disease-causing (★) | |
| EYA1 L580R | 580 | Disease-causing (★) | |
| EYA1 L483P | 483 | Disease-causing (★) | |
| SIX1 Q167R | 167 | Homeobox | Disease-causing (★) |
Uncertain variants in Melnick-Fraser syndrome that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| EYA1 R440W | 440 | Uncertain (★★) | +6: in a 3D region that tolerates change poorly (1R); R440Q at the same position is pathogenic; REVEL 0.783 |
Same protein, different disease
- Branchiootorenal syndrome 1 is also caused by EYA1 variants; they fall partly in the same places as the Melnick-Fraser syndrome variants (5 disease-causing).
- Anterior segment anomalies and cataract is also caused by EYA1 variants; they fall mostly in different places as the Melnick-Fraser syndrome variants (3 disease-causing).
- Branchiootic syndrome is also caused by SIX1 variants; they fall mostly in different places as the Melnick-Fraser syndrome variants (11 disease-causing).
- Autosomal dominant nonsyndromic hearing loss is also caused by SIX1 variants; they fall mostly in different places as the Melnick-Fraser syndrome variants (8 disease-causing).
Diseases related to Melnick-Fraser syndrome
- Branchiootic syndrome, also linked to EYA1 and SIX1
- Rare genetic deafness, also linked to EYA1
- Autosomal dominant nonsyndromic hearing loss, also linked to SIX1
- Branchiootorenal syndrome 1, also linked to EYA1
- Otofaciocervical syndrome, also linked to EYA1
Frequently asked questions
Which genes are linked to Melnick-Fraser syndrome?
In CATVariant, Melnick-Fraser syndrome is linked to 2 analyzed proteins: EYA1 (Protein phosphatase EYA1) and SIX1 (Homeobox protein SIX1).
How many genetic variants are linked to Melnick-Fraser syndrome?
103 variants: 5 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 85 are of uncertain significance or have conflicting reports.
Which uncertain variants in Melnick-Fraser syndrome look disease-causing?
1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example EYA1 R440W. These are leads for expert review, not diagnoses.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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