Alexander disease: genes and variants
Alexander disease is linked to 1 analyzed protein (GFAP). 42 DNA variants are known to cause it; 37 more are uncertain, and 0 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to Alexander disease
GFAP: Glial fibrillary acidic protein
It forms intermediate filaments that support astrocyte structure and help organize responses to injury within the central nervous system. Dominant pathogenic variants cause Alexander disease through toxic accumulation and aggregation of abnormal GFAP in astrocytes.
42 disease-causing and 37 uncertain variants in GFAP are linked to Alexander disease.
Where Alexander disease variants cluster
- GFAP Coil 1A (positions 73–104): 13 of 42 disease-causing changes, 4.2× more than its size predicts.
- GFAP Coil 2A (positions 231–252): 4 of 42 disease-causing changes, 1.9× more than its size predicts.
Known disease-causing variants in Alexander disease
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| GFAP R79H | 79 | IF rod | Disease-causing (★★) |
| GFAP R79C | 79 | IF rod | Disease-causing (★★) |
| GFAP V87I | 87 | IF rod | Disease-causing (★★) |
| GFAP V87L | 87 | IF rod | Disease-causing (★★) |
| GFAP R88C | 88 | IF rod | Disease-causing (★★) |
| GFAP R239H | 239 | IF rod | Disease-causing (★★) |
| GFAP R239L | 239 | IF rod | Disease-causing (★★) |
| GFAP R239C | 239 | IF rod | Disease-causing (★★) |
| GFAP M73I | 73 | IF rod | Disease-causing (★★) |
| GFAP E69K | 69 | IF rod | Disease-causing (★★) |
| GFAP R70W | 70 | IF rod | Disease-causing (★★) |
| GFAP I84M | 84 | IF rod | Disease-causing (★★) |
| GFAP Y366H | 366 | IF rod | Disease-causing (★★) |
| GFAP D128N | 128 | IF rod | Disease-causing (★★) |
| GFAP S385C | 385 | Tail | Disease-causing (★★) |
| GFAP R416W | 416 | Tail | Disease-causing (★★) |
| GFAP R258C | 258 | IF rod | Disease-causing (★★) |
| GFAP M73T | 73 | IF rod | Disease-causing (★) |
| GFAP A81D | 81 | IF rod | Disease-causing (★) |
| GFAP A267P | 267 | IF rod | Disease-causing (★) |
| GFAP D360V | 360 | IF rod | Disease-causing (★) |
| GFAP I363V | 363 | IF rod | Disease-causing (★) |
| GFAP L76P | 76 | IF rod | Disease-causing (★) |
| GFAP K236E | 236 | IF rod | Disease-causing (★) |
| GFAP N375K | 375 | IF rod | Disease-causing (★) |
| GFAP T412I | 412 | Tail | Disease-causing (★) |
| GFAP L123P | 123 | IF rod | Disease-causing (★) |
| GFAP E207D | 207 | IF rod | Disease-causing (★) |
| GFAP L264P | 264 | IF rod | Disease-causing (★) |
| GFAP M73V | 73 | IF rod | Disease-causing |
| GFAP R88S | 88 | IF rod | Disease-causing |
| GFAP E362D | 362 | IF rod | Disease-causing |
| GFAP E362G | 362 | IF rod | Disease-causing |
| GFAP E72G | 72 | IF rod | Disease-causing |
| GFAP N77Y | 77 | IF rod | Disease-causing |
| GFAP A268D | 268 | IF rod | Disease-causing |
| GFAP L352P | 352 | IF rod | Disease-causing |
| GFAP E223Q | 223 | IF rod | Disease-causing |
| GFAP R276L | 276 | IF rod | Disease-causing |
| GFAP R330G | 330 | IF rod | Disease-causing |
| GFAP E332K | 332 | IF rod | Disease-causing |
| GFAP S398F | 398 | Tail | Disease-causing |
Which prediction tools work for Alexander disease
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- SIFT: 93 out of 100
- PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 78 out of 100
- phyloP: 64 out of 100
Frequently asked questions
Which genes are linked to Alexander disease?
In CATVariant, Alexander disease is linked to 1 analyzed protein: GFAP (Glial fibrillary acidic protein).
How many genetic variants are linked to Alexander disease?
141 variants: 42 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 37 are of uncertain significance or have conflicting reports.
Which uncertain variants in Alexander disease look disease-causing?
None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.
Which variant effect predictor works best for Alexander disease?
Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.93, based on 39 disease-causing and 13 harmless variants).
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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