GFAP p.Pro380=
c.1140C>T · rs267607527 · VCV66446
ClinGen expert panel — Leukodystrophy and Leukoencephalopathy VCEP
Benign for Alexander disease. Applied ACMG criteria (verbatim):
BP7 BA1
Curation rationale (ClinGen, verbatim)
The c.1140C>T (NM_002055.5(GFAP)) variant in GFAP is a synonymous (silent) variant (p.Pro380=) that is not predicted to impact the splice consensus sequence, nor the creation of a new splice site, and the nucleotide is not highly conserved with a phyloP score of <2.27 (BP7). The GrpMax filtering allele frequency in gnomAD v4.1.0 is 0.0001188 from the African/African American genetic ancestry group (the lower threshold of the 95% CI of 21/74738 alleles), which is higher than the ClinGen Leukodystrophy and Leukoencephalopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GFAP Version 1.0.0 threshold ≥ 0.01% for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen Leukodystrophy and Leukoencephalopathy VCEP: BA1, BP7 (ClinGen Leukodystrophy and Leukoencephalopathy VCEP Specifications Version 1.0.0).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -1.8 | GERP -3.4 |
| Overall | ||
| CADD | 5.54 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0281% | 3,559 |
| Remaining individualsnot grpmax-eligible | 0.00649% | 15,409 |
| South Asian | 0.00231% | 43,355 |
| East Asian | 0.00227% | 44,134 |
| Admixed American | 0.00183% | 54,546 |
| European (non-Finnish) | 0.000686% | 145,779 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- GFAP
- Protein
- p.Pro380=
- Coding
- c.1140C>T
- MANE Select
- NM_002055
- dbSNP
- rs267607527
- Type
- single nucleotide variant
- Location
- chr17:44910646 (GRCh38)
- Gene constraint
- LOEUF 0.991 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 80.70 · 1 PDB
- Residue 380
- the 'tail' region
Similar variants
- GFAP p.Pro380Ser Uncertain significance ⚠ same residue
- GFAP p.Arg239Cys Pathogenic ★★ same type
- GFAP p.Arg239His Pathogenic ★★ same type
- GFAP p.Arg239Leu Pathogenic ★★ same type
- GFAP p.Arg258Cys Pathogenic ★★ ⚠ same type
- GFAP p.Arg376Trp Pathogenic ★★ same type
- GFAP p.Arg416Trp Pathogenic ★★ same type
- GFAP p.Arg70Trp Pathogenic ★★ same type
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gfap-p-pro380 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown