Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_002055.5(GFAP):c.235C>T (p.Arg79Cys)

CA217166

16171 (ClinVar)

Gene: GFAP (HGNC:2670)

Condition: Alexander disease (MONDO:0008752)

Inheritance Mode: Autosomal dominant inheritance

UUID: e30b7538-e38d-4403-93f8-1a260b126222

Approved on: 2026-08-18

Published on: 2026-08-18

HGVS expressions

NM_002055.5:c.235C>T

NM_002055.5(GFAP):c.235C>T (p.Arg79Cys)

NC_000017.11:g.44915252G>A

CM000679.2:g.44915252G>A

NC_000017.10:g.42992620G>A

CM000679.1:g.42992620G>A

NC_000017.9:g.40348146G>A

NG_008401.1:g.5295C>T

ENST00000253408.11:c.235C>T

ENST00000435360.8:c.235C>T

ENST00000253408.10:c.235C>T

ENST00000435360.7:c.235C>T

ENST00000586793.6:c.235C>T

ENST00000588735.3:c.235C>T

ENST00000591327.2:n.248C>T

ENST00000592320.6:c.235C>T

ENST00000638281.1:c.235C>T

ENST00000639277.1:c.235C>T

ENST00000640552.1:n.249C>T

ENST00000253408.9:c.235C>T

ENST00000376990.8:c.235C>T

ENST00000435360.6:c.235C>T

ENST00000585728.5:c.181+54C>T

ENST00000586793.5:c.235C>T

ENST00000588037.1:c.235C>T

ENST00000588316.1:c.235C>T

ENST00000588735.1:c.82+153C>T

ENST00000588957.5:c.-272+565C>T

ENST00000591327.1:n.249C>T

ENST00000592320.5:c.235C>T

NM_001131019.2:c.235C>T

NM_001242376.1:c.235C>T

NM_002055.4:c.235C>T

NM_001363846.1:c.235C>T

NM_001131019.3:c.235C>T

NM_001242376.2:c.235C>T

NM_001242376.3:c.235C>T

NM_001363846.2:c.235C>T

Pathogenic

PS2_Very Strong PS4 PM1 PS3_Very Strong

Evidence Links 0

Expert Panel

Leukodystrophy and Leukoencephalopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Leukodystrophy and Leukoencephalopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GFAP Version 1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Leukodystrophy and Leukoencephalopathy VCEP

The NM_002055.5(GFAP):c.235C>T, variant in GFAP is a missense variant predicted to cause a substitution of arginine by cysteine at amino acid 79 (p.Arg79Cys). This variant has been reported in three probands who met definite diagnostic criteria for Alexander Disease (PS4_Strong; PMID:15732097) and identified as a de novo occurrence with confirmed parental relationships in two individuals who met definite diagnostic criteria for Alexander Disease per ClinGen Leukodystrophy and Leukoencephalopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GFAP Version 1.0.0 (PS2_Very Strong; PMID: 23364391). An aggregation assay in a zebrafish model showed a significantly higher number of GFAP aggregates than wild-type GFAP indicating that this variant impacts protein function (PS3_Very Strong; PMID: 28882119). This variant resides within a region, amino acids 59 – 88, of GFAP that is defined as a region with significant missense constraint by the ClinGen Leukodystrophy and Leukoencephalopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GFAP Version 1.0.0 (PM1). In summary, this variant meets the criteria to be classified as a pathogenic for Alexander Disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Leukodystrophy and Leukoencephalopathy VCEP: PS2_Very Strong, PS3_Very Strong, PS4_Strong, PM1 (ClinGen Leukodystrophy and Leukoencephalopathy VCEP Specifications Version 1.0.0).

PS2_Very Strong

This variant has been identified as a de novo occurrence with confirmed paternal relationships in two individuals who met diagnostic criteria for Alexander Disease per ClinGen Leukodystrophy and Leukoencephalopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GFAP Version 1.0.0 (PS2_[Very Strong]; PMID: 23364391)

PS4

This variant has been reported in 3 probands who met diagnostic criteria for Alexander Disease per ClinGen Leukodystrophy and Leukoencephalopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GFAP Version 1.0.0 (PS4_[Strong]; PMID:15732097)

PM1

This variant resides within a region, amino acids 59 – 88, of GFAP that is defined as a region with significant missense constraint by the ClinGen Leukodystrophy and Leukoencephalopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GFAP Version 1.0.0 (PM1).

PS3_Very Strong

An aggregation assay in a zebrafish model showed a significantly higher number of GFAP aggregates than wild-type GFAP indicating that this variant impacts protein function (PMID: 28882119) (PS3_[Very Strong]).

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.