GFAP

Chr 17AD

glial fibrillary acidic protein

Also known as: ALXDRD

NCBI Gene: 2670 ENSG00000131095 UniProt: P14136 OMIM: 137780

The protein forms intermediate filaments in mature astrocytes and serves as a specific marker for these glial cells during development. Mutations cause Alexander disease, a rare astrocyte disorder of the central nervous system, inherited in an autosomal dominant pattern. The pathogenic mechanism involves a dominant-negative effect where mutant protein disrupts normal astrocyte function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes one of the major intermediate filament proteins of mature astrocytes. It is used as a marker to distinguish astrocytes from other glial cells during development. Mutations in this gene cause Alexander disease, a rare disorder of astrocytes in the central nervous system. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Alexander diseaseMIM #203450

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Alexander disease · AD · ClinGen 2024

Interpreting a novel variant

A dominant-negative effect is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

3399

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.03

LOEUF

DN*

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.03LOEUF

pLI 0.000

Z-score 1.48

OE 0.63 (0.41–1.03)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.93Z-score

OE missense 0.84 (0.76–0.94)

233 obs / 276.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.63 (0.41–1.03)

0≤0.351.4

Missense OE?0.84 (0.76–0.94)

0≤0.61.4

Synonymous OE?0.73

0≤1.21.6

LoF obs/exp: 12 / 19.0Missense obs/exp: 233 / 276.5Syn Z: 2.28

Background carrier burden — how many people carry a rare variant somewhere in GFAP?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 58

836 rare PASS variants

Rare truncating (LoF)

1 in 370

134 rare PASS variants

Rare synonymous (reference)

1 in 79

344 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GFAP. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 68	1 in 710
South Asian	~43k	1 in 59	1 in 820
Remaining (unassigned)	~30k	1 in 47	1 in 1,100
European (Finnish)	~27k	1 in 120	1 in 3,900
Admixed American	~22k	1 in 60	1 in 320
African / African American	~21k	1 in 68	1 in 420
East Asian	~20k	1 in 77	1 in 330
Ashkenazi Jewish	~13k	1 in 180	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 53	1 in 570

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓