GFAP

Chr 17AD

glial fibrillary acidic protein

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

GFAP, a class-III intermediate filament, is a cell-specific marker that, during the development of the central nervous system, distinguishes astrocytes from other glial cells

OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 1.031 OMIM phenotype

VCEP Guidelines: LeukodystrophyPilot

ClinGen Panel

Clinical Summary— GFAP

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Gene-Disease Validity (ClinGen)

Alexander disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

10 unique Pathogenic / Likely Pathogenic· 107 VUS of 198 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGFAP-related Alexander diseaseDNAD

This gene — mechanism propensity

0.96top 5%

GOF

0.87top 5%

LOF

0.1498th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation · 90% of P/LP are missense

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFDominant gain of function mutations in GFAP lead to the fatal neurodegenerative disorder, Alexander disease (AxD), which is characterized by cytoplasmic protein aggregates known as Rosenthal fibers along with variable degrees of leukodystrophy and intellectual disability.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 24259590 ↗

ClinVar Variant Classifications

198 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic6

VUS107

Likely Benign46

Benign25

Conflicting10

Pathogenic

Likely Pathogenic

107

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	1	5	0	0	6
VUS	17	82	8	0	107
Likely Benign	1	7	15	23	46
Benign	0	2	20	3	25
Conflicting	—				10
Total	19	100	43	26	198

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

1 pathogenic / likely-pathogenic (of 2) ClinVar copy-number / structural variants overlap GFAP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

GFAP · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

ALS (Amyotrophic Lateral Sclerosis)

This Study Evaluates the Safety, Target Engagement, and Preliminary Efficacy of Galunisertib (TGF-βR1/ALK5 Inhibitor)Combined With Nerandomilast (PDE4 Inhibitor) in GREM2-positive ALS, a Biomarker-defined Subgroup Hypothesized to Reflect Heightened TGF-β/SMAD-driven Astrocytic and Fibrotic Signaling

NOT YET RECRUITING

NCT07321860Phase PHASE2, PHASE3Gipfel Life Sciences GmbHStarted 2026-06-30

Galunisertib + Nerandomilast Combination

Schizophrenia

A Study of ANAVEX3-71 in Adults With Schizophrenia

ACTIVE NOT RECRUITING

NCT06245213Phase PHASE2Anavex Life Sciences Corp.Started 2024-03-15

ANAVEX3-71 oral capsulesPlacebo oral capsules

Mild Cognitive ImpairmentAlzheimer's DiseaseAlzheimer's Disease, Early Onset

Development of a Database to Investigate Digital and Blood-Based Biomarkers and Their Relationship to Tau and Amyloid PET Imaging in Older Participants Who Are Cognitively Normal (CN), Have Mild Cognitive Impairment (MCI), or Have Mild-to-Moderate AD Dementia

RECRUITING

NCT06584357GAP Innovations, PBCStarted 2024-09-26

Biomarker Data CollectionMK6240

Mild Cognitive Impairment (MCI)Mild DementiaAlzheimer's Disease

Study to Evaluate the Efficacy and Safety of KDS2010 in Patients With Alzheimer's Disease With Mild Cognitive Impairment and Mild Dementia Due to Alzheimer's Disease

RECRUITING

NCT07027072Phase PHASE2NeuroBiogen Co., LtdStarted 2025-08-06

KDS2010Placebo

Alzheimer DiseaseMild Cognitive Impairment (MCI)Subjective Cognitive Decline (SCD)

Biomarker-based Trial of NPC-1 for Alzheimer's Pathology

RECRUITING

NCT07236190Phase PHASE2Massachusetts General HospitalStarted 2026-04-01

natural product combination-1 (NPC1)

Cerebral Blood FlowAPOE 4

A Nutritional Intervention for Body, Brain, and Longevity Effects (NIBBLE)

NOT YET RECRUITING

NCT06682767Phase NACedars-Sinai Medical CenterStarted 2026-03

FMD1 (LNT22-017-1)Dietary Guidance

StrokeRehabilitationRehabilitation Outcome

Stroke Rehabilitation Through Intensive Exercise

NOT YET RECRUITING

NCT07650500Phase NAThe Swedish School of Sport and Health SciencesStarted 2026-08-01

LE-mCIMT-EXELE- mCIMT-TAU

Relapsing Remitting Multiple Sclerosis (RRMS)

Indole-3-PROpionic Acid Clinical Trials - Multiple Sclerosis

RECRUITING

NCT07318129Phase NAGlostrup University Hospital, CopenhagenStarted 2026-01-26

PlaceboIndole-3-propionic acid (IPA)

Frontotemporal DementiaFTDFTD-GRN

A Study to Evaluate the Safety and Effect of AVB-101, a Gene Therapy Product, in Subjects With a Genetic Sub-type of Frontotemporal Dementia (FTD-GRN)

RECRUITING

NCT06064890Phase PHASE1, PHASE2AviadoBio LtdStarted 2023-08-30

Intrathalamic AAV.PGRN administrationIntrathalamic AVB-101

Aging

Evaluation of the Efficacy of Calcium a -Ketoglutarate(AKG-Ca) in Improving Human Aging

ACTIVE NOT RECRUITING

NCT07114536Phase NAShenzhen Hygieia Biotech Co., LtdStarted 2025-08-20

Calcium-a-ketoglutaratePlacebo(starch)

Neurodegenerative DisordersParkinson DiseaseAlzheimer Disease

An Innovative Method in SAliva Samples for the Early Differential Diagnosis of High-impact NeuroDegenerative Diseases Through Raman Spectroscopy

ENROLLING BY INVITATION

NCT06875739Fondazione Don Carlo Gnocchi OnlusStarted 2025-02-14