GFAP

Summary

GFAP (glial fibrillary acidic protein, HGNC:4235) is a protein-coding gene on chromosome 17q21.31, encoding Glial fibrillary acidic protein (P14136). 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.

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.

Source: NCBI Gene 2670 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Alexander disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 589 total — 49 pathogenic, 24 likely-pathogenic
• Phenotypes (HPO): 54
• MANE Select transcript: NM_002055

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4235
Approved symbol	GFAP
Name	glial fibrillary acidic protein
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ45472
Ensembl gene	ENSG00000131095
Ensembl biotype	protein_coding
OMIM	137780
Entrez	2670

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 22 protein_coding, 9 retained_intron, 7 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined

ENST00000253408, ENST00000376990, ENST00000435360, ENST00000441312, ENST00000585543, ENST00000585728, ENST00000586125, ENST00000586127, ENST00000586793, ENST00000587997, ENST00000588037, ENST00000588316, ENST00000588640, ENST00000588735, ENST00000588957, ENST00000589701, ENST00000590922, ENST00000591327, ENST00000591719, ENST00000591880, ENST00000592065, ENST00000592320, ENST00000592706, ENST00000593179, ENST00000638281, ENST00000638304, ENST00000638400, ENST00000638488, ENST00000638618, ENST00000638921, ENST00000639042, ENST00000639243, ENST00000639277, ENST00000639369, ENST00000639921, ENST00000640545, ENST00000640552, ENST00000640859, ENST00000867442, ENST00000867443, ENST00000867444, ENST00000867445, ENST00000867446

RefSeq mRNA: 4 — MANE Select: NM_002055 NM_001131019, NM_001242376, NM_001363846, NM_002055

CCDS: CCDS11491, CCDS45708, CCDS59296, CCDS86602

Canonical transcript exons

ENST00000588735 — 9 exons

Exon	Start	End
ENSE00002946931	44903159	44907388
ENSE00003460971	44915026	44915500
ENSE00003466014	44910615	44910658
ENSE00003474464	44914028	44914088
ENSE00003516013	44908064	44908149
ENSE00003526422	44913269	44913430
ENSE00003551426	44911672	44911797
ENSE00003688785	44913728	44913823
ENSE00003690799	44911236	44911456

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 99.99.

FANTOM5 (CAGE): breadth broad, TPM avg 191.0838 / max 15013.8691, expressed in 196 samples.

FANTOM5 promoters (65 alternative TSS)

Promoter ID	TPM avg	Samples expressed
166472	176.2022	149
166446	1.2538	97
166466	0.8455	98
166463	0.7195	94
166440	0.6555	88
166444	0.6478	83
166454	0.6252	93
166442	0.5992	79
166426	0.5483	86
166447	0.4847	85

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
medulla oblongata	UBERON:0001896	99.99	gold quality
inferior olivary complex	UBERON:0002127	99.99	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.99	gold quality
lateral globus pallidus	UBERON:0002476	99.98	gold quality
ventral tegmental area	UBERON:0002691	99.98	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.98	gold quality
superior vestibular nucleus	UBERON:0007227	99.98	gold quality
cranial nerve II	UBERON:0000941	99.97	gold quality
hypothalamus	UBERON:0001898	99.96	gold quality
subthalamic nucleus	UBERON:0001906	99.96	gold quality
globus pallidus	UBERON:0001875	99.95	gold quality
substantia nigra pars compacta	UBERON:0001965	99.95	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.95	gold quality
olfactory bulb	UBERON:0002264	99.95	gold quality
medial globus pallidus	UBERON:0002477	99.95	gold quality
inferior vagus X ganglion	UBERON:0005363	99.95	gold quality
corpus callosum	UBERON:0002336	99.94	gold quality
amygdala	UBERON:0001876	99.92	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.92	gold quality
CA1 field of hippocampus	UBERON:0003881	99.92	gold quality
right frontal lobe	UBERON:0002810	99.89	gold quality
Ammon’s horn	UBERON:0001954	99.87	gold quality
middle frontal gyrus	UBERON:0002702	99.87	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.87	gold quality
nucleus accumbens	UBERON:0001882	99.86	gold quality
spinal cord	UBERON:0002240	99.86	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.85	gold quality
pons	UBERON:0000988	99.82	gold quality
putamen	UBERON:0001874	99.82	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.71	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	7265.03
E-MTAB-9435	yes	4616.51
E-MTAB-7316	yes	4025.47
E-HCAD-25	yes	3214.44
E-HCAD-35	yes	3086.78
E-GEOD-137537	yes	2300.90
E-GEOD-84465	yes	25.54
E-HCAD-30	no	280.93
E-MTAB-7249	no	16.81
E-ANND-3	no	3.39

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ATF5, CREB3L1, DNMT3A, DNMT3B, EGR1, EP300, EZH2, FOSB, GCM1, GLI3, ID2, ID4, JUN, KCNIP3, LHX2, MYC, NFIA, NFIC, NFIX, NFKB1, NFKB, NR2E1, NR3C1, OLIG1, OLIG2, PAX3, PDX1, PGR, RELA, SOX2, SP1, STAT1, STAT2, STAT3, TBP, TFCP2, TFEB, ZNF384

miRNA regulators (miRDB)

91 targeting GFAP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767

Literature-anchored findings (GeneRIF, showing 40)

• spectrum of GFAP mutations and genotype-phenotype correlation in infantile Alexander disease (PMID:11567214)
• The GFAP gene of a Japanese girl who presented with typical symptoms of Alexander disease but in whom the diagnosis was not proven by histopathology was sequenced. A missense mutation, R239C was identified. (PMID:11587071)
• a new heterozygous amino acid substitution, Val87Gly in exon 1 of GFAP, in palatal myoclonus, pyramidal tract signs, cerebellar signs, marked atrophy of the medulla oblongata and spinal cord, and autosomal dominant inheritance. (PMID:11867077)
• A disease-causing mutation (E362D) has been found in the GFAP protein of a 13-year-old boy with juvenile Alexander disease which characterizes the late-onset, milder form of this disease compared to the severe type. (PMID:12034796)
• interaction with presenilin 1 and 2 (PMID:12058025)
• GFAP expression correlates with cytoplasmic expression of wild-type p53 in human primary glioblastoma. (PMID:12084347)
• Menin’s interaction with glial fibrillary acidic protein and vimentin suggests a role for the intermediate filament network in regulating menin activity. (PMID:12169273)
• The first report of identification of the causative mutation of the GFAP gene for neuropathologically proven hereditary adult-onset Alexander’s disease suggests a common molecular mechanism underlying the three Alexander’s disease subtypes. (PMID:12447932)
• Alternation of arginine residue can give GFAP protein a dominant negative effect, leading to accumulation of GFAP as Rosenthal fibers. Alexander disease novel mutation R79L in Japanese patient. (PMID:12581808)
• significantly elevated in the CSF of neurocysticercosis patients compared with the control (PMID:12884016)
• Novel GFAP splice forms Delta 135 nt, Delta exon 6 and Delta 164 nt were identified. Neuronal GFAP is observed in the hippocampal pyramidal cells of Alzheimer and Down syndrome patients and aged controls, but not hippocampal sclerosis patients. (PMID:12931206)
• A heterozygous T to C transition at nucleotide 1055 of the GFAP gene resulting in an amino acid replacement of leucine by proline at codon 352 (L352P) was noted in an infant with Alexander disease (PMID:14557587)
• A decrease in levels of GFAP in the dorsolateral prefrontal cortex may contribute to the pathophysiology of major depressive disorder, particularly in subjects of relatively young age. (PMID:15238995)
• the GFAPepsilon tail prevents GFAPepsilon homodimerization and homomeric filament formation, whereas the ability to form heterodimers and filaments with GFAPalpha is retained (PMID:15284230)
• Molecular analysis showed that the patient of alexander’s disease was a heterozygote of the L331P mutation of GFAP. (PMID:15465095)
• Glial fibrillary acidic protein is reduced in cerebellum of subjects with major depression. (PMID:15469203)
• We present a case that suggests a relationship between mitochondrial abnormality and Alexander disease with GFAP mutation. (PMID:15477559)
• Dominant missense glial fibrillary acidic protein mutations account for nearly all forms of Alexander disease. (PMID:15732097)
• Perinuclear collapse of the intermediate filament GFAP is demonstrated in primary schwannoma cells, which become motile, unspecifically ensheathing the extracellular matrix and forming pseudomesaxons. (PMID:15837555)
• This study found higher levels of GFAP mRNA in white matter and at the pial surface as compared with gray matter levels in all cases of depression, bipolar disorder and schizophrenia. (PMID:15885920)
• A 60% increase in acidic isoforms of GFAP occurred in AD; these isoforms were both phosphorylated and N-glycosylated, while more basic isoforms were O-glycosylated and exhibited no differences between post-mortem AD and control brains. (PMID:15979880)
• Increased GFAP levels in autistic brains signify gliosis, reactive injury, and perturbed neuronal migration processes. (PMID:16147953)
• In a 6-year-old patient with a relatively mild form of Alexander disease, we detected a common R79H mutation in GFAP. (PMID:16168593)
• The genetic analysis revealed a new missense mutation, an A to G transition at nucleotide position 1026 in exon 6, leading to the substitution of glycine for glutamic acid at amino acid position 371(E371G). (PMID:16168595)
• GFAP levels in the CSF were highly elevated in three genetically confirmed cases of Alexander disease clinically conforming with infantile, early and late juvenile forms. (PMID:16217707)
• AP-1 is a key transcription factor that, in part, controls astrocyte-specific expression of genes including the ACT and GFAP genes (PMID:16303762)
• Intravitreal administration of NMDA caused a significant decrease in the thickness of the retinal layers and induced upregulation of glial fibrillary acidic protein (GFAP). (PMID:16365790)
• Data show that glial fibrillary acidic protein-positive progenitor cells give rise to neurons and oligodendrocytes throughout the central nervous system. (PMID:16458536)
• Co-localization, co-immunoprecipitation, and in vitro overlay analyses demonstrated direct interaction of plectin and GFAP. (PMID:16507904)
• These data suggest that the activation of caspases and cleavage of cellular proteins such as GFAP may contribute to astrocyte injury and damage in the Alzheimer’s disease brain. (PMID:16507909)
• NFI-X cooperates with (activator protein 1)AP-1 by an unknown mechanism in astrocytes, which results in the expression of a subset of astrocyte-specific genes. (PMID:16565071)
• GFAP was strong expression in both reactive astrocytes and astrocytomas. Expression of both GFAP is more focal in oligodendrogliomas, with staining of mainly intervening astrocytic processes. (PMID:16773221)
• The presence of glial fibrillary acidic protein mutant, R416W, is the characteristic histopathological feature of Alexander disease: a component of Rosenthal fibers. (PMID:16826512)
• Cerebrospinal fluid GFAP levels are of prognostic value in patients with subarachnoid hemorrhage. (PMID:16866629)
• analysis of glial fibrillary acidic protein, metallothionein, and MHC II expression in human, rat and mouse cells (PMID:17008879)
• Isolation of an evolutionary conserved novel GFAP isoform, GFAPkappa, produced by alternative splicing and polyadenylation of the 3’-region of the human GFAP pre-mRNA is described. (PMID:17203480)
• These findings suggest that the functional abnormalities of astrocytes might be induced prior to aggregation of GFAP in Alexander disease and that the functional alteration depends on the location of the domain. (PMID:17318298)
• GFAP was differentially expressed in sclerotic hippocampi compared to non-sclerotic ones. (PMID:17515952)
• A c1178G>T mutation was detected in the GFAP gene of a 35 year old female patient diagnosed with Alexander disease and also in her affected 6 year old son. (PMID:17703343)
• Here we report a case of Alexander disease with occipital predominance and a novel c.799G>C mutation in the GFAP gene. (PMID:17805552)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gfap	ENSDARG00000025301
mus_musculus	Gfap	ENSMUSG00000020932
rattus_norvegicus	Gfap	ENSRNOG00000002919

Paralogs (68): KRT33A (ENSG00000006059), VIM (ENSG00000026025), KRT31 (ENSG00000094796), NEFM (ENSG00000104722), KRT23 (ENSG00000108244), KRT37 (ENSG00000108417), KRT32 (ENSG00000108759), KRT18 (ENSG00000111057), LMNB1 (ENSG00000113368), KRT36 (ENSG00000126337), KRT17 (ENSG00000128422), KRT34 (ENSG00000131737), KRT33B (ENSG00000131738), NES (ENSG00000132688), PRPH (ENSG00000135406), KRT85 (ENSG00000135443), KRT7 (ENSG00000135480), KRT71 (ENSG00000139648), INA (ENSG00000148798), LMNTD1 (ENSG00000152936), LMNA (ENSG00000160789), KRT84 (ENSG00000161849), KRT82 (ENSG00000161850), KRT80 (ENSG00000167767), KRT1 (ENSG00000167768), KRT24 (ENSG00000167916), KRT8 (ENSG00000170421), KRT78 (ENSG00000170423), KRT86 (ENSG00000170442), KRT75 (ENSG00000170454), KRT6C (ENSG00000170465), KRT4 (ENSG00000170477), KRT74 (ENSG00000170484), KRT72 (ENSG00000170486), KRT83 (ENSG00000170523), BFSP2 (ENSG00000170819), KRT19 (ENSG00000171345), KRT15 (ENSG00000171346), KRT38 (ENSG00000171360), KRT13 (ENSG00000171401)

Protein

Protein identifiers

Glial fibrillary acidic protein — P14136 (reviewed: P14136)

All UniProt accessions (22): P14136, A0A0G2JLI8, A0A1W2PP21, A0A1W2PPA3, A0A1W2PPF0, A0A1W2PPL2, A0A1W2PQ25, A0A1W2PQS4, A0A1W2PQU7, A0A1W2PR46, A0A1W2PRT3, A0A1W2PS58, A0A1X7SBR3, A0A1X7SCE1, B4DIR1, K7EJK1, K7EJU1, K7EKD1, K7EKH9, K7ELP4, K7EPI4, K7EPT8

UniProt curated annotations — full annotation on UniProt →

Function. 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.

Subunit / interactions. Interacts with SYNM. Interacts with PSEN1 (via N-terminus).

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in cells lacking fibronectin.

Post-translational modifications. Phosphorylated by PKN1.

Disease relevance. Alexander disease (ALXDRD) [MIM:203450] A rare disorder of the central nervous system. The most common form affects infants and young children, and is characterized by progressive failure of central myelination, usually leading to death within the first decade. Infants with Alexander disease develop a leukodystrophy with macrocephaly, seizures, and psychomotor retardation. Patients with juvenile or adult forms typically experience ataxia, bulbar signs and spasticity, and a more slowly progressive course. Histologically, Alexander disease is characterized by Rosenthal fibers, homogeneous eosinophilic inclusions in astrocytes. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the intermediate filament family.

Isoforms (3)

UniProt ID	Names	Canonical?
P14136-1	1, GFAP alpha	yes
P14136-3	2, GFAP epsilon
P14136-2	3, GFAP kappa

RefSeq proteins (4): NP_001124491, NP_001229305, NP_001350775, NP_002046* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006821	Intermed_filament_DNA-bd	Domain
IPR018039	IF_conserved	Conserved_site
IPR039008	IF_rod_dom	Domain
IPR050405	Intermediate_filament	Family

Pfam: PF00038, PF04732

UniProt features (110 total): sequence variant 70, modified residue 15, sequence conflict 11, region of interest 9, splice variant 2, chain 1, domain 1, helix 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6A9P	X-RAY DIFFRACTION	2.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P14136-F1	80.70	0.60

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (15): 7, 12, 13, 30, 36, 38, 82, 110, 150, 270, 323, 383, 385, 406, 416

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1251985	Nuclear signaling by ERBB4
R-HSA-9613829	Chaperone Mediated Autophagy

MSigDB gene sets: 380 (showing top): AP1_01, GOBP_RESPONSE_TO_ETHANOL, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_NEUROTRANSMITTER_UPTAKE, GOBP_INTERMEDIATE_FILAMENT_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GCANCTGNY_MYOD_Q6, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_GLIAL_CELL_DEVELOPMENT, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_REGENERATION, GOBP_NEUROGENESIS, TGACCTY_ERR1_Q2

GO Biological Process (20): neural crest cell migration (GO:0001755), intracellular protein transport (GO:0006886), gene expression (GO:0010467), positive regulation of Schwann cell proliferation (GO:0010625), negative regulation of neuron projection development (GO:0010977), astrocyte development (GO:0014002), Schwann cell proliferation (GO:0014010), extracellular matrix organization (GO:0030198), neuron projection regeneration (GO:0031102), regulation of protein-containing complex assembly (GO:0043254), intermediate filament organization (GO:0045109), enteric nervous system development (GO:0048484), regulation of neurotransmitter uptake (GO:0051580), Bergmann glial cell differentiation (GO:0060020), long-term synaptic potentiation (GO:0060291), D-aspartate import across plasma membrane (GO:0070779), regulation of chaperone-mediated autophagy (GO:1904714), neuron projection development (GO:0031175), intermediate filament-based process (GO:0045103), positive regulation of glial cell proliferation (GO:0060252)

GO Molecular Function (5): integrin binding (GO:0005178), structural constituent of cytoskeleton (GO:0005200), kinase binding (GO:0019900), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (13): cytoplasm (GO:0005737), cytosol (GO:0005829), intermediate filament (GO:0005882), cell projection (GO:0042995), cell body (GO:0044297), intermediate filament cytoskeleton (GO:0045111), astrocyte end-foot (GO:0097450), cytoplasmic side of lysosomal membrane (GO:0098574), lysosome (GO:0005764), cytoskeleton (GO:0005856), membrane (GO:0016020), glial cell projection (GO:0097386), astrocyte projection (GO:0097449)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by ERBB4	1
Autophagy	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
neuron projection development	2
astrocyte differentiation	2
glial cell proliferation	2
cytoskeleton	2
neural crest cell development	1
mesenchymal cell migration	1
intracellular protein localization	1
protein transport	1
intracellular transport	1
macromolecule biosynthetic process	1
regulation of Schwann cell proliferation	1
Schwann cell proliferation	1
positive regulation of glial cell proliferation	1
regulation of neuron projection development	1
negative regulation of cell projection organization	1
glial cell development	1
extracellular structure organization	1
external encapsulating structure organization	1
regeneration	1
cellular response to stress	1
regulation of cellular component biogenesis	1
regulation of cellular component organization	1
protein-containing complex assembly	1
intermediate filament cytoskeleton organization	1
supramolecular fiber organization	1
autonomic nervous system development	1
system development	1
neurotransmitter uptake	1
regulation of neurotransmitter transport	1
regulation of synaptic plasticity	1
positive regulation of synaptic transmission	1
D-aspartate transmembrane transport	1
amino acid import across plasma membrane	1
regulation of autophagy	1
regulation of protein catabolic process	1
chaperone-mediated autophagy	1
neuron development	1
plasma membrane bounded cell projection organization	1
cellular process	1

Protein interactions and networks

STRING

5870 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GFAP	RBFOX3	A6NFN3	918
GFAP	AIF1	P55008	914
GFAP	OLIG2	Q13516	904
GFAP	S100B	P04271	902
GFAP	CNP	P09543	867
GFAP	DCX	O43602	857
GFAP	SLC1A2	P43004	850
GFAP	MBP	P02686	847
GFAP	PLEC	Q15149	844
GFAP	CD68	P34810	841
GFAP	SYP	P08247	827
GFAP	IL1B	P01584	815
GFAP	PXDNL	A1KZ92	806
GFAP	PXDN	Q92626	805
GFAP	BDNF	P23560	804

IntAct

844 interactions, top by confidence:

A	B	Type	Score
NEFL	GFAP	psi-mi:“MI:0915”(physical association)	0.850
VIM	GFAP	psi-mi:“MI:0915”(physical association)	0.830
KRT15	GFAP	psi-mi:“MI:0915”(physical association)	0.810
GFAP	GOLGA2	psi-mi:“MI:0915”(physical association)	0.810
GFAP	KRT15	psi-mi:“MI:0915”(physical association)	0.810
GFAP	KRT19	psi-mi:“MI:0915”(physical association)	0.810
KRT19	GFAP	psi-mi:“MI:0915”(physical association)	0.810
GFAP	LGALS14	psi-mi:“MI:0915”(physical association)	0.780
NXF1	GFAP	psi-mi:“MI:0915”(physical association)	0.780
GFAP	GFAP	psi-mi:“MI:0915”(physical association)	0.780
LGALS14	GFAP	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (283): GFAP (Two-hybrid), GFAP (Two-hybrid), GFAP (Two-hybrid), GOLGA2 (Two-hybrid), KRT13 (Two-hybrid), KRT15 (Two-hybrid), LMO2 (Two-hybrid), MOS (Two-hybrid), TRIM27 (Two-hybrid), RORA (Two-hybrid), PIAS2 (Two-hybrid), NXF1 (Two-hybrid), FAM50B (Two-hybrid), SH3YL1 (Two-hybrid), LGALS14 (Two-hybrid)

ESM2 similar proteins: A0A8C0N8E3, A6QQQ9, O62654, P02540, P02541, P02542, P02543, P02544, P03995, P05784, P08552, P08670, P09654, P14136, P17661, P20152, P23239, P23729, P24789, P24790, P25030, P31000, P31001, P31393, P35617, P35900, P47819, P48616, P48670, P48673, P48674, P48675, P48676, P48677, P84198, Q04948, Q28115, Q28706, Q4R4X4, Q58EE9

Diamond homologs: A0A8C0N8E3, A5A6M8, A5A6N0, A6QQJ3, B4F721, O62654, O77788, O93532, O95678, P02538, P02540, P02541, P02542, P02543, P02544, P02547, P02548, P03995, P04259, P05786, P05787, P07196, P07197, P08551, P08552, P08553, P08670, P08729, P08776, P09654, P11679, P12035, P12036, P12839, P13647, P14136, P15331, P16053, P16878, P16884

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
GFAP	“up-regulates quantity”	ACTB	binding
AURKB	“down-regulates activity”	GFAP	phosphorylation
ROCK1	“down-regulates activity”	GFAP	phosphorylation
PRKCA	“down-regulates activity”	GFAP	phosphorylation
PRKACA	“down-regulates activity”	GFAP	phosphorylation
CAMK2A	“down-regulates activity”	GFAP	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of the cornified envelope	6	14.2×	1e-03
Keratinization	6	9.0×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
intermediate filament organization	9	38.0×	7e-10
morphogenesis of an epithelium	6	36.2×	3e-06
epithelial cell differentiation	7	21.6×	4e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

589 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	49
Likely pathogenic	24
Uncertain significance	244
Likely benign	115
Benign	44

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1173085	NM_002055.5(GFAP):c.217A>G (p.Met73Val)	Pathogenic
16167	NM_002055.5(GFAP):c.715C>T (p.Arg239Cys)	Pathogenic
16168	NM_002055.5(GFAP):c.716G>A (p.Arg239His)	Pathogenic
16169	NM_002055.5(GFAP):c.1246C>T (p.Arg416Trp)	Pathogenic
16170	NM_002055.5(GFAP):c.236G>A (p.Arg79His)	Pathogenic
16171	NM_002055.5(GFAP):c.235C>T (p.Arg79Cys)	Pathogenic
16172	NM_002055.5(GFAP):c.262C>T (p.Arg88Cys)	Pathogenic
16173	NM_002055.5(GFAP):c.262C>A (p.Arg88Ser)	Pathogenic
16174	NM_002055.5(GFAP):c.226C>T (p.Leu76Phe)	Pathogenic
16175	NM_002055.5(GFAP):c.229A>T (p.Asn77Tyr)	Pathogenic
16176	NM_002055.5(GFAP):c.1086G>C (p.Glu362Asp)	Pathogenic
16177	NM_002055.5(GFAP):c.827G>T (p.Arg276Leu)	Pathogenic
16178	NM_002055.5(GFAP):c.1055T>C (p.Leu352Pro)	Pathogenic
16179	NM_002055.5(GFAP):c.234C>A (p.Asp78Glu)	Pathogenic
1685846	NM_002055.5(GFAP):c.1087A>G (p.Ile363Val)	Pathogenic
190334	NM_002055.5(GFAP):c.218T>C (p.Met73Thr)	Pathogenic
190339	NM_002055.5(GFAP):c.259G>A (p.Val87Ile)	Pathogenic
190345	NM_002055.5(GFAP):c.772C>T (p.Arg258Cys)	Pathogenic
190346	NM_002055.5(GFAP):c.791T>C (p.Leu264Pro)	Pathogenic
190348	NM_002055.5(GFAP):c.799G>C (p.Ala267Pro)	Pathogenic
190349	NM_002055.5(GFAP):c.803C>A (p.Ala268Asp)	Pathogenic
190357	NM_002055.5(GFAP):c.1085A>G (p.Glu362Gly)	Pathogenic
190359	NP_002046.1(GFAP):p.Glu373Asp	Pathogenic
190363	NM_002055.5(GFAP):c.1193C>T (p.Ser398Phe)	Pathogenic
190364	NP_002046.1(GFAP):p.Met415Ile	Pathogenic
190366	NM_002055.5(GFAP):c.1171+475_1171+482delinsATC	Pathogenic
190369	NP_002046.1:p.Phe261_Thr302del	Pathogenic
2138057	NM_002055.5(GFAP):c.1157A>G (p.Asn386Ser)	Pathogenic
2138058	NM_002055.5(GFAP):c.232G>T (p.Asp78Tyr)	Pathogenic
2500184	NM_002055.5(GFAP):c.53G>T (p.Gly18Val)	Pathogenic

SpliceAI

1371 predictions. Top by Δscore:

Variant	Effect	Δscore
17:44908058:CCTTA:C	donor_loss	1.0000
17:44908059:CTTAC:C	donor_loss	1.0000
17:44908060:TTA:T	donor_loss	1.0000
17:44908061:TACCT:T	donor_loss	1.0000
17:44908063:CCT:C	donor_gain	1.0000
17:44908147:TTT:T	acceptor_gain	1.0000
17:44908148:TT:T	acceptor_gain	1.0000
17:44908148:TTCTG:T	acceptor_loss	1.0000
17:44908150:C:CC	acceptor_gain	1.0000
17:44908150:CT:C	acceptor_loss	1.0000
17:44908153:CAGA:C	acceptor_gain	1.0000
17:44908156:A:AC	acceptor_gain	1.0000
17:44908156:A:C	acceptor_gain	1.0000
17:44908158:G:C	acceptor_gain	1.0000
17:44908158:G:GC	acceptor_gain	1.0000
17:44911230:GCTCA:G	donor_loss	1.0000
17:44911231:CTCA:C	donor_loss	1.0000
17:44911233:CACCG:C	donor_loss	1.0000
17:44911234:A:AC	donor_gain	1.0000
17:44911235:C:CC	donor_gain	1.0000
17:44911235:C:CG	donor_loss	1.0000
17:44911261:T:TA	donor_gain	1.0000
17:44911794:CAAA:C	acceptor_gain	1.0000
17:44911796:AA:A	acceptor_gain	1.0000
17:44911798:C:CC	acceptor_gain	1.0000
17:44913265:CTACC:C	donor_loss	1.0000
17:44913267:A:AT	donor_loss	1.0000
17:44913281:C:CT	donor_gain	1.0000
17:44913282:C:CT	donor_gain	1.0000
17:44913722:CCTCA:C	donor_loss	1.0000

AlphaMissense

2803 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:44911257:A:G	L369P	1.000
17:44911275:A:C	I363S	0.999
17:44911287:A:G	L359P	0.999
17:44911308:A:G	L352P	0.999
17:44915248:A:G	F80S	0.999
17:44915260:A:G	L76P	0.999
17:44911254:A:G	L370P	0.998
17:44911267:A:G	Y366H	0.998
17:44911273:C:G	A364P	0.998
17:44911275:A:T	I363N	0.998
17:44911277:C:A	E362D	0.998
17:44911277:C:G	E362D	0.998
17:44911278:T:C	E362G	0.998
17:44911293:A:G	L357P	0.998
17:44911295:C:A	K356N	0.998
17:44911295:C:G	K356N	0.998
17:44911297:T:C	K356E	0.998
17:44911305:A:G	L353P	0.998
17:44915218:A:G	L90P	0.998
17:44915251:C:G	R79P	0.998
17:44915257:T:A	N77I	0.998
17:44915260:A:T	L76H	0.998
17:44911267:A:C	Y366D	0.997
17:44911275:A:G	I363T	0.997
17:44911278:T:A	E362V	0.997
17:44915248:A:C	F80C	0.997
17:44915256:A:C	N77K	0.997
17:44915256:A:T	N77K	0.997
17:44911262:C:A	R367S	0.996
17:44911262:C:G	R367S	0.996

dbSNP variants (sampled 300 via entrez): RS1000196134 (17:44903509 C>T), RS1000407440 (17:44906232 C>T), RS1000449179 (17:44912738 T>C), RS1000769044 (17:44906588 G>A), RS1000790186 (17:44906259 C>G), RS1001180263 (17:44909178 A>G), RS1001350705 (17:44903376 C>T), RS1001698702 (17:44902924 T>C), RS1001714953 (17:44916278 G>A), RS1001848382 (17:44905651 T>C), RS1002082791 (17:44907633 G>A), RS1002109636 (17:44912177 T>A), RS1002746379 (17:44916313 C>T), RS1002758328 (17:44910457 G>C), RS1002967954 (17:44904255 C>G,T)

Disease associations

OMIM: gene MIM:137780 | disease phenotypes: MIM:203450, MIM:617296, MIM:303350, MIM:614679

GenCC curated gene-disease

Disease	Classification	Inheritance
Alexander disease	Definitive	Autosomal dominant
Alexander disease type II	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Alexander disease	Definitive	AD

Mondo (7): Alexander disease (MONDO:0008752), spastic paraplegia, intellectual disability, nystagmus, and obesity (MONDO:0015007), hereditary spastic paraplegia (MONDO:0019064), primary ciliary dyskinesia 17 (MONDO:0013854), metachromatic leukodystrophy (MONDO:0018868), scoliosis (MONDO:0005392), Alexander disease type II (MONDO:0018210)

Orphanet (5): Alexander disease (Orphanet:58), Spastic paraplegia-intellectual disability-nystagmus-obesity syndrome (Orphanet:521390), Hereditary spastic paraplegia (Orphanet:685), Primary ciliary dyskinesia (Orphanet:244), Metachromatic leukodystrophy (Orphanet:512)

HPO phenotypes

54 total (30 of 54 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000238	Hydrocephalus
HP:0000639	Nystagmus
HP:0000741	Apathy
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001310	Dysmetria
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001618	Dysphonia
HP:0002013	Vomiting
HP:0002015	Dysphagia
HP:0002063	Rigidity
HP:0002313	Spastic paraparesis
HP:0002329	Drowsiness
HP:0002360	Sleep disturbance
HP:0002376	Developmental regression
HP:0002483	Bulbar signs
HP:0002500	Abnormal cerebral white matter morphology
HP:0002518	Abnormal periventricular white matter morphology
HP:0002650	Scoliosis
HP:0002839	Urinary bladder sphincter dysfunction
HP:0002922	Increased CSF protein concentration

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002774_28	Cognitive function	5.000000e-06
GCST004412_12	Craniofacial microsomia	9.000000e-06
GCST008916_39	Asthma	8.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D038261	Alexander Disease	C10.228.140.163.100.362.312; C10.228.140.695.625.312; C10.314.400.312; C10.574.500.024; C16.320.400.024; C16.320.565.189.362.312; C18.452.132.100.362.312; C18.452.648.189.362.312
D007966	Leukodystrophy, Metachromatic	C10.228.140.163.100.362.550; C10.228.140.163.100.435.825.850.500; C10.228.140.695.625.550; C10.314.400.550; C16.320.565.189.362.550; C16.320.565.189.435.825.850.500; C16.320.565.398.641.803.925.500; C16.320.565.595.554.825.850.500; C18.452.132.100.362.550; C18.452.132.100.435.825.850.500; C18.452.584.563.641.803.925.500; C18.452.648.189.362.550; C18.452.648.189.435.825.850.500; C18.452.648.398.641.803.925.500; C18.452.648.595.554.825.850.500
D012600	Scoliosis	C05.116.900.800.875
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

73 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tretinoin	affects cotreatment, increases expression, affects expression, decreases expression	7
sodium arsenite	decreases expression, increases expression	4
Paraquat	affects expression, increases expression	4
Resveratrol	affects cotreatment, decreases expression, increases expression, increases reaction	3
nordy	increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Lead	affects expression, increases expression, decreases reaction	2
Plant Extracts	affects cotreatment, decreases expression, increases expression	2
Acrylamide	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
moringin	affects cotreatment, increases expression	1
N,N’-Bis(2-mercaptoethyl)isophthalamide	decreases reaction, increases expression	1
EG-018	increases expression	1
THJ-018	increases expression	1
methylmercuric chloride	increases expression	1
bisphenol A	decreases expression	1
lead acetate	decreases reaction, increases expression	1
sodium arsenate	decreases expression	1
tanshinone	increases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
trimethyltin	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
wogonin	decreases reaction, increases expression	1
monoisoamyl-2,3-dimercaptosuccinate	decreases expression	1
2,2’-(hydroxynitrosohydrazono)bis-ethanamine	decreases expression	1
15-deoxy-delta(12,14)-prostaglandin J2	increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
mepanipyrim	increases expression, increases reaction, affects cotreatment	1

Cellosaurus cell lines

32 cell lines: 25 induced pluripotent stem cell, 3 transformed cell line, 2 finite cell line, 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A3MG	HPS1442	Induced pluripotent stem cell	Male
CVCL_A3MH	HPS1443	Induced pluripotent stem cell	Male
CVCL_A3MI	HPS1444	Induced pluripotent stem cell	Male
CVCL_A3MJ	HPS1445	Induced pluripotent stem cell	Male
CVCL_A3MK	HPS1446	Induced pluripotent stem cell	Male
CVCL_A3ML	HPS1447	Induced pluripotent stem cell	Male
CVCL_A9J6	KCMC-2060	Finite cell line	Female
CVCL_C6VY	Alex1	Induced pluripotent stem cell	Male
CVCL_C6VZ	Alex2	Induced pluripotent stem cell	Female
CVCL_C6W0	Alex3	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

296 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT00508066	PHASE4	COMPLETED	Continuous Local Infusion of Anesthetic at the Incisional Site for Scoliosis Surgery
NCT00510575	PHASE4	COMPLETED	Surgical Outcomes Using Variable Rod Diameters in the Treatment of Idiopathic Scoliosis
NCT00768313	PHASE4	WITHDRAWN	Phase IV Comparing Rods of Yield Strengths to Correct Adolescent Idiopathic Scoliosis.
NCT00880607	PHASE4	COMPLETED	Intrathecal Morphine Versus Epidural Extended Release Morphine for Pediatric Patients Undergoing Spinal Fusion
NCT00958581	PHASE4	COMPLETED	Tranexamic Acid (TXA) Versus Epsilon Aminocaproic Acid (EACA) Versus Placebo for Spine Surgery
NCT01852747	PHASE4	TERMINATED	Comparison of Actifuse ABX and Local Bone in Spinal Surgery
NCT02464813	PHASE4	COMPLETED	Effect of Pregabalin on Immediate Post-operative and Longterm Pain
NCT02465099	PHASE4	TERMINATED	Posterior Spinal Fusion With Two Energy Dissection Techniques
NCT06540885	PHASE4	RECRUITING	A Comparison Between Palonosetron Versus Granisetron as PONV Prophylaxis in Scoliotic Patients Undergoing Spine Surgery
NCT06616220	PHASE4	COMPLETED	Dexamethasone for ESPB in Pain Management After Pediatric Idiopathic Scoliosis Surgery
NCT06789016	PHASE4	COMPLETED	Dexmedetomidine for ESPB in Pain Management After Pediatric Idiopathic Scoliosis Surgery
NCT04849741	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Efficacy of Zilganersen (ION373) in Patients With Alexander Disease (AxD)
NCT04283227	PHASE3	ACTIVE_NOT_RECRUITING	OTL-200 in Patients With Late Juvenile Metachromatic Leukodystrophy (MLD)
NCT00323752	PHASE3	COMPLETED	Recombinant Human Erythropoietin Compared to Autologous Pre-Donation Prior to Scoliosis Surgery in Children.
NCT00684112	PHASE3	COMPLETED	Analgesic Effects of Gabapentin After Scoliosis Surgery in Children
NCT00737997	PHASE3	COMPLETED	Effect of Early Morphine Administration on the Development of Acute Opioid Tolerance During Pediatric Scoliosis Surgery
NCT01103115	PHASE3	COMPLETED	Calcium + Vitamin D Supplementation for Low Bone Mass in Adolescent Idiopathic Scoliosis (AIS)
NCT01108211	PHASE3	COMPLETED	Improving Low Bone Mass With Vibration Therapy in Adolescent Idiopathic Scoliosis (AIS)
NCT01205256	PHASE3	COMPLETED	IRB-HSR# 14145 R,S Methadone: Analgesia and Pharmacokinetics in Adolescents Undergoing Scoliosis Correction
NCT02558010	PHASE3	COMPLETED	Perioperative Methadone Use to Decrease Opioid Requirement in Pediatric Spinal Fusion Patients
NCT03537612	PHASE3	TERMINATED	Sensorial and Physiological Mechanism-based Assessments of Perioperative Pain
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT00383448	PHASE2	COMPLETED	HSCT for High Risk Inherited Inborn Errors
NCT01043640	PHASE2	COMPLETED	Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders
NCT01303146	PHASE2	COMPLETED	Efficacy METAZYM for the Treatment Metachromatic Leukodystrophy Treated With Hematopoietic Stem Cell Transplantation
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT03392987	PHASE2	COMPLETED	A Safety and Efficacy Study of Cryopreserved OTL-200 for Treatment of Metachromatic Leukodystrophy (MLD)
NCT03771898	PHASE2	ACTIVE_NOT_RECRUITING	A Study of Intrathecal SHP611 in Children With Metachromatic Leukodystrophy
NCT00273598	PHASE2	COMPLETED	Comparing Two Instrumentation Systems for the Treatment of Adolescent Scoliosis
NCT01148888	PHASE2	COMPLETED	The Effect of Magnesium Sulfate on Motor and Somatosensory Evoked Potentials in Children Undergoing Scoliosis Surgery
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT00418561	PHASE1	COMPLETED	Metazym for the Treatment of Patients With Late Infantile Metachromatic Leukodystrophy (MLD)
NCT01586455	PHASE1	COMPLETED	Human Placental-Derived Stem Cell Transplantation
NCT00154505	PHASE1	COMPLETED	Effects of Lateral Trunk Support on Spinal Alignment in Spinal Cord Injured Persons
NCT00155545	PHASE1	COMPLETED	Influence of Leg Length Discrepancy on the Spinal Shape and Biomechanics in Functional and Idiopathic Scoliosis Patients
NCT00671931	PHASE1	COMPLETED	Susceptibility of Motor-Evoked Potentials to Varying Targeted Blood Levels of Dexmedetomidine
NCT01677650	PHASE1	WITHDRAWN	Pharmacogenomics of Methadone in Spine Fusion Surgery
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies