GFRA1

Summary

GFRA1 (GDNF family receptor alpha 1, HGNC:4243) is a protein-coding gene on chromosome 10q25.3, encoding GDNF family receptor alpha-1 (P56159). Coreceptor for GDNF, a neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake.

This gene encodes a member of the glial cell line-derived neurotrophic factor receptor (GDNFR) family of proteins. The encoded preproprotein is proteolytically processed to generate the mature receptor. Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent neurotrophic factors that play key roles in the control of neuron survival and differentiation. This receptor is a glycosylphosphatidylinositol (GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for Hirschsprung disease. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed.

Source: NCBI Gene 2674 — RefSeq curated summary.

At a glance

• Gene–disease (curated): renal hypodysplasia/aplasia 4 (Strong, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 83 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 25
• Druggable target: yes
• MANE Select transcript: NM_005264

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4243
Approved symbol	GFRA1
Name	GDNF family receptor alpha 1
Location	10q25.3
Locus type	gene with protein product
Status	Approved
Aliases	RETL1, GDNFR, GFR-ALPHA-1, RET1L, TRNR1
Ensembl gene	ENSG00000151892
Ensembl biotype	protein_coding
OMIM	601496
Entrez	2674

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 19 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000355422, ENST00000369234, ENST00000369236, ENST00000439649, ENST00000490345, ENST00000682194, ENST00000682489, ENST00000682724, ENST00000682743, ENST00000683474, ENST00000683792, ENST00000684105, ENST00000861432, ENST00000861433, ENST00000861434, ENST00000861435, ENST00000861436, ENST00000861437, ENST00000952622, ENST00000952623

RefSeq mRNA: 12 — MANE Select: NM_005264 NM_001145453, NM_001348096, NM_001348098, NM_001348099, NM_001382556, NM_001382557, NM_001382558, NM_001382559, NM_001382560, NM_001382561, NM_005264, NM_145793

CCDS: CCDS44481, CCDS7593

Canonical transcript exons

ENST00000355422 — 11 exons

Exon	Start	End
ENSE00001000308	116125221	116125557
ENSE00001002285	116270822	116271115
ENSE00001002286	116269503	116269586
ENSE00001097159	116096655	116096764
ENSE00001097164	116089741	116089922
ENSE00001097165	116065573	116065626
ENSE00001097167	116093702	116093836
ENSE00001449270	116271990	116272275
ENSE00001449276	116056925	116064544
ENSE00001869083	116273163	116273206
ENSE00002468251	116211631	116211645

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 95.49.

FANTOM5 (CAGE): breadth broad, TPM avg 22.0294 / max 1147.6393, expressed in 886 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111533	7.8239	640
111539	4.0945	433
111526	2.0531	270
111535	1.6145	463
111537	1.5526	507
111532	1.4103	367
111534	1.1708	262
111531	0.5242	202
111542	0.3958	113
111541	0.3596	199

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	95.49	gold quality
trigeminal ganglion	UBERON:0001675	94.85	gold quality
dorsal root ganglion	UBERON:0000044	93.99	gold quality
substantia nigra pars reticulata	UBERON:0001966	91.05	gold quality
parietal pleura	UBERON:0002400	88.80	gold quality
corpus epididymis	UBERON:0004359	88.65	gold quality
mammary duct	UBERON:0001765	88.59	gold quality
substantia nigra pars compacta	UBERON:0001965	87.99	gold quality
nipple	UBERON:0002030	87.17	gold quality
left uterine tube	UBERON:0001303	86.85	gold quality
cardia of stomach	UBERON:0001162	86.18	gold quality
skin of hip	UBERON:0001554	86.15	gold quality
vena cava	UBERON:0004087	86.04	gold quality
pericardium	UBERON:0002407	85.96	gold quality
pylorus	UBERON:0001166	85.74	gold quality
mammary gland	UBERON:0001911	85.48	gold quality
thoracic mammary gland	UBERON:0005200	85.45	gold quality
epithelium of mammary gland	UBERON:0003244	85.09	gold quality
tibial nerve	UBERON:0001323	85.06	gold quality
muscle layer of sigmoid colon	UBERON:0035805	84.75	gold quality
mucosa of stomach	UBERON:0001199	84.10	gold quality
germinal epithelium of ovary	UBERON:0001304	84.06	gold quality
nucleus accumbens	UBERON:0001882	83.81	gold quality
ventral tegmental area	UBERON:0002691	83.40	gold quality
superior surface of tongue	UBERON:0007371	83.11	gold quality
caudate nucleus	UBERON:0001873	83.07	gold quality
colonic epithelium	UBERON:0000397	82.90	gold quality
mammalian vulva	UBERON:0000997	82.74	gold quality
tibia	UBERON:0000979	82.53	gold quality
pleura	UBERON:0000977	82.51	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	37.89
E-MTAB-9543	no	3034.96
E-MTAB-2983	no	679.81
E-ENAD-17	no	241.94

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): APEX1, NFKB

miRNA regulators (miRDB)

226 targeting GFRA1, 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-4455	100.00	65.48	1587
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-651-3P	99.94	73.48	5177

Literature-anchored findings (GeneRIF, showing 40)

• The expression of GFRA1 in normal infants and normoganglionic colon of patients with Hirschsprung’s disease was restricted to receptor tyrosine kinase(RET)-negative glial cells and RET-positive neurons of the ganglionic plexus. (PMID:12065680)
• GFRA1-193C > G and 537T > C could be in linkage disequilibrium with other loci responsible for medullary thyroid cancer (PMID:12490080)
• analysis of binding surface for the GDNF-GFR alpha 1 (PMID:14514671)
• Gas1 is related to the GDNF alpha receptors and regulates Ret signaling (PMID:16551639)
• Loss of dopaminergic neurons in the substantia nigra may induce changes in the expression of GDNF but not its receptor snd Parkinson disease. (PMID:16644101)
• The role of heparin and heparan sulfate in GDNF signalling remains unclear, but the present study indicates that it does not occur in the first step of the pathway, namely GDNF-GFRalpha1 engagement. (PMID:17298301)
• GFRalpha-1 were observed within sensory and motor nuclei of cranial nerves, dorsal column nuclei, olivary nuclear complex, reticular formation, pontine nuclei, locus caeruleus, raphe nuclei, substantia nigra, and quadrigeminal plate. (PMID:17825269)
• GDNF can act as an important component of the inflammatory response in breast cancers and its effects aare mediated by GFR alpha 1 receptors. (PMID:18089803)
• direct receptor-receptor interactions are not required for high affinity GDNF binding to NCAM but play an important role in the regulation of NCAM-mediated cell adhesion by GFRalpha1 (PMID:18353777)
• GDNF is a key component to preserve several cell populations in the nervous system and also participates in the survival and differentiation of peripheral neurons. (PMID:18394855)
• analysis of how GDNF.GFR alpha 1 can mediate cell adhesion and how heparin might inhibit GDNF signaling through RET (PMID:18845535)
• 38 cases of germ cell tumors: 26 cases contained immature teratoma, of which 24 had immature neuroepithelium and showed strong membrane staining for GFRalpha-1. staining for GFRalpha-1 in immature neuroepithelium may facilitate its identification. (PMID:19019765)
• Ape1 is a novel physiological regulator of GDNF responsiveness, and Ape1-induced GFRalpha1 expression may play important roles in pancreatic cancer progression and neuronal cell survival. (PMID:19188437)
• GFR-alpha1 mRNA transcripts were detected in oocytes and GCs from all samples from fetuses, girls and adult women. (PMID:19896648)
• This study found nominally-significant evidence for interactions between GFRA1, 2 and 3 associated with schizophrenia and clozapine response, consistent with the locations of these three genes within linkage regions for schizophrenia. (PMID:20116071)
• Here we report that human nigral dopaminergic neurons express GFRalpha1 and RET receptors at all ages. There was no reduction in the number of neurons expressing these receptors as a function of age. (PMID:20347960)
• Results identify persephin, a GDNF family member, as a novel ligand for GFRalpha1/RET receptor complex. (PMID:20350599)
• MEN2 arises from activating missense mutations in RET, causing autodimerization under certain conditions. The position of missense mutations influences medullary thyroid carcinoma aggressiveness. Review. (PMID:20669561)
• Post-synaptic transgenic GFRalpha1 has profound effects on the development of dopamine neurons, resulting in a 40% increase in the adult number. (PMID:21133924)
• Mutations in GFRA1 gene is associated with urinary tract malformations. (PMID:22729463)
• The expression of GFRalpha1 and/or GFRalpha3, especially when combined with ARTN expression, may be useful predictors of disease progression and outcome in specific subtypes of mammary carcinoma. (PMID:23351331)
• The study shows co-localization of RET with GFRA1 and GFRA2 in myenteric ganglia of the adult human colon. (PMID:23881409)
• In the cochlea, GFRalpha-1 was identified mainly in the cell bodies of the spiral neurons. In the organ of Corti, GFRalpha-1 was demonstrated in the Deiters’ cells, Hensen cells, inner pillar cells, and weakly in inner hair cells but not in the outer hair cells. (PMID:24139947)
• These findings collectively demonstrate that GFRalpha1 released by nerves enhances perineural invasion through GDNF-RET signaling and that GFRalpha1 expression by cancer cells enhances but is not required for it. (PMID:24778213)
• Methylation changes of GFRA1, SRF, and ZNF382 may be a potential biomarker set for prediction of gastric carcinoma metastasis. (PMID:25009298)
• GFRalpha1 levels in neurons from autopsied AD brains are significantly decreased. (PMID:25253858)
• This study demonstrate, using a knock-in mouse model in which GFRalpha1 is no longer located in lipid rafts, that the developmental functions of GDNF in the periphery require the translocation of the GDNF receptor complex into lipid rafts. (PMID:26400951)
• Hox proteins coordinate motor neuron differentiation and connectivity programs through Ret/Gfra genes. (PMID:26904955)
• that the consequences of this is that GFRalpha-1-mediated signalling is altered during the ageing process (PMID:27346872)
• RET c.1296A may be a common susceptibility allele for nephron underdosing-related diseases. The 5’-UTR and intronic variants near exon 5 of GFRA1 are not associated with nephron endowment. (PMID:27533506)
• the methylation status of CpG sites in GFRA1 and GSTM2 may have a role and could be used as potential biomarkers for the screening of rectal cancer (PMID:27566576)
• GFRA1 regulates AMPK-dependent autophagy by promoting SRC phosphorylation independent of proto-oncogene RET kinase (PMID:27754745)
• identified a novel susceptibility locus (rs3781545in GFRA1) with suggestive significance for migraine risk in Han Chinese (PMID:28952330)
• circGFRA1 may function as a competing endogenous RNA (ceRNA) to regulate GFRA1 expression through sponging miR-34a to exert regulatory functions in TNBC. (PMID:29037220)
• Data suggest that GDNF family receptor alpha 1 protein (GFRA1) is a protein target of ST3 beta-galactoside alpha-23-sialyltransferase 1 (ST3GAL1). (PMID:30040982)
• Low expression of EZH2 in the colon tissue of children with Hirschsprung’s disease may be one of the causes of inadequate expression of GFRalpha1 and onset of Hirschsprung’s disease (PMID:31642440)
• GFRA1 expression is frequently reactivated by DNA demethylation in colon cancer (CC) tissues and is significantly associated with a poor prognosis in patients with CC, especially those with metastatic CC. GFRA1 can promote the proliferation/growth of CC cells, probably by the activation of AKT and ERK pathways. (PMID:31988584)
• LncRNA LINC00210 regulated radiosensitivity of osteosarcoma cells via miR-342-3p/GFRA1 axis. (PMID:32841458)
• Biallelic Pathogenic GFRA1 Variants Cause Autosomal Recessive Bilateral Renal Agenesis. (PMID:33020172)
• Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer. (PMID:33175846)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	gfra1a	ENSDARG00000099732
danio_rerio	gfra1b	ENSDARG00000102564
mus_musculus	Gfra1	ENSMUSG00000025089
rattus_norvegicus	Gfra1	ENSRNOG00000017438
drosophila_melanogaster	Gfrl	FBGN0262869
caenorhabditis_elegans		WBGENE00022100

Paralogs (4): GFRA4 (ENSG00000125861), GFRA3 (ENSG00000146013), GFRA2 (ENSG00000168546), GFRAL (ENSG00000187871)

Protein

Protein identifiers

GDNF family receptor alpha-1 — P56159 (reviewed: P56159)

Alternative names: RET ligand 1, TGF-beta-related neurotrophic factor receptor 1

All UniProt accessions (3): P56159, A0A804HJK2, A0A804HL20

UniProt curated annotations — full annotation on UniProt →

Function. Coreceptor for GDNF, a neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake. GDNF-binding leads to autophosphorylation and activation of the RET receptor.

Subunit / interactions. Interacts with GDNF ligand and RET: forms a 2:2:2 ternary complex composed of GDNF ligand, GFRA1 and RET receptor. Interacts with SORL1, either alone or in complex with GDNF. Interaction between SORL1 and GFRA1 leads to GFRA1 internalization, but not degradation.

Subcellular location. Cell membrane. Golgi apparatus. trans-Golgi network. Endosome. Multivesicular body.

Disease relevance. Renal hypodysplasia/aplasia 4 (RHDA4) [MIM:619887] An autosomal recessive, severe congenital anomaly of the kidney and urinary tract characterized by bilateral renal agenesis, and severely reduced or absent amniotic fluid during pregnancy. Patients exhibit the Potter sequence, including flattened nose, ear anomalies, and receding chin. Some affected individuals have limb contractures and joint dislocations. Bilateral renal agenesis is almost invariably fatal in utero or in the perinatal period. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the GDNFR family.

Isoforms (2)

UniProt ID	Names	Canonical?
P56159-1	1	yes
P56159-2	2

RefSeq proteins (11): NP_001138925, NP_001335025, NP_001335027, NP_001369485, NP_001369486, NP_001369487, NP_001369488, NP_001369489, NP_001369490, NP_005255, NP_665736 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003438	GDNF_rcpt	Family
IPR003503	GDNF_rcpt_A1	Family
IPR016017	GDNF/GAS1	Domain
IPR017372	Glial_neurotroph_fac_rcpt_a1/2	Family
IPR037193	GDNF_alpha	Homologous_superfamily

Pfam: PF02351

UniProt features (29 total): disulfide bond 11, sequence variant 5, repeat 3, glycosylation site 3, sequence conflict 2, signal peptide 1, chain 1, propeptide 1, splice variant 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6Q2N	ELECTRON MICROSCOPY	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56159-F1	74.95	0.48

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 (1): 429

Disulfide bonds (11): 36–42, 154–214, 161–167, 178–192, 187–233, 216–221, 243–313, 250–256, 267–285, 277–337, 315–325

Glycosylation sites (3): 59, 347, 406

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-419037	NCAM1 interactions
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-8853659	RET signaling
R-HSA-9830674	Formation of the ureteric bud

MSigDB gene sets: 328 (showing top): MYOGENIN_Q6, HOFFMANN_SMALL_PRE_BII_TO_IMMATURE_B_LYMPHOCYTE_DN, GCANCTGNY_MYOD_Q6, GOZGIT_ESR1_TARGETS_DN, MAZ_Q6, GOCC_CELL_SURFACE, REACTOME_NCAM_SIGNALING_FOR_NEURITE_OUT_GROWTH, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GOBP_NEUROGENESIS, TAL1ALPHAE47_01, FOXO1_01, SP1_Q2_01, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, FREAC3_01

GO Biological Process (9): kidney development (GO:0001822), cell surface receptor signaling pathway (GO:0007166), nervous system development (GO:0007399), male gonad development (GO:0008584), cell migration (GO:0016477), neuron projection development (GO:0031175), glial cell-derived neurotrophic factor receptor signaling pathway (GO:0035860), neuron differentiation (GO:0030182), neurotrophin signaling pathway (GO:0038179)

GO Molecular Function (6): neurotrophin receptor activity (GO:0005030), signaling receptor binding (GO:0005102), integrin binding (GO:0005178), glial cell-derived neurotrophic factor receptor activity (GO:0016167), signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (14): multivesicular body (GO:0005771), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), extrinsic component of membrane (GO:0019898), axon (GO:0030424), neuronal cell body (GO:0043025), signaling receptor complex (GO:0043235), extracellular exosome (GO:0070062), plasma membrane protein complex (GO:0098797), obsolete extracellular space (GO:0005615), endosome (GO:0005768), membrane (GO:0016020), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
NCAM signaling for neurite out-growth	1
MAPK1/MAPK3 signaling	1
Axon guidance	1
Kidney development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
membrane	3
cellular anatomical structure	3
endomembrane system	2
plasma membrane	2
animal organ development	1
renal system development	1
signal transduction	1
system development	1
gonad development	1
development of primary male sexual characteristics	1
cell motility	1
neuron development	1
plasma membrane bounded cell projection organization	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cell differentiation	1
generation of neurons	1
cell surface receptor signaling pathway	1
cellular response to growth factor stimulus	1
signaling receptor activity	1
neurotrophin signaling pathway	1
neurotrophin binding	1
protein binding	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
cytokine receptor activity	1
glial cell-derived neurotrophic factor receptor signaling pathway	1
molecular transducer activity	1
binding	1
late endosome	1
cytoplasm	1
intracellular membrane-bounded organelle	1
cell periphery	1
cell surface	1
side of membrane	1
neuron projection	1
somatodendritic compartment	1
cell body	1
protein-containing complex	1
extracellular vesicle	1

Protein interactions and networks

STRING

1428 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GFRA1	NRTN	Q99748	999
GFRA1	RET	P07949	999
GFRA1	GDNF	P39905	999
GFRA1	PSPN	O60542	998
GFRA1	ARTN	Q5T4W7	998
GFRA1	NGF	P01138	949
GFRA1	NCAM1	P13591	938
GFRA1	BDNF	P23560	928
GFRA1	NTRK1	P04629	884
GFRA1	EDNRB	P24530	835
GFRA1	SOX10	P56693	823
GFRA1	NANOS2	P60321	731
GFRA1	ZBTB16	Q05516	729
GFRA1	EDN3	P14138	708
GFRA1	STRA8	Q7Z7C7	687

IntAct

9 interactions, top by confidence:

A	B	Type	Score
SOCS3	GFRA1	psi-mi:“MI:0915”(physical association)	0.370
SYNGAP1	POTEF	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	IGLON5	psi-mi:“MI:0914”(association)	0.350
SLC16A10	STXBP3	psi-mi:“MI:0914”(association)	0.350
SLC30A10	GOLIM4	psi-mi:“MI:0914”(association)	0.350
SLC34A2	SNAP23	psi-mi:“MI:0914”(association)	0.350
SLC43A3	PLPP3	psi-mi:“MI:0914”(association)	0.350

BioGRID (55): GFRA1 (Affinity Capture-MS), GDNF (Reconstituted Complex), NRTN (Reconstituted Complex), GFRA1 (Proximity Label-MS), GFRA1 (Reconstituted Complex), GDNF (Reconstituted Complex), NRTN (Reconstituted Complex), GFRA1 (Reconstituted Complex), GFRA1 (Affinity Capture-RNA), GFRA1 (Co-fractionation), GFRA1 (Co-fractionation), GFRA1 (Co-fractionation), GFRA1 (Co-fractionation), GFRA1 (Co-fractionation), GFRA1 (Co-fractionation)

ESM2 similar proteins: A1XQX1, A2ATD1, B2RZ42, D4A6L0, O00451, O08842, O13097, O13156, O13157, O93512, O95156, O95980, P0DJQ9, P15473, P17936, P20959, P21744, P22692, P24854, P47878, P47879, P52796, P56159, P58659, P97785, Q05716, Q17QD6, Q28145, Q28893, Q58CS8, Q5E9X0, Q5RAD6, Q5T848, Q62997, Q6PCX7, Q6PFE7, Q6S5C2, Q7TQ33, Q80UG6, Q8C419

Diamond homologs: O00451, O08842, O13156, O13157, O35118, O60609, O93512, P56159, P97785, Q5E9X0, Q5RAD6, Q62997, Q9EPI2, Q9GZZ7, Q9JJT2

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
GDNF	up-regulates	GFRA1	binding
NRTN	up-regulates	GFRA1	binding
RET	up-regulates	GFRA1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	53
Likely benign	13
Benign	6

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1686971	NM_005264.8(GFRA1):c.1294del (p.Thr432fs)	Pathogenic
1686972	NM_005264.8(GFRA1):c.628G>T (p.Gly210Ter)	Pathogenic
3349352	NM_005264.8(GFRA1):c.792dup (p.Thr265fs)	Pathogenic
1686970	NM_005264.8(GFRA1):c.676C>T (p.Arg226Ter)	Likely pathogenic

SpliceAI

2495 predictions. Top by Δscore:

Variant	Effect	Δscore
10:116125216:CTTA:C	donor_loss	1.0000
10:116125217:TTA:T	donor_loss	1.0000
10:116125218:TACCT:T	donor_loss	1.0000
10:116125219:A:AG	donor_loss	1.0000
10:116125220:C:CA	donor_loss	1.0000
10:116125553:CTCCA:C	acceptor_gain	1.0000
10:116125554:TCCA:T	acceptor_gain	1.0000
10:116125555:CCA:C	acceptor_gain	1.0000
10:116125555:CCAC:C	acceptor_gain	1.0000
10:116125556:CA:C	acceptor_gain	1.0000
10:116125556:CAC:C	acceptor_gain	1.0000
10:116125557:ACTG:A	acceptor_loss	1.0000
10:116125558:C:CC	acceptor_gain	1.0000
10:116125559:T:A	acceptor_loss	1.0000
10:116125561:CAAA:C	acceptor_gain	1.0000
10:116125564:A:AC	acceptor_gain	1.0000
10:116125564:A:C	acceptor_gain	1.0000
10:116269497:GCTTA:G	donor_loss	1.0000
10:116269498:CTTA:C	donor_loss	1.0000
10:116269499:TTA:T	donor_loss	1.0000
10:116269500:TA:T	donor_loss	1.0000
10:116269501:A:AC	donor_gain	1.0000
10:116269501:ACC:A	donor_loss	1.0000
10:116269502:C:CC	donor_gain	1.0000
10:116269502:C:CG	donor_loss	1.0000
10:116269582:ATTTC:A	acceptor_gain	1.0000
10:116269583:TTTC:T	acceptor_gain	1.0000
10:116269584:TTC:T	acceptor_gain	1.0000
10:116269585:TC:T	acceptor_gain	1.0000
10:116269586:CC:C	acceptor_gain	1.0000

AlphaMissense

3063 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:116093742:G:C	C325W	1.000
10:116093778:A:C	C313W	1.000
10:116093780:A:G	C313R	1.000
10:116093836:C:T	G294D	1.000
10:116096655:C:A	G294C	1.000
10:116096655:C:G	G294R	1.000
10:116096680:G:C	C285W	1.000
10:116096682:A:G	C285R	1.000
10:116096734:G:C	C267W	1.000
10:116096735:C:G	C267S	1.000
10:116096736:A:G	C267R	1.000
10:116096736:A:T	C267S	1.000
10:116125223:G:C	C256W	1.000
10:116125224:C:G	C256S	1.000
10:116125224:C:T	C256Y	1.000
10:116125225:A:G	C256R	1.000
10:116125225:A:T	C256S	1.000
10:116125241:G:C	C250W	1.000
10:116125242:C:T	C250Y	1.000
10:116125243:A:G	C250R	1.000
10:116125262:A:C	C243W	1.000
10:116125263:C:G	C243S	1.000
10:116125264:A:G	C243R	1.000
10:116125264:A:T	C243S	1.000
10:116125294:A:G	C233R	1.000
10:116125314:C:G	R226P	1.000
10:116125316:C:A	R225S	1.000
10:116125316:C:G	R225S	1.000
10:116125317:C:G	R225T	1.000
10:116125320:C:G	R224P	1.000

dbSNP variants (sampled 300 via entrez): RS1000000765 (10:116112611 C>T), RS1000005589 (10:116191835 T>C), RS1000007780 (10:116245171 C>G), RS1000010167 (10:116229018 T>C,G), RS1000018147 (10:116134148 C>T), RS1000035230 (10:116174003 C>T), RS1000042372 (10:116168084 T>C), RS1000045750 (10:116230240 C>A), RS1000081548 (10:116199438 C>T), RS1000098074 (10:116215710 C>T), RS1000107329 (10:116261940 A>G), RS1000109770 (10:116095740 C>T), RS1000119252 (10:116093310 G>T), RS1000125996 (10:116147323 G>A,C), RS1000132552 (10:116075344 C>T)

Disease associations

OMIM: gene MIM:601496 | disease phenotypes: MIM:619887, MIM:142623

GenCC curated gene-disease

Disease	Classification	Inheritance
renal hypodysplasia/aplasia 4	Strong	Autosomal recessive

Mondo (3): renal hypodysplasia/aplasia 4 (MONDO:0030822), Hirschsprung disease, susceptibility to, 1 (MONDO:0007723), Hirschsprung disease (MONDO:0018309)

Orphanet (1): Hirschsprung disease (Orphanet:388)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000104	Renal agenesis
HP:0000175	Cleft palate
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000457	Depressed nasal ridge
HP:0001562	Oligohydramnios
HP:0001563	Fetal polyuria
HP:0001958	Nonketotic hypoglycemia
HP:0002009	Potter facies
HP:0002089	Pulmonary hypoplasia
HP:0002242	Abnormal intestine morphology
HP:0002575	Tracheoesophageal fistula
HP:0002878	Respiratory failure
HP:0003577	Congenital onset
HP:0005107	Abnormal sacrum morphology
HP:0010497	Sirenomelia
HP:0010958	Bilateral renal agenesis
HP:0025700	Anhydramnios
HP:0030680	Abnormal cardiovascular system morphology
HP:0034198	Second trimester onset
HP:0100335	Non-midline cleft of the upper lip
HP:0100589	Urogenital fistula

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002949_12	Epilepsy and lamotrigine-induced maculopapular eruptions	1.000000e-07
GCST003329_3	Response to anti-TNF therapy in rheumatoid arthritis	8.000000e-07
GCST003329_5	Response to anti-TNF therapy in rheumatoid arthritis	5.000000e-06
GCST004900_1	Migraine without aura	1.000000e-07
GCST005851_22	Delirium	3.000000e-06
GCST006585_694	Blood protein levels	8.000000e-23
GCST010725_100	Malaria	3.000000e-06
GCST010725_45	Malaria	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:1001253	maculopapular eruption
EFO:0004653	response to TNF antagonist

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3833481 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — GDNF Family Receptor (GFR)

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
[125I]GDNF (rat)		11.52	pKd

ChEMBL bioactivities

3 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.60	IC50	250	nM	CHEMBL5596770
6.00	IC50	1000	nM	CHEMBL5597875
5.68	IC50	2100	nM	CHEMBL5591042

PubChem BioAssay actives

3 with measured affinity, of 32 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2R)-2-[[2-[3-[[(2R)-5-(2-anilinopyrimidin-5-yl)-2,3-dihydro-1H-inden-2-yl]oxy]phenyl]acetyl]amino]-2-cyclohexyl-N-methylacetamide	2120385: Inhibition of GFRalpha1 (unknown origin)	ic50	0.2500	uM
(2R)-2-[[2-[3-[[(1S)-5-(5-anilinopyrimidin-2-yl)-2,3-dihydro-1H-inden-1-yl]oxy]phenyl]acetyl]amino]-2-cyclohexylacetamide	2120385: Inhibition of GFRalpha1 (unknown origin)	ic50	1.0000	uM
(2R)-2-[[2-[3-[[(1S)-5-(2-anilinopyrimidin-5-yl)-2,3-dihydro-1H-inden-1-yl]oxy]phenyl]acetyl]amino]-2-cyclohexyl-N-methylacetamide	2120385: Inhibition of GFRalpha1 (unknown origin)	ic50	2.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	8
trichostatin A	increases expression, decreases expression, affects cotreatment	3
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression, increases expression	3
bisphenol A	affects cotreatment, increases methylation, increases expression	2
entinostat	affects cotreatment, decreases expression	2
belinostat	decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Arsenic	affects expression, affects methylation	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	affects cotreatment, increases expression	2
Cyclosporine	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
didecyldimethylammonium	decreases expression	1
potassium chromate(VI)	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
aflatoxin B2	decreases methylation	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5585984	Binding	Inhibition of GFRalpha1 (unknown origin)	Discovery of the first selective, small-molecule GFRα2/3 inhibitors through DNA-encoded library technology. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT03660176	PHASE3	UNKNOWN	Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung’s Disease
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT01985646	EARLY_PHASE1	COMPLETED	A Trial on Conservative Treatment for Infants’ Hirschsprung Disease
NCT00478712	Not specified	RECRUITING	Hirschsprung Disease Genetic Study
NCT01515501	Not specified	COMPLETED	Endoscopic Mucosal Resection for the Diagnosis of a-Ganglionosis, a Controlled Prospective Trial (EDGE Trial)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01927809	Not specified	UNKNOWN	Genetic Mosaicism in Hirschsprung’s Disease
NCT02193685	Not specified	UNKNOWN	Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease
NCT02216994	Not specified	UNKNOWN	A New Scoring System Improves Diagnostic Accuracy of Intestinal Dysganglionosis –a Prospective Study
NCT02296008	Not specified	COMPLETED	3D High Resolution Anorectal Manometry in Children After Surgery for Anorectal Disorders
NCT02776176	Not specified	UNKNOWN	Enhanced Recovery After Surgery In Hirschsprung Disease
NCT02857205	Not specified	COMPLETED	MICROPRUNG : Intestinal Microbiota Analysis in Patients With or Without Hirschsprung’s Associated EnteroColitis
NCT03269812	Not specified	UNKNOWN	Laparoscopic Assisted Pull-through Versus Other Surgical Procedures for Treatment of Hirschsprung Disease
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT04020939	Not specified	COMPLETED	The Role of Indocyanine Green Angiography Fluorescence on Intestinal Resections in Pediatric Surgery.
NCT04106947	Not specified	UNKNOWN	Transition of Care for Patients With Hirschsprung Disease and Anorectal Malformations
NCT04149093	Not specified	UNKNOWN	The Association Between Calretinin and the Function of Ganglion Cells in Hirschsprung Disease
NCT04150120	Not specified	COMPLETED	eHealth as an Aid for Facilitating and Supporting Self-management in Families With Long-term Childhood Illness
NCT04213976	Not specified	UNKNOWN	Ostomy in Continuity or Conventional Ileostomy: a Retrospective Multicentric Analysis
NCT04476225	Not specified	COMPLETED	Induced Pluripotent Stem Cells for Disease Research
NCT04598841	Not specified	COMPLETED	Nutrition Support for Hirschsprung Disease
NCT04622410	Not specified	RECRUITING	Registry for Hirschsprung Disease of the BELAPS
NCT04624334	Not specified	TERMINATED	Non-invasive Assessment of Colonic Motility
NCT04730128	Not specified	COMPLETED	Translation and Validation of a Disease-specific Questionnaire for Hirschsprung’s Disease in Danish Patients
NCT04837963	Not specified	COMPLETED	Does Hirschsprung Disease Increase the Risk of Febrile Urinary Tract Infection in Children
NCT04957667	Not specified	COMPLETED	Scintigraphic Defecography for Evaluation of Functional Outcome in an Adult Hirschsprung Population
NCT05038345	Not specified	TERMINATED	Hirschsprung Disease Trends in the United States: Analysis of the National Inpatient Sample
NCT05044741	Not specified	COMPLETED	Risk Factors of Perforated HSCR in Neonates
NCT05293353	Not specified	UNKNOWN	Neokare Safety and Tolerability Assessment in Neonates With GI Problems
NCT05307419	Not specified	UNKNOWN	Full Thickness vs. Rectal Suction Biopsy in the Diagnosis of Hirschsprungs Disease
NCT05450991	Not specified	RECRUITING	Long-term Qualitative and Quantitative Outcomes of Children With Hirschsprung’s Disease and Anorectal Malformations
NCT05655845	Not specified	UNKNOWN	Risk Factors for Bowel Dysfunction at Preschool and Early Childhood Age in Children With Hirschsprung Disease
NCT06072976	Not specified	RECRUITING	The Influence of Feeding Source on the Gut Microbiome and Time to Full Feeds in Neonates With Congenital Gastrointestinal Pathologies
NCT06197061	Not specified	UNKNOWN	Comparison of Robot-assisted With Laparoscopic-assisted Modified Soave Procedure for Classical Hirschsprung Disease
NCT06573723	Not specified	RECRUITING	Institutional Registry of Rare Diseases
NCT06590142	Not specified	RECRUITING	Hirschsprung’s Advances; Working Towards Autologous tIssue therapIes
NCT06592534	Not specified	NOT_YET_RECRUITING	Babies With Enterocolitis - A Study of Faecal Calprotectin in Hirschsprung Disease (The BEACH Study)