SPRED1

Summary

SPRED1 (sprouty related EVH1 domain containing 1, HGNC:20249) is a protein-coding gene on chromosome 15q14, encoding Sprouty-related, EVH1 domain-containing protein 1 (Q7Z699). Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a member of the Sprouty family of proteins and is phosphorylated by tyrosine kinase in response to several growth factors. The encoded protein can act as a homodimer or as a heterodimer with SPRED2 to regulate activation of the MAP kinase cascade. Defects in this gene are a cause of neurofibromatosis type 1-like syndrome (NFLS).

Source: NCBI Gene 161742 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Legius syndrome (Definitive, ClinGen)
• GWAS associations: 8
• Clinical variants (ClinVar): 1,235 total — 115 pathogenic, 46 likely-pathogenic
• Phenotypes (HPO): 59
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_152594

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20249
Approved symbol	SPRED1
Name	sprouty related EVH1 domain containing 1
Location	15q14
Locus type	gene with protein product
Status	Approved
Aliases	FLJ33903, PPP1R147, SPRED-1
Ensembl gene	ENSG00000166068
Ensembl biotype	protein_coding
OMIM	609291
Entrez	161742

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000299084, ENST00000561205, ENST00000561317, ENST00000881380, ENST00000881381, ENST00000925370, ENST00000951937, ENST00000951938, ENST00000951939, ENST00000951940

RefSeq mRNA: 1 — MANE Select: NM_152594 NM_152594

CCDS: CCDS32193

Canonical transcript exons

ENST00000299084 — 7 exons

Exon	Start	End
ENSE00001099510	38349422	38349523
ENSE00001099512	38339737	38339895
ENSE00001251369	38351014	38357249
ENSE00002554709	38252836	38253217
ENSE00003505357	38322241	38322409
ENSE00003513959	38299373	38299547
ENSE00003590128	38324763	38324809

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 91.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.4810 / max 162.8225, expressed in 1727 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
145861	15.2264	1711
145862	4.0050	1239
145863	0.2496	106

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	91.70	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.43	gold quality
calcaneal tendon	UBERON:0003701	90.72	gold quality
adrenal tissue	UBERON:0018303	90.53	gold quality
entorhinal cortex	UBERON:0002728	90.29	gold quality
lower lobe of lung	UBERON:0008949	90.22	gold quality
germinal epithelium of ovary	UBERON:0001304	90.15	gold quality
colonic epithelium	UBERON:0000397	89.84	gold quality
epithelial cell of pancreas	CL:0000083	89.78	silver quality
cartilage tissue	UBERON:0002418	89.60	gold quality
Brodmann (1909) area 46	UBERON:0006483	89.50	gold quality
postcentral gyrus	UBERON:0002581	89.35	gold quality
colonic mucosa	UBERON:0000317	89.19	gold quality
corpus callosum	UBERON:0002336	88.97	gold quality
superior frontal gyrus	UBERON:0002661	88.38	gold quality
layer of synovial tissue	UBERON:0007616	88.19	gold quality
parietal lobe	UBERON:0001872	88.12	gold quality
epithelium of mammary gland	UBERON:0003244	88.01	gold quality
mammary duct	UBERON:0001765	87.97	gold quality
nucleus accumbens	UBERON:0001882	87.89	gold quality
temporal lobe	UBERON:0001871	87.87	gold quality
caudate nucleus	UBERON:0001873	87.36	gold quality
putamen	UBERON:0001874	87.20	gold quality
amygdala	UBERON:0001876	86.87	gold quality
caput epididymis	UBERON:0004358	86.53	gold quality
synovial joint	UBERON:0002217	86.39	gold quality
lung	UBERON:0002048	86.25	gold quality
prefrontal cortex	UBERON:0000451	86.21	gold quality
Ammon’s horn	UBERON:0001954	86.21	gold quality
ganglionic eminence	UBERON:0004023	86.08	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.18

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

446 targeting SPRED1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-34A-5P	99.99	71.21	1784

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• We show here that Spred-1 and Spred-2 appear to have distinct mechanisms whereby they induce their effects, as the Sprouty domain of Spred-1 is not required to block MAPK (mitogen-activated protein kinase) activation, while that of Spred-2 is required. (PMID:15683364)
• reduction of Spred expression in hepatocellular carcinoma (HCC) is one of the causes of the acquisition of malignant features. Thus, Spred could be not only a novel prognostic factor but also a new therapeutic target for human HCC (PMID:16652141)
• the apparent occurrence of an unusual TG 3’ splice site in intron 1 is discussed (PMID:17672918)
• Studies show that the clinical features of the reported disorder resemble those of neurofibromatosis type 1 provide the first report of mutations of SPRED1 (SPROUTY)/SPRED family of genes) in human disease. (PMID:17704776)
• enhanced TESK1 activity results in increased stress fibers (via phospho-cofilin), but this can be blocked by elevating Spred1 (PMID:18216281)
• Linkage analysis of SPRED1 excluded its involvement in Cafe-au-lait spots in a patient with a severe form of Noonan syndrome. (PMID:19120036)
• SPRED1 mutations occurred with a prevalence of 0.5% in NF1 patients and in 5% of NF1 patients displaying an NF1-like phenotype. (PMID:19366998)
• Unrelated mild NF1 patients were screened for mutations of the SPRED1-3 and the SPRY1-4 genes. SPRED1 mutations were identified in 6 cases. (PMID:19443465)
• A high SPRED1 mutation detection rate was found in NF1 mutation-negative families with an autosomal dominant phenotype of CALMs (cafe au lait macules)with or without freckling and no other NF1 features. (PMID:19920235)
• The frequency of SPRED1 mutations in patients meeting diagnostic criteria for neurofibromatosis 1 in a hospital-based clinic is 1% to 2%. The likelihood an individual is harboring a SPRED1 mutation increases with age. (PMID:20179001)
• no evidence of leukemogenic SPRED1 involement in juvenile myelomonocytic leukemia (PMID:20339110)
• Sprouty and Spred proteins are negative regulators of the ERK/Elk-1 pathway activation induced not only by growth-factors, but also by reactive lipidic mediators. (PMID:21364986)
• SPRED1 is a likely substrate of SHP2, whose tyrosine dephosphorylation is required to attenuate the inhibitory action of SPRED1 in the Ras/ERK pathway. (PMID:21531714)
• Interaction of FGFRL1 with Spred1 increases the proportion of the receptor at the plasma membrane. (PMID:21616146)
• a cohort of 115 NF1-like patients were screened for SPRED1 gene mutations and six mutations were identified. 12 potentially pathogenic SPRED1 mutations have been detected in 200 such NF1-like patients (PMID:21649642)
• show that neurofibromin, the NF1 gene product, is a Spred1-interacting protein that is necessary for Spred1’s inhibitory function (PMID:22751498)
• Sixty-three mutations and deletions are definitely pathogenic or most likely pathogenic, eight SPRED1 mutations are probably benign rare variants, and 17 SPRED1 missense mutations are still unclassified. Review. (PMID:22753041)
• Based on our current understanding of KIT and SPRED1 protein interactions, we propose that cafe-au-lait macules and freckling may be seen in some patients with piebaldism and does not necessarily represent coexistence of neurofibromatosis type 1. (PMID:23016555)
• Data indicate that upregulated miR-126 upon coxsackievirus B3 (CVB3) infection targets SPRED1, LRP6, and WRCH1 genes, mediating cross-talk between ERK1/2 and Wnt/beta-catenin pathways, and thus promoting viral replication. (PMID:23811937)
• Older age and deletions of IKZF1 and SPRED1 were also associated with poor overall survival of pediatric B-cell precursor acute lymphoblastic leukemia. (PMID:23823658)
• Microrna-126 was transported into recipient human coronary artery endothelial cells by endothelial microparticles and functionally regulated the target protein sprouty-related, EVH1 domain-containing protein 1 (SPRED1). (PMID:24014835)
• SPRED1 seems to play an important role in recruiting neurofibromin to the plasma membrane. (Review) (PMID:24334617)
• SPRED1 decreased expression correlated with genetic features of AML. Our study reveals a new mechanism which contributes to deregulate RAS MAPK pathway in the vast majority of paediatric AMLs (PMID:24469042)
• Antisense-mediated knockdown (anti-miR) revealed that miR-206/21 coordinately promote RAS-ERK signaling and the corresponding cell phenotypes by inhibiting translation of the pathway suppressors RASA1 and SPRED1. (PMID:25202123)
• This study constitutes the first report from Japan of Legius syndrome occurring in siblings. Mutation analysis showed a mutation of c.349C>T resulting in p.Arg117* in exon 4. (PMID:25981987)
• Cosuppression of Sprouty and Sprouty-related negative regulators of FGF signalling in prostate cancer (PMID:26075267)
• Data suggest SPRED1 EVH1 domain interacts with NF1 GRD domain [N-term. 16AA/C-term. 20AA of GTPase-activating protein-related domain]; SPRED1 EVH1 and NF1 GRD mutations observed in Legius syndrome reduce binding affinity between EVH1/GRD domains. (PMID:26635368)
• Results provide genetic evidence that miR-126, through its target gene Spred-1, plays a critical role in the development of retinal vascular layers. (PMID:27203443)
• The EVH1 domain of Spred1 binds to the noncatalytic portion of the GAP-related domain of neurofibromin. (PMID:27313208)
• PURA may be a potential target of miR-144 and observed downregulation of PURA may be caused by increased expression of miR-144. The other predicted target of miR-144 SPRED1, was found to be downregulated in 69 per cent EC tissues as compared to matched distant non-malignant tissues. (PMID:27748283)
• In one case we identified a nonsense mutation c.46C>T (p.Arg16*) in exon 2 of SPRED1 gene, confirming diagnosis of Legius syndrome. This mutation was reported previously. (PMID:28150585)
• SPRED1 is down-regulated by E2 and negatively correlated to ER status in BC cells. SPRED1 was a new direct target of miR-196a which participated in miR-196a-promoted BC development and was suppressed by ligand-activated ER-alpha signal pathway. (PMID:29685157)
• this study establishes SPRED1 as a major tumor suppressor gene in mucosal melanoma. (PMID:30385465)
• Aberrant methylation statuses of the SPRED1 promoter regions are associated with the downregulation of gene transcription in acute myeloid leukemia. (PMID:30745814)
• These data provide structural insight into the interaction of Spred1 and neurofibromin. (PMID:31401120)
• Simultaneous Detection of NF1, SPRED1, LZTR1, and NF2 Gene Mutations by Targeted NGS in an Italian Cohort of Suspected NF1 Patients. (PMID:32575496)
• Constitutional mismatch repair deficiency is the diagnosis in 0.41% of pathogenic NF1/SPRED1 variant negative children suspected of sporadic neurofibromatosis type 1. (PMID:32773772)
• A Study on the Expression of SPRED1 and PBRM1 (Baf180) and their Clinical Significances in Patients with Gastric Cancer. (PMID:33073945)
• Moyamoya syndrome in a child with Legius syndrome: Introducing a cerebral vasculopathy to the SPRED1 phenotype? (PMID:33078527)
• SPRED1 deletion confers resistance to MAPK inhibition in melanoma. (PMID:33306107)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	spred1	ENSDARG00000041449
mus_musculus	Spred1	ENSMUSG00000027351
rattus_norvegicus	Spred1	ENSRNOG00000070996
drosophila_melanogaster	ena	FBGN0000578
drosophila_melanogaster	Spred	FBGN0020767
caenorhabditis_elegans		WBGENE00006770

Paralogs (5): VASP (ENSG00000125753), ENAH (ENSG00000154380), SPRED3 (ENSG00000188766), EVL (ENSG00000196405), SPRED2 (ENSG00000198369)

Protein

Protein identifiers

Sprouty-related, EVH1 domain-containing protein 1 — Q7Z699 (reviewed: Q7Z699)

All UniProt accessions (2): H0YMN8, Q7Z699

UniProt curated annotations — full annotation on UniProt →

Function. Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase. Negatively regulates hematopoiesis of bone marrow. Inhibits fibroblast growth factor (FGF)-induced retinal lens fiber differentiation, probably by inhibiting FGF-mediated phosphorylation of ERK1/2. Attenuates actin stress fiber formation via inhibition of TESK1-mediated phosphorylation of cofilin. Inhibits TGFB-induced epithelial-to-mesenchymal transition in lens epithelial cells.

Subunit / interactions. Homodimer and heterodimer. Able to interact with SPRED2 to form heterodimers. Interacts (via C-terminus) with TAOK1/MARKK (via C-terminus); the interaction does not affect TAOK1 kinase activity. Interacts (via C-terminus) with TESK1 (via C-terminus); the interaction inhibits TESK1 kinase activity. Interacts with CAV1. Interacts with RAS. Interacts with palmitoyltransferase ZDHHC17/HIP14; the interaction leads to palmitoylation of SPRED1.

Subcellular location. Cell membrane. Membrane. Caveola. Nucleus.

Tissue specificity. Weakly expressed in embryonic cell line HEK293.

Post-translational modifications. Palmitoylated by ZDHHC17/HIP14. Phosphorylated on tyrosine. Ubiquitinated.

Disease relevance. Legius syndrome (LGSS) [MIM:611431] An autosomal dominant syndrome characterized mainly by cafe-au-lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1, axillary freckling, and macrocephaly. Additional clinical manifestations include Noonan-like facial dysmorphism, lipomas, learning disabilities, and features of attention deficit-hyperactivity disorder. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_689807* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000697	WH1/EVH1_dom	Domain
IPR007875	Sprouty	Family
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR023337	KBD	Domain
IPR041937	SPRE_EVH1	Domain

Pfam: PF00568, PF05210

UniProt features (27 total): strand 9, modified residue 4, domain 3, sequence variant 2, helix 2, region of interest 2, initiator methionine 1, chain 1, sequence conflict 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3SYX	X-RAY DIFFRACTION	2.45
6V6F	X-RAY DIFFRACTION	2.54
6V65	X-RAY DIFFRACTION	2.76

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z699-F1	63.67	0.21

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 (4): 238, 308, 2, 224

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-5658442	Regulation of RAS by GAPs
R-HSA-5658623	FGFRL1 modulation of FGFR1 signaling
R-HSA-6802953	RAS signaling downstream of NF1 loss-of-function variants
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-190236	Signaling by FGFR
R-HSA-5654736	Signaling by FGFR1
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-6802957	Oncogenic MAPK signaling
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 657 (showing top): AGGAAGC_MIR5163P, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, AP1_01, GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_DNA_DAMAGE_RESPONSE_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, TGCGCANK_UNKNOWN, GOBP_CORONARY_VASCULATURE_DEVELOPMENT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_NEGATIVE_REGULATION_OF_BLOOD_VESSEL_ENDOTHELIAL_CELL_MIGRATION, REACTOME_SIGNALING_BY_FGFR, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_CELL_MIGRATION_INVOLVED_IN_SPROUTING_ANGIOGENESIS, chr15q14

GO Biological Process (13): negative regulation of epithelial to mesenchymal transition (GO:0010719), negative regulation of angiogenesis (GO:0016525), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), regulation of MAPK cascade (GO:0043408), negative regulation of MAPK cascade (GO:0043409), positive regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043517), vasculogenesis involved in coronary vascular morphogenesis (GO:0060979), negative regulation of ERK1 and ERK2 cascade (GO:0070373), negative regulation of cell migration involved in sprouting angiogenesis (GO:0090051), negative regulation of intracellular signal transduction (GO:1902532), negative regulation of lens fiber cell differentiation (GO:1902747), multicellular organism development (GO:0007275), regulation of signal transduction (GO:0009966)

GO Molecular Function (5): stem cell factor receptor binding (GO:0005173), protein kinase binding (GO:0019901), phosphatase binding (GO:0019902), protein serine/threonine kinase inhibitor activity (GO:0030291), protein binding (GO:0005515)

GO Cellular Component (8): nucleoplasm (GO:0005654), cytosol (GO:0005829), plasma membrane (GO:0005886), caveola (GO:0005901), nucleus (GO:0005634), cytoplasm (GO:0005737), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Signal Transduction	2
RAF/MAP kinase cascade	1
Signaling by FGFR1	1
Oncogenic MAPK signaling	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by FGFR	1
Disease	1
MAPK1/MAPK3 signaling	1
MAPK family signaling cascades	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
negative regulation of multicellular organismal process	2
MAPK cascade	2
regulation of intracellular signal transduction	2
cytoplasm	2
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
regulation of MAPK cascade	1
negative regulation of intracellular signal transduction	1
DNA damage response, signal transduction by p53 class mediator	1
regulation of DNA damage response, signal transduction by p53 class mediator	1
positive regulation of signal transduction by p53 class mediator	1
vasculogenesis	1
coronary vasculature morphogenesis	1
negative regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
cell migration involved in sprouting angiogenesis	1
negative regulation of blood vessel endothelial cell migration	1
regulation of cell migration involved in sprouting angiogenesis	1
negative regulation of signal transduction	1
intracellular signal transduction	1
negative regulation of epithelial cell differentiation	1
lens fiber cell differentiation	1
regulation of lens fiber cell differentiation	1
multicellular organismal process	1
anatomical structure development	1
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
cytokine receptor binding	1
kinase binding	1

Protein interactions and networks

STRING

1213 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPRED1	NF1	P21359	946
SPRED1	EGFL7	Q9UHF1	808
SPRED1	PIK3R2	O00459	805
SPRED1	KIT	P10721	744
SPRED1	RAF1	P04049	699
SPRED1	CRTC1	Q6UUV9	671
SPRED1	NRAS	P01111	642
SPRED1	KRAS	P01116	639
SPRED1	SHOC2	Q9UQ13	632
SPRED1	SOS1	Q07889	596
SPRED1	BRAF	P15056	594
SPRED1	RASA1	P20936	592
SPRED1	CREB1	P16220	537
SPRED1	CAV1	Q03135	520
SPRED1	MAP2K2	P36507	519

IntAct

1469 interactions, top by confidence:

A	B	Type	Score
NCALD	SPRED1	psi-mi:“MI:0915”(physical association)	0.720
IL16	SPRED1	psi-mi:“MI:0915”(physical association)	0.720
SPRED1	HPCAL4	psi-mi:“MI:0915”(physical association)	0.720
CREB5	SPRED1	psi-mi:“MI:0915”(physical association)	0.720
SPRED1	PIH1D2	psi-mi:“MI:0915”(physical association)	0.720
CDKN1A	SPRED1	psi-mi:“MI:0915”(physical association)	0.670
SPRED1	NF1	psi-mi:“MI:0915”(physical association)	0.570
NF1	SPRED1	psi-mi:“MI:0915”(physical association)	0.570
SPRED1	NF1	psi-mi:“MI:0914”(association)	0.570
SPRED1	BLZF1	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	ZNF408	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	ZNF655	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	ZNF417	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	FAM90A1	psi-mi:“MI:0915”(physical association)	0.560
RIN1	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
AQP1	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	BEX2	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	CCDC185	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	SPG21	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	MAB21L3	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	HEXIM2	psi-mi:“MI:0915”(physical association)	0.560
SPRED1	ZNF587	psi-mi:“MI:0915”(physical association)	0.560
VSNL1	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
C2orf68	SPRED1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (62): SPRED1 (Two-hybrid), SPRED1 (Affinity Capture-Western), ZDHHC17 (Affinity Capture-Western), SPRED1 (Synthetic Lethality), SPRED1 (Proximity Label-MS), SPRED1 (Affinity Capture-RNA), NF1 (Affinity Capture-Western), NF1 (Reconstituted Complex), NF1 (Co-fractionation), NF1 (Two-hybrid), NF1 (Affinity Capture-Western), SPRED1 (Two-hybrid), SPRED1 (Two-hybrid), SPRED1 (Two-hybrid), SPRED1 (Two-hybrid)

ESM2 similar proteins: A2RT67, A2RV80, E1C3P4, O94967, P48553, P51593, Q0VEJ0, Q3UVG3, Q3ZT31, Q4R8N2, Q5FVM6, Q5KSL6, Q5R903, Q5R989, Q5RAQ5, Q5RBY5, Q5RCP7, Q5TKA1, Q5ZKN3, Q641K1, Q658Y4, Q6AXN4, Q6IC98, Q70Z35, Q7TMY8, Q7Z699, Q7Z6Z7, Q80TA6, Q8BHY8, Q8C561, Q8C735, Q8CB19, Q8CB44, Q8CGF6, Q8N3S3, Q8TAP6, Q8VCB1, Q8VDD9, Q8WWQ0, Q91W96

Diamond homologs: A2VDU1, A5D992, O43597, O43609, O43610, O44783, Q08E39, Q1L0X2, Q2MJR0, Q2PFN5, Q3C2P8, Q3UUD2, Q5R959, Q5RDN2, Q5Y171, Q6NYK3, Q6P6N5, Q7Z698, Q7Z699, Q866R9, Q924S7, Q924S8, Q9C004, Q9PTL1, Q9PTL2, Q9QXV8, Q9QXV9, Q9WTP2, Q66JG9, P50551, O08719, P50552, P70429, P70460, Q03173, Q2TA49, Q64GL0, Q8N8S7, Q8T4F7, Q5R896

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
EGFR	“down-regulates activity”	SPRED1	phosphorylation
SPRED1	“up-regulates quantity”	NF1	binding
hsa-mir-126-5p	“down-regulates quantity by repression”	SPRED1	“post transcriptional regulation”
hsa-mir-132-3p	“down-regulates quantity by repression”	SPRED1	“post transcriptional regulation”
hsa-miR-31-5p	“down-regulates quantity by repression”	SPRED1	“post transcriptional regulation”
has-mir-126-3p	“down-regulates quantity by repression”	SPRED1	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1235 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	115
Likely pathogenic	46
Uncertain significance	622
Likely benign	299
Benign	45

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068067	NM_152594.3(SPRED1):c.207+1G>T	Pathogenic
1068652	NM_152594.3(SPRED1):c.1232_1241del (p.Ser411fs)	Pathogenic
1068945	NM_152594.3(SPRED1):c.794dup (p.Asp265fs)	Pathogenic
1072751	NM_152594.3(SPRED1):c.385G>T (p.Glu129Ter)	Pathogenic
1073447	NC_000015.9:g.(?38545367)(38545438_?)del	Pathogenic
1073448	NC_000015.9:g.(?38591568)(38643870_?)del	Pathogenic
1073547	NM_152594.3(SPRED1):c.841C>T (p.Gln281Ter)	Pathogenic
1075013	NM_152594.3(SPRED1):c.783C>A (p.Tyr261Ter)	Pathogenic
1300146	NM_152594.3(SPRED1):c.148C>T (p.Gln50Ter)	Pathogenic
1334196	NM_152594.3(SPRED1):c.1044_1045del (p.Arg349fs)	Pathogenic
1334310	NM_152594.3(SPRED1):c.229A>T (p.Lys77Ter)	Pathogenic
1386579	NM_152594.3(SPRED1):c.40del (p.Tyr14fs)	Pathogenic
1389357	NM_152594.3(SPRED1):c.1175C>A (p.Ser392Ter)	Pathogenic
1391856	NM_152594.3(SPRED1):c.1011C>A (p.Tyr337Ter)	Pathogenic
1401830	NM_152594.3(SPRED1):c.1132_1139del (p.His378fs)	Pathogenic
1415230	NM_152594.3(SPRED1):c.692del (p.Pro230_Leu231insTer)	Pathogenic
1420112	NM_152594.3(SPRED1):c.305del (p.Thr102fs)	Pathogenic
1451597	NM_152594.3(SPRED1):c.613C>T (p.Gln205Ter)	Pathogenic
1452330	NM_152594.3(SPRED1):c.1237_1238del (p.Ile413fs)	Pathogenic
1457112	NC_000015.9:g.(?38545387)(38643865_?)del	Pathogenic
1693579	NM_152594.3(SPRED1):c.1273del (p.Met425fs)	Pathogenic
1699114	NM_152594.3(SPRED1):c.475del (p.Gln159fs)	Pathogenic
1761178	NM_152594.3(SPRED1):c.790delinsAA (p.Pro264fs)	Pathogenic
1804995	NM_152594.3(SPRED1):c.950C>G (p.Ser317Ter)	Pathogenic
1809	NM_152594.3(SPRED1):c.349C>T (p.Arg117Ter)	Pathogenic
1810	NM_152594.3(SPRED1):c.70C>T (p.Arg24Ter)	Pathogenic
1811	NM_152594.3(SPRED1):c.423+1G>A	Pathogenic
1812	NM_152594.3(SPRED1):c.643C>T (p.Gln215Ter)	Pathogenic
1813	NM_152594.3(SPRED1):c.190C>T (p.Arg64Ter)	Pathogenic
1814	NM_152594.3(SPRED1):c.637C>T (p.Gln213Ter)	Pathogenic

SpliceAI

1970 predictions. Top by Δscore:

Variant	Effect	Δscore
15:38253216:GA:G	donor_gain	1.0000
15:38253218:G:GG	donor_gain	1.0000
15:38299371:A:AG	acceptor_gain	1.0000
15:38299372:G:GA	acceptor_gain	1.0000
15:38299372:GTA:G	acceptor_gain	1.0000
15:38299372:GTAAT:G	acceptor_gain	1.0000
15:38299491:G:GT	donor_gain	1.0000
15:38322237:TCAGG:T	acceptor_loss	1.0000
15:38322238:CAGGT:C	acceptor_loss	1.0000
15:38322239:AGGT:A	acceptor_gain	1.0000
15:38322240:G:A	acceptor_loss	1.0000
15:38322240:GGT:G	acceptor_gain	1.0000
15:38322240:GGTG:G	acceptor_gain	1.0000
15:38322408:AG:A	donor_gain	1.0000
15:38322408:AGG:A	donor_loss	1.0000
15:38322409:GG:G	donor_gain	1.0000
15:38322410:G:GG	donor_gain	1.0000
15:38322410:GTAG:G	donor_loss	1.0000
15:38324757:TCTTA:T	acceptor_loss	1.0000
15:38324758:CTTAG:C	acceptor_loss	1.0000
15:38324759:TTAG:T	acceptor_loss	1.0000
15:38324760:TAG:T	acceptor_loss	1.0000
15:38324761:A:AG	acceptor_gain	1.0000
15:38324762:G:GG	acceptor_gain	1.0000
15:38324762:G:GT	acceptor_loss	1.0000
15:38324762:GGAT:G	acceptor_gain	1.0000
15:38324810:G:GG	donor_gain	1.0000
15:38324810:G:T	donor_loss	1.0000
15:38324811:T:A	donor_loss	1.0000
15:38339734:TAG:T	acceptor_loss	1.0000

AlphaMissense

2967 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:38299396:C:A	A19D	1.000
15:38299405:T:C	M22T	1.000
15:38299405:T:G	M22R	1.000
15:38299406:G:A	M22I	1.000
15:38299406:G:C	M22I	1.000
15:38299406:G:T	M22I	1.000
15:38299431:T:A	W31R	1.000
15:38299431:T:C	W31R	1.000
15:38299432:G:C	W31S	1.000
15:38299433:G:C	W31C	1.000
15:38299433:G:T	W31C	1.000
15:38299465:T:A	V42D	1.000
15:38299471:T:A	V44D	1.000
15:38299525:G:A	G62E	1.000
15:38322298:T:C	F89L	1.000
15:38322299:T:C	F89S	1.000
15:38322299:T:G	F89C	1.000
15:38322300:T:A	F89L	1.000
15:38322300:T:G	F89L	1.000
15:38322304:C:G	H91D	1.000
15:38322307:T:A	W92R	1.000
15:38322307:T:C	W92R	1.000
15:38322308:G:C	W92S	1.000
15:38322309:G:C	W92C	1.000
15:38322309:G:T	W92C	1.000
15:38322331:G:C	G100R	1.000
15:38322332:G:A	G100D	1.000
15:38322335:T:A	L101H	1.000
15:38322335:T:C	L101P	1.000
15:38322340:T:C	F103L	1.000

dbSNP variants (sampled 300 via entrez): RS1000012922 (15:38325104 A>G), RS1000047143 (15:38296423 G>C), RS1000086004 (15:38334338 C>T), RS1000125189 (15:38314237 A>G), RS1000149293 (15:38290679 A>G), RS1000156833 (15:38346984 C>T), RS1000156986 (15:38288628 A>T), RS1000175547 (15:38352133 T>G), RS1000236336 (15:38307887 T>C), RS1000259834 (15:38352624 A>G), RS1000266389 (15:38272666 C>T), RS1000284191 (15:38320766 A>C,T), RS1000378056 (15:38278617 T>C), RS1000404665 (15:38285310 A>G), RS1000419176 (15:38335175 C>T)

Disease associations

OMIM: gene MIM:609291 | disease phenotypes: MIM:611431, MIM:162200, MIM:601321, MIM:163950, MIM:218040

GenCC curated gene-disease

Disease	Classification	Inheritance
Legius syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Legius syndrome	Definitive	AD

Mondo (7): Legius syndrome (MONDO:0012669), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), neurofibromatosis type 1 (MONDO:0018975), neurofibromatosis-Noonan syndrome (MONDO:0011035), Noonan syndrome (MONDO:0018997), RASopathy (MONDO:0021060), Costello syndrome (MONDO:0009026)

Orphanet (8): Legius syndrome (Orphanet:137605), Noonan syndrome and Noonan-related syndrome (Orphanet:98733), Neurofibromatosis type 1 (Orphanet:636), Neurofibromatosis-Noonan syndrome (Orphanet:638), Male infertility with spermatogenesis disorder (Orphanet:399775), Noonan syndrome (Orphanet:648), RASopathy (Orphanet:536391), Costello syndrome (Orphanet:3071)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000218	High palate
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000470	Short neck
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000708	Atypical behavior
HP:0000736	Short attention span
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000766	Abnormal sternum morphology
HP:0000767	Pectus excavatum
HP:0000787	Nephrolithiasis
HP:0000957	Cafe-au-lait spot
HP:0000997	Axillary freckling
HP:0001012	Multiple lipomas
HP:0001067	Neurofibroma
HP:0001114	Xanthelasma
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001328	Specific learning disability

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001729_20	Crohn’s disease	4.000000e-09
GCST001971_3	Hypersomnia (HLA-DQB1*06:02 negative)	7.000000e-07
GCST006218_106	Erosive tooth wear (severe vs non-severe)	6.000000e-06
GCST006226_7	Erosive tooth wear (severe vs none or mild)	5.000000e-06
GCST006865_3	Bipolar disorder	4.000000e-06
GCST008362_78	Birth weight	5.000000e-11
GCST008891_16	Cognitive performance (processing speed)	4.000000e-06
GCST009368_57	HDL cholesterol levels x long total sleep time interaction (2df test)	2.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight
EFO:0004363	information processing speed
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D056685	Costello Syndrome	C05.660.207.219; C16.131.077.256; C16.320.188
D009456	Neurofibromatosis 1	C04.557.580.600.580.590.650; C04.700.631.650; C10.562.600.500; C10.574.500.549.400; C10.668.829.675; C16.320.400.560.400; C16.320.700.633.650
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690
C548032	Legius syndrome (supp.)
C537393	Neurofibromatosis-Noonan syndrome (supp.)
C537846	Noonan like syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation, affects cotreatment, decreases expression	6
Benzo(a)pyrene	decreases expression, increases expression	4
Tetrachlorodibenzodioxin	affects expression, increases expression	3
Aflatoxin B1	affects expression, decreases methylation, increases expression	3
bisphenol A	decreases methylation, increases expression, affects cotreatment	2
trichostatin A	affects cotreatment, decreases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Estradiol	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
sulforaphane	increases expression	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, increases reaction	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
torcetrapib	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Cadmium	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00169611	PHASE4	COMPLETED	NF1-Attention: Study of Children With Neurofibromatosis Type 1 Treated by Methylphenidate
NCT03975829	PHASE4	RECRUITING	Pediatric Long-Term Follow-up and Rollover Study
NCT02471339	PHASE3	COMPLETED	Acceptance and Commitment Training for Adolescents and Young Adults With Neurofibromatosis Type 1, Plexiform Neurofibromas, and Chronic Pain
NCT03871257	PHASE3	ACTIVE_NOT_RECRUITING	A Study of the Drugs Selumetinib Versus Carboplatin/Vincristine in Patients With Neurofibromatosis and Low-Grade Glioma
NCT04461886	PHASE3	TERMINATED	A Long-term Study of NPC-12G Gel in Neurofibromatosis Type I
NCT04924608	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Selumetinib in Adults With NF1 Who Have Symptomatic, Inoperable Plexiform Neurofibromas
NCT05913037	PHASE3	ACTIVE_NOT_RECRUITING	FCN-159 in Adult Patients With Symptomatic, Inoperable Neurofibromatosis Type 1-Related Plexiform Neurofibromas
NCT00021541	PHASE2	COMPLETED	R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
NCT00030264	PHASE2	COMPLETED	Combination Chemotherapy in Treating Patients With Neurofibromatosis and Progressive Plexiform Neurofibromas
NCT00076102	PHASE2	COMPLETED	Pirfenidone in Children and Young Adults With Neurofibromatosis Type I and Progressive Plexiform Neurofibromas
NCT00304083	PHASE2	COMPLETED	Combination Chemotherapy in Treating Patients With Stage III or Stage IV Malignant Peripheral Nerve Sheath Tumors
NCT00326872	PHASE2	TERMINATED	AZD2171 in Treating Patients With Neurofibromatosis Type 1 and Plexiform Neurofibroma and/or Neurofibroma Near the Spine
NCT00589784	PHASE2	COMPLETED	Phase II Trial of Sunitinib (SU011248) in Patients With Recurrent or Inoperable Meningioma
NCT00634270	PHASE2	COMPLETED	A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas
NCT00754780	PHASE2	COMPLETED	Clinical Trial of Pirfenidone in Adult Patients With Neurofibromatosis 1
NCT00846430	PHASE2	COMPLETED	Medical Treatment of High-Risk Neurofibromas
NCT00853580	PHASE2	COMPLETED	A Randomized Placebo-Controlled Study of Lovastatin in Children With Neurofibromatosis Type 1
NCT01125046	PHASE2	COMPLETED	Bevacizumab in Treating Patients With Recurrent or Progressive Meningiomas
NCT01402817	PHASE2	TERMINATED	Study of Sutent®/Sunitinib (SU11248) in Subjects With NF-1 Plexiform Neurofibromas
NCT01412892	PHASE2	COMPLETED	Use of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas
NCT01553149	PHASE2	COMPLETED	Low-Dose or High-Dose Lenalidomide in Treating Younger Patients With Recurrent, Refractory, or Progressive Pilocytic Astrocytoma or Optic Pathway Glioma
NCT01673009	PHASE2	COMPLETED	Phase II Study of Gleevec/Imatinib Mesylate (STI-571, NCS 716051) in Neurofibromatosis (NF1) Patients With Plexiform Neurofibromas
NCT01968590	PHASE2	TERMINATED	Vitamin D Supplementation for Adults With Neurofibromatosis Type 1 (NF1)
NCT02096471	PHASE2	COMPLETED	MEK Inhibitor PD-0325901 Trial in Adolescents and Adults With NF1
NCT02101736	PHASE2	COMPLETED	Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 in Children and Adults
NCT02332902	PHASE2	COMPLETED	Everolimus for Treatment of Disfiguring Cutaneous Lesions in Neurofibromatosis1 CRAD001CUS232T
NCT02407405	PHASE2	ACTIVE_NOT_RECRUITING	MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas
NCT02728388	PHASE2	RECRUITING	Photodynamic Therapy for Benign Dermal Neurofibromas- Phase II
NCT02839720	PHASE2	COMPLETED	Selumetinib in Treating Patients With Neurofibromatosis Type 1 and Cutaneous Neurofibroma
NCT02964884	PHASE2	ACTIVE_NOT_RECRUITING	Interventions for Reading Disabilities in NF1
NCT03090971	PHASE2	COMPLETED	Use of Topical Liquid Diclofenac Following Laser Microporation of Cutaneous Neurofibromas in Patients With NF1
NCT03109301	PHASE2	WITHDRAWN	Mitogen Activated Protein Kinase Kinase (MEK1/2) Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in People With Neurofibromatosis Type 1 (NF1) Mutated Gastrointestinal Stromal Tumors (GIST)
NCT03190915	PHASE2	ACTIVE_NOT_RECRUITING	Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia
NCT03231306	PHASE2	COMPLETED	Phase II Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas
NCT03433183	PHASE2	COMPLETED	SARC031: MEK Inhibitor Selumetinib (AZD6244) in Combination With the mTOR Inhibitor Sirolimus for Patients With Malignant Peripheral Nerve Sheath Tumors
NCT03741101	PHASE2	UNKNOWN	Treatment of NF1-related Plexiform Neurofibroma With Trametinib
NCT03962543	PHASE2	ACTIVE_NOT_RECRUITING	MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas
NCT04435665	PHASE2	COMPLETED	NFX-179 Topical Gel Treatment in Adults With Neurofibromatosis 1 (NF1) and Cutaneous Neurofibromas (cNF)
NCT04481035	PHASE2	COMPLETED	Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1
NCT04481048	PHASE2	ACTIVE_NOT_RECRUITING	Antioxidant Therapy With N-acetylcysteine for Children With Neurofibromatosis Type 1