SPRED2

Summary

SPRED2 (sprouty related EVH1 domain containing 2, HGNC:17722) is a protein-coding gene on chromosome 2p14, encoding Sprouty-related, EVH1 domain-containing protein 2 (Q7Z698). Negatively regulates Ras signaling pathways and downstream activation of MAP kinases.

SPRED2 is a member of the Sprouty (see SPRY1; MIM 602465)/SPRED family of proteins that regulate growth factor-induced activation of the MAP kinase cascade (see MAPK1; MIM 176948) (Nonami et al., 2004 [PubMed 15465815]).

Source: NCBI Gene 200734 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome 14 (Strong, GenCC)
• GWAS associations: 51
• Clinical variants (ClinVar): 96 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 107
• MANE Select transcript: NM_181784

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17722
Approved symbol	SPRED2
Name	sprouty related EVH1 domain containing 2
Location	2p14
Locus type	gene with protein product
Status	Approved
Aliases	Spred-2, FLJ21897, FLJ31917
Ensembl gene	ENSG00000198369
Ensembl biotype	protein_coding
OMIM	609292
Entrez	200734

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 nonsense_mediated_decay

ENST00000356388, ENST00000421087, ENST00000426832, ENST00000427238, ENST00000440972, ENST00000443619, ENST00000452315, ENST00000474228, ENST00000931351

RefSeq mRNA: 2 — MANE Select: NM_181784 NM_001128210, NM_181784

CCDS: CCDS33211, CCDS46308

Canonical transcript exons

ENST00000356388 — 6 exons

Exon	Start	End
ENSE00001656347	65431962	65432599
ENSE00001819105	65310851	65314169
ENSE00003508229	65316734	65316883
ENSE00003532057	65344719	65344896
ENSE00003620795	65334605	65334773
ENSE00003667333	65331987	65332051

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 90.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.5030 / max 407.0484, expressed in 1812 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28814	23.0216	1800
28815	5.7673	1525
28812	1.2772	751
28817	0.9142	541
28809	0.8081	342
28816	0.5577	295
28813	0.4081	167
28808	0.3164	147
28807	0.2788	128
28810	0.1281	51

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	90.51	gold quality
mucosa of sigmoid colon	UBERON:0004993	89.72	gold quality
ventricular zone	UBERON:0003053	89.71	gold quality
colonic mucosa	UBERON:0000317	89.11	gold quality
cartilage tissue	UBERON:0002418	88.90	gold quality
colonic epithelium	UBERON:0000397	88.13	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.85	gold quality
postcentral gyrus	UBERON:0002581	87.83	gold quality
omental fat pad	UBERON:0010414	87.81	gold quality
prefrontal cortex	UBERON:0000451	87.80	gold quality
peritoneum	UBERON:0002358	87.74	gold quality
superior frontal gyrus	UBERON:0002661	87.73	gold quality
adipose tissue of abdominal region	UBERON:0007808	87.44	gold quality
Brodmann (1909) area 46	UBERON:0006483	86.94	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	86.90	gold quality
ascending aorta	UBERON:0001496	86.74	gold quality
thoracic aorta	UBERON:0001515	86.68	gold quality
cingulate cortex	UBERON:0003027	86.66	gold quality
ganglionic eminence	UBERON:0004023	86.64	gold quality
anterior cingulate cortex	UBERON:0009835	86.57	gold quality
right lung	UBERON:0002167	86.36	gold quality
descending thoracic aorta	UBERON:0002345	86.36	gold quality
neocortex	UBERON:0001950	86.24	gold quality
rectum	UBERON:0001052	86.15	gold quality
frontal cortex	UBERON:0001870	86.13	gold quality
right frontal lobe	UBERON:0002810	85.99	gold quality
tibial nerve	UBERON:0001323	85.92	gold quality
middle temporal gyrus	UBERON:0002771	85.70	gold quality
parotid gland	UBERON:0001831	85.67	gold quality
subcutaneous adipose tissue	UBERON:0002190	85.57	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.25

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

162 targeting SPRED2, 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-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-9-3P	99.96	70.88	2068

Literature-anchored findings (GeneRIF, showing 28)

• NMR assignment of the human Spred2 EVH1 domain (PMID:15213456)
• Spred-2 was found to be strongly expressed in glandular epithelia and, at the subcellular level, its immunoreactivity was associated with secretory vesicles. It becomes most likely that Spred-2 is involved in the regulation of secretory pathways (PMID:15580519)
• 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)
• Loss of Spred-2 inhibits bone growth in transgenic mice by inhibiting chondrocyte differentiation through up-regulation of the MAPK signaling pathway. (PMID:15946934)
• 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)
• These results suggest a role for Spred-2 tyrosine phosphorylation and ubiquitination in controlling Spred-2 expression levels. (PMID:17094949)
• Linkage analysis of SPRED2 excluded its involvement in Cafe-au-lait spots in a patient with a severe form of Noonan syndrome. (PMID:19120036)
• findings suggest a critical function for NBR1 in the regulation of receptor trafficking and provide a mechanism for down-regulation of signaling by Spred2 via NBR1. (PMID:19822672)
• data in the present study suggests that Spred2 is a regulator of TGF-beta1-induced malignance in transformed keratinocytes (PMID:19908229)
• 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)
• the knockdown of Spred2 markedly enhanced tumor growth in vivo. (PMID:21703232)
• Tyrosines 303/343/353 within the Sprouty-related domain of Spred2 are essential for its interaction with the p85 subunit of phosphatidylinositol 3-kinase. (PMID:22305891)
• Data present that galectin-1, ataxin-3 and sprouty-related EVH1 domain-containing protein 2 (SPRED2) may be associated with the progression and development of Down syndrome. (PMID:22777171)
• Downregulation of SPRED2 mRNA is associated with prostate cancer. (PMID:23169297)
• Spred2 was involved in erythroid differentiation of chronic myeloid leukemia cells and participated in imatinib induced erythroid differentiation partly through ERK signaling. (PMID:25688862)
• Cosuppression of Sprouty and Sprouty-related negative regulators of FGF signalling in prostate cancer (PMID:26075267)
• data indicate that Spred2 induces tumor cell death in an autophagy-dependent manner. (PMID:27028858)
• Our findings show that miR-487a, mediated by heat shock factor 1, promotes proliferation and metastasis of Hepatocellular carcinoma (HCC) by PIK3R1 and SPRED2 binding, respectively. Our study provides a rationale for developing miR-487a as a potential prognostic marker or a potential therapeutic target against HCC. (PMID:27827315)
• SPRED2 deficiency impairs autophagy, leading to cardiac dysfunction and life-threatening arrhythmias. (PMID:30771306)
• this study revealed more severe Ischemia-reperfusion injury in the lung grafts transplanted to Spred2-/- recipients (PMID:31446154)
• Spred2 inhibits epithelialmesenchymal transition of colorectal cancer cells by impairing ERK signaling. (PMID:32319644)
• miR-19 Promotes Cell Proliferation, Invasion, Migration, and EMT by Inhibiting SPRED2-mediated Autophagy in Osteosarcoma Cells. (PMID:33023313)
• SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype. (PMID:34626534)
• Autosomal recessive Noonan-like syndrome caused by homozygosity for a previously unreported variant in SPRED2. (PMID:36608738)
• SPRED2: A Novel Regulator of Epithelial-Mesenchymal Transition and Stemness in Hepatocellular Carcinoma Cells. (PMID:36902429)
• SPRED2 promotes autophagy and attenuates inflammatory response in IL-1beta induced osteoarthritis chondrocytes via regulating the p38 MAPK signaling pathway. (PMID:37058811)
• The ribosomal S6 kinase 2 (RSK2)-SPRED2 complex regulates the phosphorylation of RSK substrates and MAPK signaling. (PMID:37149146)
• SPRED2 Is a Novel Regulator of Autophagy in Hepatocellular Carcinoma Cells and Normal Hepatocytes. (PMID:38892460)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	spred2b	ENSDARG00000008372
danio_rerio	spred2a	ENSDARG00000052435
mus_musculus	Spred2	ENSMUSG00000045671
rattus_norvegicus	Spred2	ENSRNOG00000004888
drosophila_melanogaster	ena	FBGN0000578
drosophila_melanogaster	Spred	FBGN0020767
caenorhabditis_elegans		WBGENE00006770

Paralogs (5): VASP (ENSG00000125753), ENAH (ENSG00000154380), SPRED1 (ENSG00000166068), SPRED3 (ENSG00000188766), EVL (ENSG00000196405)

Protein

Protein identifiers

Sprouty-related, EVH1 domain-containing protein 2 — Q7Z698 (reviewed: Q7Z698)

All UniProt accessions (7): A0AAQ5BHY7, C9J623, C9JG63, Q7Z698, H7C065, H7C2T4, H7C3Y6

UniProt curated annotations — full annotation on UniProt →

Function. Negatively regulates Ras signaling pathways and downstream activation of MAP kinases. Recruits and translocates NF1 to the cell membrane, thereby enabling NF1-dependent hydrolysis of active GTP-bound Ras to inactive GDP-bound Ras. Inhibits fibroblast growth factor (FGF)-induced retinal lens fiber differentiation, probably by inhibiting FGF-mediated phosphorylation of ERK1/2. Inhibits TGFB-induced epithelial-to-mesenchymal transition in lens epithelial cells.

Subunit / interactions. Homodimer and heterodimer. Able to interact with SPRED1 to form heterodimers. Interacts with RAS. May interact with ZDHHC13 (via ANK repeats) and ZDHHC17 (via ANK repeats). Interacts with TESK1. Interacts with NF1.

Subcellular location. Cell membrane. Cytoplasmic vesicle. Secretory vesicle membrane. Cytoplasm.

Tissue specificity. Expressed in liver, skin, small intestine, salivary gland and prostate.

Post-translational modifications. Phosphorylated on serine and threonine residues. Phosphorylated on tyrosine. Phosphorylation of Tyr-228 and Tyr-231 are required for ubiquitination. Ubiquitinated; leading to degradation by the proteasome.

Disease relevance. Noonan syndrome 14 (NS14) [MIM:619745] A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. NS14 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7Z698-1	1	yes
Q7Z698-2	2

RefSeq proteins (2): NP_001121682, NP_861449* (*=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 (35 total): mutagenesis site 10, strand 9, domain 3, modified residue 3, sequence variant 2, sequence conflict 2, region of interest 2, chain 1, splice variant 1, helix 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8EQ5	X-RAY DIFFRACTION	1.8
2JP2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z698-F1	68.61	0.32

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 (3): 206, 228, 231

Mutagenesis-validated functional residues (10):

Position	Phenotype
228	reduces ubiquitination and cbl-induced phosphorylation; when associated with f-231.
231	reduces ubiquitination and cbl-induced phosphorylation; when associated with f-228.
240	no effect on phosphorylation or ubiquitination.
251	no effect on phosphorylation or ubiquitination.
264	no effect on phosphorylation or ubiquitination; when associated with f-266.
266	no effect on phosphorylation or ubiquitination; when associated with f-264.
268	no effect on phosphorylation or ubiquitination.
311	no effect on phosphorylation or ubiquitination.
351	no effect on phosphorylation or ubiquitination.
394	no effect on phosphorylation or ubiquitination.

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: 612 (showing top): ATF_B, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, 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, YAGI_AML_WITH_INV_16_TRANSLOCATION, MORF_MSH3, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, chr2p14, REACTOME_SIGNALING_BY_FGFR, MORF_BRCA1, GOZGIT_ESR1_TARGETS_DN, MORF_ATRX, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (9): negative regulation of epithelial to mesenchymal transition (GO:0010719), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), negative regulation of MAPK cascade (GO:0043409), positive regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043517), negative regulation of ERK1 and ERK2 cascade (GO:0070373), 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 (4): stem cell factor receptor binding (GO:0005173), protein kinase binding (GO:0019901), protein serine/threonine kinase inhibitor activity (GO:0030291), protein binding (GO:0005515)

GO Cellular Component (6): cytosol (GO:0005829), plasma membrane (GO:0005886), transport vesicle membrane (GO:0030658), 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	3
negative regulation of multicellular organismal process	2
cytoplasm	2
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	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
MAPK cascade	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
negative regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
negative regulation of signal transduction	1
intracellular signal transduction	1
regulation of 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 serine/threonine kinase activity	1
protein kinase inhibitor activity	1
binding	1
membrane	1
cell periphery	1
transport vesicle	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1

Protein interactions and networks

STRING

1029 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPRED2	SPRY4	Q9C004	683
SPRED2	KIT	P10721	678
SPRED2	NF1	P21359	648
SPRED2	NBR1	Q14596	628
SPRED2	DUSP5	Q16690	555
SPRED2	RAF1	P04049	552
SPRED2	SPRY2	O43597	505
SPRED2	CAV1	Q03135	482
SPRED2	PXK	Q7Z7A4	474
SPRED2	DUSP6	Q16828	462
SPRED2	METTL3	Q86U44	435
SPRED2	BRAF	P15056	431
SPRED2	KITLG	P21583	431
SPRED2	CRTC1	Q6UUV9	424
SPRED2	SPRED1	Q7Z699	414

IntAct

170 interactions, top by confidence:

A	B	Type	Score
SPG21	SPRED2	psi-mi:“MI:0915”(physical association)	0.780
SPRED2	SPG21	psi-mi:“MI:0915”(physical association)	0.780
SPRED2	TOP3B	psi-mi:“MI:0915”(physical association)	0.670
TOP3B	SPRED2	psi-mi:“MI:0915”(physical association)	0.670
SPRED2	RPS6KA3	psi-mi:“MI:0915”(physical association)	0.670
ZDHHC17	SPRED2	psi-mi:“MI:0915”(physical association)	0.630
SPRED2	ZDHHC17	psi-mi:“MI:0915”(physical association)	0.630
SPRED2	ZNF837	psi-mi:“MI:0915”(physical association)	0.560
SPRED2	KRTAP2-4	psi-mi:“MI:0915”(physical association)	0.560
QARS1	SPRED2	psi-mi:“MI:0915”(physical association)	0.560
SPRED2	MDFI	psi-mi:“MI:0915”(physical association)	0.560
MYO15B	SPRED2	psi-mi:“MI:0915”(physical association)	0.560
AQP1	SPRED2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP12-2	SPRED2	psi-mi:“MI:0915”(physical association)	0.560
SPRED2	TSNAX	psi-mi:“MI:0915”(physical association)	0.560
ZNF250	SPRED2	psi-mi:“MI:0915”(physical association)	0.560
NCS1	SPRED2	psi-mi:“MI:0915”(physical association)	0.560
SPRED2	ZNF417	psi-mi:“MI:0915”(physical association)	0.560
LCE1C	SPRED2	psi-mi:“MI:0915”(physical association)	0.560
VSNL1	SPRED2	psi-mi:“MI:0915”(physical association)	0.560
KPRP	SPRED2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (84): SPRED2 (Two-hybrid), SPRED2 (Two-hybrid), SPRED2 (Two-hybrid), SPRED2 (Affinity Capture-Western), PDP1 (Affinity Capture-MS), DPP9 (Affinity Capture-MS), PRTFDC1 (Affinity Capture-MS), RPS6KA3 (Affinity Capture-MS), GNG5 (Affinity Capture-MS), RPS6KA2 (Affinity Capture-MS), STOM (Affinity Capture-MS), GNAQ (Affinity Capture-MS), SPRED2 (Proximity Label-MS), SPRED2 (Protein-RNA), SPRED2 (Affinity Capture-Western)

ESM2 similar proteins: A3KN95, A4IFG4, A4IG66, A7E2I7, A7S641, O77737, P53563, Q07817, Q0IHF1, Q0VCF5, Q17QW2, Q23387, Q2M146, Q3C2P8, Q4QQM5, Q5BLE2, Q5RDN2, Q5U2V9, Q5XJS0, Q5Y171, Q5YLM1, Q5ZLD4, Q626N3, Q66H44, Q68EF0, Q68FE7, Q6DF19, Q6GL42, Q6GQT5, Q6GR21, Q6NRB7, Q6NRI4, Q6NYK3, Q6WQJ1, Q6ZPQ6, Q7Z698, Q810L4, Q8BG50, Q8IW70, Q8N4L1

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, O08719, P50551, P50552, P70429, P70460, Q03173, Q2TA49, Q5R896, Q5TJ65, Q64GL0, Q8N8S7, Q8T4F7

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
hsa-mir-210-3p	“down-regulates quantity by repression”	SPRED2	“post transcriptional regulation”
hsa-miR-31-5p	“down-regulates quantity by repression”	SPRED2	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	73
Likely benign	8
Benign	2

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1209657	NM_181784.3(SPRED2):c.1142_1143del (p.Leu381fs)	Pathogenic
1209658	NM_181784.3(SPRED2):c.299T>C (p.Leu100Pro)	Pathogenic
1210167	NM_181784.3(SPRED2):c.187C>T (p.Arg63Ter)	Pathogenic
3362677	NM_181784.3(SPRED2):c.89G>A (p.Trp30Ter)	Likely pathogenic
4849286	NM_181784.3(SPRED2):c.125_146dup (p.Pro49_Glu50insGlyLeuTer)	Likely pathogenic

SpliceAI

1104 predictions. Top by Δscore:

Variant	Effect	Δscore
2:65314166:TCGG:T	acceptor_gain	1.0000
2:65314167:CGGC:C	acceptor_gain	1.0000
2:65314174:CCCG:C	acceptor_gain	1.0000
2:65314175:CCG:C	acceptor_gain	1.0000
2:65314176:C:CT	acceptor_gain	1.0000
2:65314176:C:T	acceptor_gain	1.0000
2:65314177:G:C	acceptor_gain	1.0000
2:65314177:G:GC	acceptor_gain	1.0000
2:65316728:GCTCA:G	donor_loss	1.0000
2:65316729:CTCAC:C	donor_loss	1.0000
2:65316730:TCACC:T	donor_loss	1.0000
2:65316731:CAC:C	donor_loss	1.0000
2:65316732:A:AT	donor_loss	1.0000
2:65316880:CTGT:C	acceptor_gain	1.0000
2:65316886:G:C	acceptor_gain	1.0000
2:65331981:ACTT:A	donor_loss	1.0000
2:65331982:CTT:C	donor_loss	1.0000
2:65331983:TTA:T	donor_loss	1.0000
2:65331984:TACT:T	donor_loss	1.0000
2:65331985:A:AC	donor_gain	1.0000
2:65331985:A:C	donor_loss	1.0000
2:65331986:C:CA	donor_gain	1.0000
2:65331986:CT:C	donor_gain	1.0000
2:65331986:CTG:C	donor_gain	1.0000
2:65331986:CTGT:C	donor_gain	1.0000
2:65331986:CTGTA:C	donor_gain	1.0000
2:65332047:TGAAC:T	acceptor_gain	1.0000
2:65332048:GAAC:G	acceptor_gain	1.0000
2:65332050:AC:A	acceptor_gain	1.0000
2:65332050:ACC:A	acceptor_loss	1.0000

AlphaMissense

2773 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:65313735:G:C	S341R	1.000
2:65313735:G:T	S341R	1.000
2:65313737:T:G	S341R	1.000
2:65313780:G:C	C326W	1.000
2:65313781:C:G	C326S	1.000
2:65313781:C:T	C326Y	1.000
2:65313782:A:G	C326R	1.000
2:65313782:A:T	C326S	1.000
2:65313810:G:C	F316L	1.000
2:65313810:G:T	F316L	1.000
2:65313811:A:G	F316S	1.000
2:65313812:A:G	F316L	1.000
2:65313822:G:C	C312W	1.000
2:65313823:C:T	C312Y	1.000
2:65313831:G:C	C309W	1.000
2:65313832:C:G	C309S	1.000
2:65313833:A:G	C309R	1.000
2:65313833:A:T	C309S	1.000
2:65334645:A:C	F111L	1.000
2:65334645:A:T	F111L	1.000
2:65334646:A:G	F111S	1.000
2:65334647:A:G	F111L	1.000
2:65334655:G:T	A108D	1.000
2:65334672:G:C	F102L	1.000
2:65334672:G:T	F102L	1.000
2:65334673:A:C	F102C	1.000
2:65334673:A:G	F102S	1.000
2:65334674:A:G	F102L	1.000
2:65334674:A:T	F102I	1.000
2:65334679:A:G	L100P	1.000

dbSNP variants (sampled 300 via entrez): RS1000025134 (2:65380225 C>T), RS1000037614 (2:65337042 A>C,G), RS1000060360 (2:65312024 C>T), RS1000068764 (2:65343539 T>C), RS1000081989 (2:65380440 T>C), RS1000114405 (2:65364268 G>A), RS1000126990 (2:65422505 A>G), RS1000177257 (2:65336837 G>A,C,T), RS1000177489 (2:65380055 C>G), RS1000289818 (2:65422324 G>C), RS1000305345 (2:65386687 C>T), RS1000308168 (2:65356880 G>C), RS1000335166 (2:65375155 G>A), RS1000335542 (2:65308853 C>A,G,T), RS1000337263 (2:65409508 A>G)

Disease associations

OMIM: gene MIM:609292 | disease phenotypes: MIM:163950, MIM:619745

GenCC curated gene-disease

Disease	Classification	Inheritance
Noonan syndrome 14	Strong	Autosomal recessive

Mondo (2): Noonan syndrome (MONDO:0018997), Noonan syndrome 14 (MONDO:0030679)

Orphanet (1): Noonan syndrome (Orphanet:648)

HPO phenotypes

107 total (30 of 107 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000078	Abnormality of the genital system
HP:0000154	Wide mouth
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000391	Thickened helices
HP:0000407	Sensorineural hearing impairment
HP:0000426	Prominent nasal bridge
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000474	Thickened nuchal skin fold
HP:0000476	Cystic hygroma
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000635	Blue irides

GWAS associations

51 associations (top):

Study	Trait	p-value
GCST000987_3	Celiac disease or Rheumatoid arthritis	2.000000e-08
GCST001725_45	Inflammatory bowel disease	2.000000e-08
GCST002318_57	Rheumatoid arthritis	3.000000e-15
GCST002318_58	Rheumatoid arthritis	2.000000e-09
GCST002318_59	Rheumatoid arthritis	1.000000e-08
GCST002434_1	Rheumatoid arthritis	2.000000e-08
GCST003075_108	Cognitive decline rate in late mild cognitive impairment	6.000000e-11
GCST003075_38	Cognitive decline rate in late mild cognitive impairment	2.000000e-10
GCST003123_4	Severe influenza A (H1N1) infection	2.000000e-17
GCST003156_43	Systemic lupus erythematosus	1.000000e-10
GCST003602_11	Inflammatory bowel disease	2.000000e-06
GCST003622_69	Systemic lupus erythematosus	2.000000e-07
GCST003995_11	Tonsillectomy	5.000000e-12
GCST004608_54	Granulocyte percentage of myeloid white cells	3.000000e-09
GCST004610_44	White blood cell count	8.000000e-09
GCST004624_65	Sum eosinophil basophil counts	4.000000e-09
GCST004744_46	Lung adenocarcinoma	3.000000e-06
GCST004748_81	Lung cancer	2.000000e-06
GCST005014_126	Tonsillectomy	5.000000e-12
GCST005568_25	Rheumatoid arthritis (ACPA-positive)	8.000000e-07
GCST005568_28	Rheumatoid arthritis (ACPA-positive)	7.000000e-10
GCST005569_3	Rheumatoid arthritis	3.000000e-08
GCST005580_173	Intraocular pressure	1.000000e-08
GCST005580_301	Intraocular pressure	3.000000e-09
GCST006019_23	Gamma glutamyl transferase levels	4.000000e-08
GCST006048_44	Rheumatoid arthritis (ACPA-positive)	3.000000e-09
GCST006614_115	Total cholesterol levels	6.000000e-10
GCST006959_13	Rheumatoid arthritis	7.000000e-07
GCST006959_145	Rheumatoid arthritis	8.000000e-14
GCST006959_16	Rheumatoid arthritis	6.000000e-10

EFO canonical traits (21, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement
EFO:1001488	influenza A (H1N1)
EFO:0007924	tonsillectomy risk measurement
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0004842	eosinophil count
EFO:0005090	basophil count
EFO:0004695	intraocular pressure measurement
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0004574	total cholesterol measurement
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0006335	systolic blood pressure
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004980	appendicular lean mass
EFO:0007992	basophil percentage of leukocytes
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume
EFO:0004833	neutrophil count
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
Estradiol	decreases expression, increases expression	3
Cadmium Chloride	increases expression, decreases expression, increases abundance	3
Acetaminophen	decreases expression, increases expression	2
Valproic Acid	decreases methylation, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, increases methylation	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
sulforaphane	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	increases expression, affects cotreatment	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	decreases expression, affects cotreatment	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
vanadium pentoxide	affects expression	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
thifluzamide	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	affects expression, affects methylation	1
dorsomorphin	affects cotreatment, decreases expression	1
PCI 5002	increases expression, affects cotreatment	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TQ25	HAP1 SPRED2 (-) 1	Cancer cell line	Male
CVCL_TQ26	HAP1 SPRED2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00452725	PHASE3	COMPLETED	Effect of MAXOMAT ® on the Growth of Small Children to NOONAN’s Syndrome
NCT01529840	PHASE3	COMPLETED	Somatropin Effect on Linear Growth and Final Height in Subjects With Noonan Syndrome
NCT01529944	PHASE3	COMPLETED	Genetic Testing of Noonan Subjects Previously Treated With Norditropin®. An Extension to Trial GHNOO-1658
NCT01927861	PHASE3	COMPLETED	Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome
NCT02713945	PHASE3	COMPLETED	Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
NCT05723835	PHASE3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT00351221	PHASE2	TERMINATED	Research Study Using Recombinant Human Insulin-Like Growth Factor-1/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 for Children With Noonan Syndrome
NCT06555237	PHASE2	RECRUITING	MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies
NCT06668805	PHASE2	RECRUITING	A Study of Vosoritide in Children With Noonan Syndrome With Inadequate Growth During or After Human Growth Hormone Treatment
NCT00960128	Not specified	COMPLETED	Observational Prospective Study on Patients Treated With Norditropin®
NCT02486731	Not specified	COMPLETED	Hormonal Sensitivity in Patients With Noonan and LEOPARD Syndromes
NCT03435627	Not specified	COMPLETED	Post Marketing Surveillance on Long-term Use With Norditropin® (Short Stature Due to Noonan Syndrome)
NCT04395495	Not specified	RECRUITING	RASopathy Biorepository
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04888936	Not specified	RECRUITING	Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
NCT05202210	Not specified	RECRUITING	Constitution of a Biological Collection to Study the Pathophysiology in Noonan Syndrome
NCT05308927	Not specified	ENROLLING_BY_INVITATION	French Registry of Children Treated With Norditropin® for Short Stature Associated With Noonan Syndrome
NCT05361811	Not specified	RECRUITING	Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Randomized Controlled Trial
NCT05761314	Not specified	RECRUITING	Solid Tumors in RASopathies
NCT06267807	Not specified	COMPLETED	Lymphatic Phenotype in Noonan Syndrome Spectrum Disorders
NCT06331117	Not specified	UNKNOWN	Effect of RAS/MAPK Pathway Hyperactivation on Growth’ and Bone’ Profile of the RASopathies
NCT06355622	Not specified	UNKNOWN	Prevalence and Characterization of Pain in RASopathies
NCT06550635	Not specified	COMPLETED	Joint and Hematologic Disorders of Noonan Syndrome: French Descriptive Cross-sectional Study
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT07259135	Not specified	NOT_YET_RECRUITING	Link Between Abnormal Bleeding and Coagulation Disorders in Noonan Syndromes
NCT07336394	Not specified	RECRUITING	Precision Diagnosis and Risk Stratification of Rare Cardiomyopathies Based on Novel Cardiac Magnetic Resonance Techniques
NCT07464821	Not specified	RECRUITING	National Multicentre Study on Lipid Profile in Noonan Syndrome and Related Disorders: Trends by Age, Gender and Genotype