SPRY4

Summary

SPRY4 (sprouty RTK signaling antagonist 4, HGNC:15533) is a protein-coding gene on chromosome 5q31.3, encoding Protein sprouty homolog 4 (Q9C004). Suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras.

This gene encodes a member of a family of cysteine- and proline-rich proteins. The encoded protein is an inhibitor of the receptor-transduced mitogen-activated protein kinase (MAPK) signaling pathway. Activity of this protein impairs the formation of active GTP-RAS. Nucleotide variation in this gene has been associated with hypogonadotropic hypogonadism 17 with or without anosmia. Alternative splicing results in a multiple transcript variants.

Source: NCBI Gene 81848 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism 17 with or without anosmia (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 18
• Clinical variants (ClinVar): 125 total — 1 pathogenic
• Phenotypes (HPO): 79
• MANE Select transcript: NM_001127496

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15533
Approved symbol	SPRY4
Name	sprouty RTK signaling antagonist 4
Location	5q31.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000187678
Ensembl biotype	protein_coding
OMIM	607984
Entrez	81848

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000344120, ENST00000434127, ENST00000503582, ENST00000509364, ENST00000511815, ENST00000643792, ENST00000889413, ENST00000889414, ENST00000889415, ENST00000921737, ENST00000921738, ENST00000921739, ENST00000953727

RefSeq mRNA: 4 — MANE Select: NM_001127496 NM_001127496, NM_001293289, NM_001293290, NM_030964

CCDS: CCDS4274, CCDS47296

Canonical transcript exons

ENST00000434127 — 2 exons

Exon	Start	End
ENSE00001316166	142324844	142325021
ENSE00002301412	142310430	142315155

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 90.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.4248 / max 657.6469, expressed in 1492 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63890	31.1999	1490
63887	0.0782	22
63889	0.0769	14
63888	0.0698	29

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left coronary artery	UBERON:0001626	90.78	gold quality
right lung	UBERON:0002167	90.49	gold quality
ascending aorta	UBERON:0001496	90.35	gold quality
thoracic aorta	UBERON:0001515	90.31	gold quality
omental fat pad	UBERON:0010414	89.85	gold quality
peritoneum	UBERON:0002358	89.78	gold quality
upper lobe of left lung	UBERON:0008952	89.56	gold quality
descending thoracic aorta	UBERON:0002345	89.50	gold quality
coronary artery	UBERON:0001621	89.47	gold quality
cartilage tissue	UBERON:0002418	89.33	gold quality
upper lobe of lung	UBERON:0008948	89.30	gold quality
right coronary artery	UBERON:0001625	89.24	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.90	gold quality
lower lobe of lung	UBERON:0008949	88.74	gold quality
aorta	UBERON:0000947	88.57	gold quality
tibial artery	UBERON:0007610	87.35	gold quality
popliteal artery	UBERON:0002250	87.34	gold quality
lung	UBERON:0002048	86.85	gold quality
left adrenal gland	UBERON:0001234	86.15	gold quality
adrenal gland	UBERON:0002369	86.07	gold quality
right atrium auricular region	UBERON:0006631	86.04	gold quality
left adrenal gland cortex	UBERON:0035825	85.87	gold quality
left lobe of thyroid gland	UBERON:0001120	85.66	gold quality
metanephros cortex	UBERON:0010533	85.45	gold quality
adenohypophysis	UBERON:0002196	85.33	gold quality
adrenal cortex	UBERON:0001235	85.32	gold quality
apex of heart	UBERON:0002098	85.31	gold quality
right lobe of thyroid gland	UBERON:0001119	85.26	gold quality
adrenal tissue	UBERON:0018303	85.09	gold quality
pituitary gland	UBERON:0000007	84.97	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	18.95
E-MTAB-5061	yes	6.14
E-MTAB-6678	no	2.42

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
CD82	Activation
CDKN1A	Activation
TIMP1	Activation
TP53	Activation

Upstream regulators (CollecTRI, top): FZD9, HES7, WNT7A

miRNA regulators (miRDB)

249 targeting SPRY4, 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-5011-5P	100.00	83.46	5820
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
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-126-5P	100.00	72.71	3180
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-513B-5P	99.99	69.96	2150

Literature-anchored findings (GeneRIF, showing 40)

• interacts with the dual specificity kinase TESK1; maps to 5q31.3 (PMID:12027893)
• Sprouty4 suppresses vascular epithelial growth factor (VEGF)-induced, Ras-independent activation of Raf1 but does not affect epidermal growth factor (EGF)-induced, Ras-dependent activation of Raf1. (PMID:12717443)
• Core promoter activity is located within proximal 0.4-kb region. Minimal ERK-inducible promoter activity is between -69 and -31. Core promoter region of hSpry4 gene exhibits significant homology to 5’-flanking region of mouse gene. (PMID:14977631)
• Sprouty4 expression is down regulated in human prostate cancer by DNA methylation and this decreased expression may contribute to increased cell migration. (PMID:16388505)
• Human, chimpanzee, rat and mouse SPRY4 orthologs, consisting of three exons, were well conserved (PMID:16465403)
• the Sprouty/Caveolin-1 interaction modulates signaling in a growth factor- and Sprouty isoform-specific manner (PMID:16877379)
• SPRY4 gene was found to be associated with schizophrenia. (PMID:18298822)
• These results demonstrate that common genetic variants affect TGCT risk and implicate KITLG and SPRY4 as genes involved in Testicular germ cell tumors susceptibility. (PMID:19483682)
• cell adaptation to activated FGFR3 include Sprouty4 activity, which silences the premature receptor signaling and suppress apoptosis. (PMID:19761767)
• The Spry4 might be involved in the timely restriction of MAPK signals under hypoxic conditions, similar to its role in mitogen-regulated processes. (PMID:20482313)
• Spry4 is a downstream target of Wnt7A/Fzd 9 signaling and may have efficacy in the treatment of non-small cell lung cancer. (PMID:20501643)
• The SPRY4 (rs4324715) variants were significantly associated with germ cell tumors only in the adolescent age group. (PMID:22072546)
• siRNA-mediated knockdown of Spry1, Spry2, or Spry4 promotes IFN-inducible antileukemic effects in vitro and results in enhanced suppressive effects on malignant hematopoietic progenitors from patients with polycythemia vera. (PMID:23074222)
• Spry1 and Spry4 have opposing roles in VSMC phenotypic modulation, and Spry1 maintains the VSMC differentiation phenotype in vitro in part through an Akt/FoxO/myocardin pathway. (PMID:23554919)
• results validated previously reported genetic associations with testicular germ cell tumor in a Scandinavian population, and observed suggestive evidence of a parent-of-origin effect in SPRY4. (PMID:23640991)
• Sprouty2 (but not Sprouty4) has a role in inhibition of cell proliferation and migration of osteosarcoma cells (PMID:23831057)
• Overexpressed Spry4 in endothelial cells inhibited migration and vitronectin adhesion. Spry4 knockdown enhanced these. Overexpression decreased integrin beta3 protein post-transcriptionally by modulating its tyrosine phosphorylation by c-Src. (PMID:23955631)
• Sprouty4 expression negatively influences cell migration. (PMID:24402575)
• involvement of PAX9, EDA, SPRY2, SPRY4, and WNT10A as risk factors for MLIA. uncovered 3 strong synergistic interactions between MLIA liability and MSX1-TGFA, AXIN2-TGFA, and SPRY2-SPRY4 gene pairs. 1st evidence of sprouty genes in MLIA susceptibility. (PMID:24554542)
• Downregulation of Dusp6, Sprouty4, and Sef–negative modulators of FGF2/ERK1/2 signaling–was present in eutopic endometria of adenomyosis, which may play critical roles in the development of adenomyosis. (PMID:24681741)
• Overexpression of Sprouty4 or pharmacological inhibition of ERK upregulated IL-1R1 expression in primary T cells.Sprouty4 and ERK play a critical role in developing iTh17 cells in Th17 cell-driven autoimmune diseases. (PMID:24732356)
• demonstrated that knockdown of SPRY4-IT1 reduced cell proliferation, invasiveness, and migration (PMID:24810925)
• SPRY4 may function as a tumor suppressor in endometrial adenocarcinoma. (PMID:24811094)
• these results suggest the possibility that SPRY4-IT1 knockdown may induce apoptosis via lipin 2-mediated alterations in lipid metabolism leading to cellular lipotoxicity. (PMID:25344859)
• Sprouty 2 protein, but not Sprouty 4, is an independent prognostic biomarker for human epithelial ovarian cancer. (PMID:25630587)
• ZNF703 was a target of SPRY4-IT1. (PMID:25742952)
• Specific protein 1 plays a crucial role in the regulation of Sprouty4 in response to serum. (PMID:25957915)
• SPRY4 is often deleted in secondary acute myeloid leukemia. (PMID:26204823)
• Data show that proto-oncogene protein B-raf (BRAF) inhibition induces c-Jun N-terminal kinase (c-JUN) expression and c-JUN abundance and activation by down-regulating SPRY2/4 protein expression. (PMID:26286024)
• Results identify the tumor suppressor SPRY4 as a novel molecular effector of MT1-MMP affecting melanoma cell motility. (PMID:26392417)
• Small interfering RNA (siRNA)-mediated knockdown of SPRY4 attenuated the AREG-induced down-regulation of E-cadherin. (PMID:26768617)
• These findings suggest that SPRY4-IT1 plays a direct role in the regulation of metastasis and progression of osteosarcoma. (PMID:26982001)
• results found that histone methylation mediated by CCAT1 could also contribute to the lower expression of SPRY4 in esophageal squamous cell carcinoma (PMID:27956498)
• SPRY4 is involved in the development and progression of colorectal cancer. (PMID:27997895)
• Polymorphisms of KITLG, SPRY4, and BAK1 genes in patients with testicular germ cell tumors and individuals with infertility associated with AZFc deletion of the Y chromosome (PMID:28064312)
• mechanistic evidence that KSRP promotes the down-regulation of Spry4 by a previously unidentified mechanism, i.e. post-transcriptional mRNA regulation. (PMID:28275056)
• Studied BAK1, SPRY4 and GAB2 SNPs in pediatric germ cell tumors(GCT); found a variant in SPRY4 was associated with reduced risk of GCT; a variant in BAK1 was positively associated with GCT with a strong estimated effect for testis tumors; and a SNP in GAB2 was associated with increased risk for GCT. (PMID:28295819)
• Our data indicate that KMT2C ELs are associated with specific genetic features and that SPRY4 ELs may add prognostic information. (PMID:28940816)
• Results show that SPRY4 expression level was significantly decreased in glioma tissues, associated with short survival time, and a key target gene of miR-1908. (PMID:29048686)
• The findings indicate that SPRY4 and SPRY4-IT1 may act as oncogenes in testicular germ cell tumors via activation of the PI3K/Akt signaling pathway. (PMID:29410498)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	spry4	ENSDARG00000068732
mus_musculus	Spry4	ENSMUSG00000024427
rattus_norvegicus	Spry4	ENSRNOG00000013851
drosophila_melanogaster	sty	FBGN0014388

Paralogs (3): SPRY2 (ENSG00000136158), SPRY1 (ENSG00000164056), SPRY3 (ENSG00000168939)

Protein

Protein identifiers

Protein sprouty homolog 4 — Q9C004 (reviewed: Q9C004)

All UniProt accessions (3): A0A0C4DFS6, D6RB56, Q9C004

UniProt curated annotations — full annotation on UniProt →

Function. Suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras. Probably impairs the formation of GTP-Ras. Inhibits Ras-independent, but not Ras-dependent, activation of RAF1. Represses integrin-mediated cell spreading via inhibition of TESK1-mediated phosphorylation of cofilin.

Subunit / interactions. Interacts (via C-terminus) with TESK1 (via both C- and N-termini); the interaction inhibits TESK1 kinase activity. Interacts with RAF1. Interacts with CAV1 (via C-terminus).

Subcellular location. Cytoplasm. Cell projection. Ruffle membrane.

Disease relevance. Hypogonadotropic hypogonadism 17 with or without anosmia (HH17) [MIM:615266] A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in SPRY4 also have a heterozygous mutation in another HH-associated gene including DUSP6 and FGFR1.

Domain organisation. The Cys-rich domain is responsible for the localization of the protein to the membrane ruffles.

Similarity. Belongs to the sprouty family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9C004-1	A, Sprouty-4A	yes
Q9C004-2	C, Sprouty-4C

RefSeq proteins (4): NP_001120968, NP_001280218, NP_001280219, NP_112226 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007875	Sprouty	Family
IPR051192	Sprouty_domain	Family

Pfam: PF05210

UniProt features (18 total): sequence variant 7, region of interest 3, modified residue 2, splice variant 2, chain 1, domain 1, sequence conflict 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3BUN	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9C004-F1	61.05	0.06

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 (2): 1, 125

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 459 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, RNGTGGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, TGCGCANK_UNKNOWN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_NEGATIVE_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, TGACCTY_ERR1_Q2, GOCC_RUFFLE, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5

GO Biological Process (8): negative regulation of fibroblast growth factor receptor signaling pathway (GO:0040037), negative regulation of Ras protein signal transduction (GO:0046580), animal organ development (GO:0048513), negative regulation of ERK1 and ERK2 cascade (GO:0070373), negative regulation of substrate adhesion-dependent cell spreading (GO:1900025), cellular response to leukemia inhibitory factor (GO:1990830), multicellular organism development (GO:0007275), regulation of signal transduction (GO:0009966)

GO Molecular Function (2): protein kinase inhibitor activity (GO:0004860), protein binding (GO:0005515)

GO Cellular Component (7): cytoplasm (GO:0005737), cytosol (GO:0005829), focal adhesion (GO:0005925), ruffle membrane (GO:0032587), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
anatomical structure development	2
fibroblast growth factor receptor signaling pathway	1
negative regulation of signal transduction	1
regulation of fibroblast growth factor receptor signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
Ras protein signal transduction	1
regulation of Ras protein signal transduction	1
negative regulation of small GTPase mediated signal transduction	1
negative regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
negative regulation of cell-substrate adhesion	1
substrate adhesion-dependent cell spreading	1
regulation of substrate adhesion-dependent cell spreading	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
multicellular organismal process	1
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
protein kinase activity	1
kinase inhibitor activity	1
protein kinase regulator activity	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
cell-substrate junction	1
ruffle	1
cell projection membrane	1
leading edge membrane	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

860 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPRY4	IL17RD	Q8NFM7	868
SPRY4	TESK1	Q15569	751
SPRY4	DUSP6	Q16828	725
SPRY4	RAF1	P04049	714
SPRY4	FGF8	P55075	710
SPRY4	SPRED2	Q7Z698	683
SPRY4	FGFR1	P11362	637
SPRY4	FGF3	P11487	607
SPRY4	FRS2	Q8WU20	598
SPRY4	BRAF	P15056	579
SPRY4	FLRT3	Q9NZU0	562
SPRY4	FGFR2	P18443	561
SPRY4	ATF7IP	Q6VMQ6	555
SPRY4	MAPK3	P27361	553
SPRY4	DUSP4	Q13115	552

IntAct

157 interactions, top by confidence:

A	B	Type	Score
CBL	SPRY4	psi-mi:“MI:0407”(direct interaction)	0.610
CBL	SPRY4	psi-mi:“MI:0915”(physical association)	0.610
SPRY4	CBL	psi-mi:“MI:0915”(physical association)	0.610
SPRY4	PIP4K2B	psi-mi:“MI:0915”(physical association)	0.560
HOXA1	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
FHL2	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
EFEMP2	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-11	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
KLHL38	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
COL8A1	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
NUTF2	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
POU4F2	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
ADAM12	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
CREB5	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
OTX1	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
VENTX	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
CASP6	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
CCK	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
CHAT	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
CRYAA	SPRY4	psi-mi:“MI:0915”(physical association)	0.560
SPRY4	CTSD	psi-mi:“MI:0915”(physical association)	0.560
SPRY4	DMWD	psi-mi:“MI:0915”(physical association)	0.560
SPRY4	ATN1	psi-mi:“MI:0915”(physical association)	0.560
SPRY4		psi-mi:“MI:0915”(physical association)	0.560

BioGRID (101): SPRY4 (Two-hybrid), SPRY4 (Affinity Capture-Western), SPRY4 (Two-hybrid), SPRY4 (Two-hybrid), SPRY4 (Proximity Label-MS), PIP4K2B (Affinity Capture-MS), SPRY4 (Affinity Capture-MS), SPRY4 (Proximity Label-MS), SPRY4 (Proximity Label-MS), SPRY4 (Proximity Label-MS), SPRY4 (Proximity Label-MS), SPRY4 (Proximity Label-MS), SPRY4 (Proximity Label-MS), SPRY4 (Proximity Label-MS), SPRY4 (Proximity Label-MS)

ESM2 similar proteins: A0A1B0GRQ0, A0A1B0GSZ0, A0A1B0GVT2, A0A590UK83, A0PK05, A2VDU1, A2VE22, A4QNL6, A5D7B5, A5D992, O43609, O75324, P0DKX4, P29414, P61807, P61808, Q0VFM5, Q15053, Q16655, Q17Q87, Q1L0X2, Q2KIK3, Q2TBG9, Q3MHM8, Q498C7, Q4V921, Q58CU5, Q5RBD8, Q5RF07, Q5RGQ8, Q64448, Q6UWT2, Q80ZU4, Q8BGN6, Q8BUM6, Q8C3K5, Q8C817, Q8K1D8, Q8N6S5, Q91VT8

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

15 interactions.

A	Effect	B	Mechanism
SPRY4	“down-regulates activity”	TESK1	binding
SPRY4	“down-regulates activity”	RAF1	binding
WNT7A	“down-regulates quantity by repression”	SPRY4	“transcriptional regulation”
FZD9	“down-regulates quantity by repression”	SPRY4	“transcriptional regulation”
SPRY4	down-regulates	Epithelial-mesenchymal_transition
SPRY4	“down-regulates activity”	MMP9
SPRY4	“up-regulates quantity by expression”	TIMP1	“transcriptional regulation”
SPRY4	“up-regulates quantity by expression”	CD82	“transcriptional regulation”
SPRY4	“up-regulates quantity by expression”	TP53	“transcriptional regulation”
SPRY4	“up-regulates quantity by expression”	CDKN1A	“transcriptional regulation”
SPRY4	down-regulates	Cell_growth
SPRY4	down-regulates	Metastasis
SPRY4	down-regulates	Cell_migration
SPRY4	down-regulates	Cell_invasion
hsa-miR-31-5p	“down-regulates quantity by repression”	SPRY4	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	78
Likely benign	33
Benign	5

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
50875	NM_001127496.3(SPRY4):c.46G>A (p.Val16Ile)	Pathogenic

SpliceAI

508 predictions. Top by Δscore:

Variant	Effect	Δscore
5:142324838:ACTT:A	donor_loss	1.0000
5:142324840:TTA:T	donor_loss	1.0000
5:142324841:TAC:T	donor_loss	1.0000
5:142324842:A:AC	donor_gain	1.0000
5:142324842:ACTTT:A	donor_loss	1.0000
5:142324843:C:CA	donor_gain	1.0000
5:142324843:CT:C	donor_gain	1.0000
5:142315162:G:C	acceptor_gain	0.9900
5:142324837:GACTT:G	donor_loss	0.9900
5:142324843:CTT:C	donor_gain	0.9900
5:142324843:CTTTG:C	donor_gain	0.9900
5:142315154:CC:C	acceptor_gain	0.9800
5:142315155:CC:C	acceptor_gain	0.9800
5:142315156:C:CC	acceptor_gain	0.9800
5:142315162:G:GC	acceptor_gain	0.9800
5:142324843:CTTT:C	donor_gain	0.9800
5:142315151:GGGCC:G	acceptor_gain	0.9700
5:142315152:GGCC:G	acceptor_gain	0.9700
5:142315156:C:A	acceptor_loss	0.9700
5:142315157:T:A	acceptor_loss	0.9700
5:142315167:G:C	acceptor_gain	0.9700
5:142324890:T:TA	donor_gain	0.9700
5:142315153:GCC:G	acceptor_gain	0.9600
5:142315154:CCC:C	acceptor_gain	0.9600
5:142315167:G:GC	acceptor_gain	0.9500
5:142315156:C:T	acceptor_gain	0.9300
5:142319731:A:AC	donor_gain	0.9100
5:142319732:C:CC	donor_gain	0.9100
5:142317136:GGGCT:G	acceptor_gain	0.9000
5:142317137:GGCTG:G	acceptor_gain	0.9000

AlphaMissense

1961 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:142314291:C:G	C273S	0.999
5:142314292:A:T	C273S	0.999
5:142314370:A:G	C247R	0.999
5:142314292:A:G	C273R	0.998
5:142314406:A:G	W235R	0.998
5:142314406:A:T	W235R	0.998
5:142314514:A:G	C199R	0.998
5:142314615:C:G	C165S	0.998
5:142314616:A:T	C165S	0.998
5:142314633:C:G	C159S	0.998
5:142314633:C:T	C159Y	0.998
5:142314634:A:G	C159R	0.998
5:142314634:A:T	C159S	0.998
5:142314285:C:G	C275S	0.997
5:142314286:A:T	C275S	0.997
5:142314351:G:T	P253H	0.997
5:142314358:A:C	Y251D	0.997
5:142314361:A:G	C250R	0.997
5:142314600:C:G	C170S	0.997
5:142314601:A:T	C170S	0.997
5:142314633:C:A	C159F	0.997
5:142314286:A:G	C275R	0.996
5:142314348:G:T	A254D	0.996
5:142314351:G:C	P253R	0.996
5:142314484:G:C	H209D	0.996
5:142314512:G:C	C199W	0.996
5:142314513:C:T	C199Y	0.996
5:142314528:A:T	V194D	0.996
5:142314601:A:G	C170R	0.996
5:142314609:C:G	C167S	0.996

dbSNP variants (sampled 300 via entrez): RS1000161069 (5:142313893 G>A), RS1000494665 (5:142312525 C>A,T), RS1000900820 (5:142318492 AAAAAAAAG>A), RS1001152851 (5:142318211 G>A), RS1001415797 (5:142324153 T>A), RS1001438706 (5:142317874 G>A,C), RS1001533779 (5:142319201 G>A), RS1001565438 (5:142312939 C>A), RS1001609129 (5:142323218 T>C), RS1001649910 (5:142319558 G>A), RS1001847932 (5:142324465 C>G), RS1001870858 (5:142317387 C>T), RS1001942744 (5:142324197 A>G,T), RS1001985447 (5:142317697 T>A,C), RS1002270749 (5:142313137 CTTG>C)

Disease associations

OMIM: gene MIM:607984 | disease phenotypes: MIM:615266, MIM:146110

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism 17 with or without anosmia	Moderate	Autosomal dominant
hypogonadotropic hypogonadism	Supportive	Autosomal dominant
Kallmann syndrome	Supportive	Autosomal dominant

Mondo (6): disorder of sexual differentiation (MONDO:0002145), amenorrhea (MONDO:0001836), hypogonadotropic hypogonadism 17 with or without anosmia (MONDO:0014102), hypogonadotropic hypogonadism 7 with or without anosmia (MONDO:0007794), Kallmann syndrome (MONDO:0018800), hypogonadotropic hypogonadism (MONDO:0018555)

Orphanet (3): Difference of sex development (Orphanet:90771), Kallmann syndrome (Orphanet:478), Normosmic congenital hypogonadotropic hypogonadism (Orphanet:432)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000002	Abnormality of body height
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000013	Hypoplasia of the uterus
HP:0000026	Male hypogonadism
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000104	Renal agenesis
HP:0000118	Phenotypic abnormality
HP:0000134	Female hypogonadism
HP:0000144	Decreased fertility
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000316	Hypertelorism
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000458	Anosmia
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000551	Color vision defect
HP:0000639	Nystagmus
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000802	Impotence

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST000414_4	Testicular germ cell tumor	3.000000e-13
GCST000701_1	Testicular germ cell cancer	1.000000e-14
GCST001725_84	Inflammatory bowel disease	4.000000e-14
GCST002022_8	Testicular germ cell tumor	3.000000e-31
GCST002023_8	Testicular germ cell tumor	8.000000e-10
GCST003875_1	Gut microbiota (bacterial taxa)	5.000000e-10
GCST004635_13	Testicular germ cell tumor	3.000000e-57
GCST004713_22	Testicular germ cell tumor	3.000000e-46
GCST005212_36	Asthma	8.000000e-09
GCST006218_16	Erosive tooth wear (severe vs non-severe)	6.000000e-08
GCST006218_93	Erosive tooth wear (severe vs non-severe)	7.000000e-06
GCST006226_18	Erosive tooth wear (severe vs none or mild)	5.000000e-06
GCST006862_4	Asthma	9.000000e-10
GCST007267_94	Systolic blood pressure	7.000000e-10
GCST008158_27	Body mass index	5.000000e-06
GCST008839_143	Height	2.000000e-07
GCST009798_63	Asthma	9.000000e-14
GCST010059_7	Physiological traits	6.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0007883	taxonomic microbiome measurement
EFO:0006335	systolic blood pressure
EFO:0004340	body mass index
EFO:0005937	longitudinal BMI measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D012734	Disorders of Sex Development	C12.050.351.875.253; C12.200.706.316; C12.800.316; C16.131.939.316; C19.391.119
D017436	Kallmann Syndrome	C12.050.351.875.253.096.750; C12.200.706.316.096.750; C12.800.316.096.750; C16.131.939.316.096.750; C16.320.467; C19.391.119.096.750; C19.391.482.600
C562785	Idiopathic Hypogonadotropic Hypogonadism (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	6
Estradiol	decreases expression, increases expression, affects cotreatment	4
Cyclosporine	increases expression	3
Asbestos, Crocidolite	affects expression, increases expression	3
mono-(2-ethylhexyl)phthalate	decreases expression, increases expression	2
epigallocatechin gallate	decreases expression, affects cotreatment, increases expression	2
Acetaminophen	increases expression	2
Air Pollutants	increases expression, affects cotreatment, decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Progesterone	affects cotreatment, decreases expression, increases expression	2
Silicon Dioxide	increases expression	2
Smoke	increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Valproic Acid	affects expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
bisphenol A	decreases expression	1
lead acetate	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
hydroxyhydroquinone	increases expression	1
beta-lapachone	increases expression	1
arsenite	increases methylation	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1

Cellosaurus cell lines

16 cell lines: 16 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1393	Lu-99A	Cancer cell line	Male
CVCL_1714	SUP-T1	Cancer cell line	Male
CVCL_1E03	BC7	Cancer cell line	Male
CVCL_1H35	Sup-T1 Nef-ER 31	Cancer cell line	Male
CVCL_A9NU	Sup-T1 CCR5+ H6	Cancer cell line	Male
CVCL_A9NV	Sup-T1 CCR5+ L23	Cancer cell line	Male
CVCL_A9NW	Sup-T1 CCR5+ M10	Cancer cell line	Male
CVCL_C6JB	SupT1-CIITA	Cancer cell line	Male
CVCL_M772	SUP-T1/Z29	Cancer cell line	Male
CVCL_M773	Sup-T1/JI	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00328926	PHASE4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT01454011	PHASE4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	PHASE4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	PHASE4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03490513	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	PHASE4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	PHASE4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
NCT03687606	PHASE4	UNKNOWN	Efficacy and Safety of Long Term Use of hCG or hCG Plus hMG in Males With Isolated Hypogonadotropic Hypogonadism (IHH)
NCT01103518	PHASE4	UNKNOWN	Ethinyl Estradiol and Cyproterone Acetate in Irregular Menstruation
NCT01206153	PHASE4	COMPLETED	Metformin for Treatment Antipsychotic Induced Amenorrhea in Female Schizophrenic Patients
NCT02393482	PHASE4	UNKNOWN	Psychological Impact of Amenorrhea in Women With Endometriosis
NCT00467870	PHASE3	COMPLETED	Long-term Safety Study of Intramuscular Injections of 750 mg and 1000 mg Testosterone Undecanoate in Hypogonadal Men
NCT00962637	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal™ Treatment in Men With Secondary Hypogonadism
NCT01067365	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal Treatment in Men With Secondary Hypogonadism
NCT01532414	PHASE3	COMPLETED	Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism
NCT01534208	PHASE3	COMPLETED	Safety Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01709331	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adult Men With Hypogonadotropic Hypogonadism (HH) (P07937)
NCT01739582	PHASE3	COMPLETED	An Extension Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01739595	PHASE3	COMPLETED	Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism
NCT01993212	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT01993225	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT02110368	PHASE3	COMPLETED	Bioequivalence Study of Test and Reference Testosterone Topical Gel, 1.62% Metered Pump in Testosterone Deficient Adult Male Subjects Under Fasting Conditions
NCT03019575	PHASE3	COMPLETED	Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adolescent Males With Hypogonadotropic Hypogonadism (HH) (MK-8962-043)
NCT06561594	PHASE3	NOT_YET_RECRUITING	To Evaluate Recombinant Human Follicle Stimulating Hormone-CTP Fusion Protein Injection or Placebo Combined With Chorionic Gonadotropin for Injection
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT00193661	PHASE2	COMPLETED	Observation Study of T-Gel (1%) in Treatment of Adolescent Boys With Hypogonadism
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00697814	PHASE2	COMPLETED	Clomiphene in Males With Prolactinomas and Persistent Hypogonadism
NCT00706719	PHASE2	COMPLETED	To Evaluate Sperm Parameters in Men With Secondary Hypogonadism Previously Treated With Topical Testosterone
NCT00911586	PHASE2	COMPLETED	Pharmacokinetic Study to Determine Time to Steady-state
NCT01155518	PHASE2	TERMINATED	Hypogonadism in Young Men With Type 2 Diabetes
NCT01191320	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Androxal in Controlling Blood Glucose in Men With Type-2 Diabetes Mellitus
NCT01270841	PHASE2	COMPLETED	Normalization of Morning Testosterone Levels in Men With Secondary Hypogonadism
NCT01386606	PHASE2	COMPLETED	The Effect on Androxal Versus Androgel on Morning Testosterone in Men With Secondary Hypogonadism (Low Testosterone)
NCT01894308	PHASE2	NOT_YET_RECRUITING	A Dose Ranging Study to Examine TDS-Testosterone 5%
NCT02369796	PHASE2	TERMINATED	A Phase 2a Pharmacodynamic Study of TAK-448 in Participants With Hypogonadotropic Hypogonadism
NCT02443090	PHASE2	UNKNOWN	Safety and Efficacy Study of Oral Fispemifene for the Treatment of Sexual Dysfunction in Hypogonadal Men
NCT02651688	PHASE2	COMPLETED	A Multi-Center Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters With Diet and Exercise in Conjunction With Treatment With 12.5 mg or 25 mg Enclomiphene