SPRY4

Chr 5AD

sprouty RTK signaling antagonist 4

Also known as: HH17

NCBI Gene: 81848ENSG00000187678UniProt: Q9C004

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. [provided by RefSeq, Jun 2014]

Primary Disease Associations & Inheritance

Hypogonadotropic hypogonadism 17 with or without anosmiaMIM #615266
AD
136
ClinVar variants
13
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SPRY4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
13 Pathogenic / Likely Pathogenic· 80 VUS of 136 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.37LOEUF
pLI 0.000
Z-score 0.81
OE 0.70 (0.38–1.37)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.50Z-score
OE missense 0.90 (0.81–1.02)
198 obs / 218.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.70 (0.38–1.37)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.90 (0.81–1.02)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06
0≤1.21.6
LoF obs/exp: 6 / 8.6Missense obs/exp: 198 / 218.9Syn Z: -0.44

ClinVar Variant Classifications

136 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
VUS80
Likely Benign35
Benign5
Conflicting3
13
Pathogenic
80
VUS
35
Likely Benign
5
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
12
0
13
Likely Pathogenic
0
0
0
0
0
VUS
0
74
5
1
80
Likely Benign
0
5
2
28
35
Benign
0
1
3
1
5
Conflicting
—3
Total0812230136

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SPRY4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hypogonadotropic hypogonadism 17 with or without anosmia

MIM #615266

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SPRY4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A heterozygous SPRY4 variant identified in female infertility characterized by reduced oocyte potential and early embryonic arrest.
Xia L et al.·Hum Reprod
2024
The long non-coding RNA SPRY4-IT1: An emerging player in tumorigenesis and osteosarcoma.
Li Z et al.·Cell Prolif
2018Review
Long non-coding RNA in bladder cancer.
Cao Y et al.·Clin Chim Acta
2020Review
Long Non-Coding RNA SPRY4-IT1 Can Predict Poor Prognosis in Digestive System Malignancies: a Meta-Analysis.
Sun C et al.·Pathol Oncol Res
2019Meta-analysis
Prognostic Value of Long Noncoding RNA SPRY4-IT1 on Survival Outcomes in Human Carcinomas: A Systematic Review and Meta-Analysis with TCGA Database.
Wang HM et al.·Biomed Res Int
2020Meta-analysis
Clinical significance of SPRY4-IT1 in efficacy and survival prediction in breast cancer patients undergoing neoadjuvant chemotherapy.
Zheng A et al.·Histol Histopathol
2020Cohort
Dysregulation of lncRNAs in autoimmune neuropathies.
Gholipour M et al.·Sci Rep
2021
Long non-coding RNA SPRY4-IT1 promotes proliferation and metastasis in nasopharyngeal carcinoma cell.
Li Y et al.·PeerJ
2022
Dissecting the role of SPRY4-IT1 and TUG1 in modulating miR-425/TGF-β/ Smad signaling in mediating renal fibrosis and inflammation in lupus nephritis: Novel biomarkers and therapeutic targets.
Abd-Elmawla MA et al.·Int Immunopharmacol
2025
Long Non-coding RNAs and their Role in Metastasis.
Weidle UH et al.·Cancer Genomics Proteomics
2017Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools