SPRED1

Chr 15AD

sprouty related EVH1 domain containing 1

Also known as: LGSS, NFLS, PPP1R147, hSpred1, spred-1

NCBI Gene: 161742ENSG00000166068UniProt: Q7Z699

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). [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Legius syndromeMIM #611431
AD
389
ClinVar variants
43
Pathogenic / LP
0.97
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SPRED1
🧬
Gene-Disease Validity (ClinGen)
Legius syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
43 Pathogenic / Likely Pathogenic· 245 VUS of 389 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.32LOEUF
pLI 0.972
Z-score 4.00
OE 0.12 (0.06–0.32)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
1.17Z-score
OE missense 0.79 (0.70–0.89)
194 obs / 245.6 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.0.12 (0.06–0.32)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.79 (0.70–0.89)
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.0.80
0≤1.21.6
LoF obs/exp: 3 / 24.3Missense obs/exp: 194 / 245.6Syn Z: 1.42

ClinVar Variant Classifications

389 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic16
VUS245
Likely Benign100
Benign1
27
Pathogenic
16
Likely Pathogenic
245
VUS
100
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
0
15
0
27
Likely Pathogenic
13
1
2
0
16
VUS
1
227
16
1
245
Likely Benign
0
3
12
85
100
Benign
0
0
1
0
1
Total262314686389

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

View in ClinVar →

Protein Context — Lollipop Plot

SPRED1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SPRED1-related Legius syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Legius syndrome

MIM #611431

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SPRED1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders.
Giugliano T et al.·Genes (Basel)
2019
LZTR1 molecular genetic overlap with clinical implications for Noonan syndrome and schwannomatosis.
Farncombe KM et al.·BMC Med Genomics
2022Review
Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules.
Mastromoro G et al.·Genet Med
2024
Comprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only.
Evans DG et al.·EBioMedicine
2016Cohort
Undiagnosed RASopathies in infertile men.
Juchnewitsch AG et al.·Front Endocrinol (Lausanne)
2024
Review and update of SPRED1 mutations causing Legius syndrome.
Brems H et al.·Hum Mutat
2012Review
Novel causative variants in Legius syndrome: SPRED1 Genotype spectrum expansion.
Chelleri C et al.·Am J Med Genet A
2024
Legius syndrome, an Update. Molecular pathology of mutations in SPRED1.
Brems H et al.·Keio J Med
2013Review
TTC36-Mediated Tumor Suppression via YBX3/SPRED1 Axis Paradoxically Reduces Sorafenib Sensitivity in Hepatocellular Carcinoma.
Zhao W et al.·Int J Biol Sci
2025
Pharmacological inhibition of miR-126 enhances venetoclax activity in acute myeloid leukemia.
Zhang L et al.·Blood
2026
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