SPRED1

Chr 15AD

sprouty related EVH1 domain containing 1

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

NCBI Gene: 161742 ENSG00000166068 UniProt: Q7Z699 OMIM: 609291

The SPRED1 protein regulates activation of the MAP kinase cascade by forming homodimers or heterodimers with SPRED2, and is phosphorylated by tyrosine kinases in response to growth factors. Loss-of-function mutations cause Legius syndrome (also known as neurofibromatosis type 1-like syndrome), which follows autosomal dominant inheritance. The pathogenic mechanism involves loss of normal MAP kinase regulation due to reduced SPRED1 function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.321 OMIM phenotype

VCEP Guidelines: NeurofibromatosesIn Progress

ClinGen Panel

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

177 unique Pathogenic / Likely Pathogenic· 621 VUS of 1235 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — SPRED1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

1.17Z-score

OE missense 0.79 (0.70–0.89)

194 obs / 245.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.06–0.32)

0≤0.351.4

Missense OE?0.79 (0.70–0.89)

0≤0.61.4

Synonymous OE?0.80

0≤1.21.6

LoF obs/exp: 3 / 24.3Missense obs/exp: 194 / 245.6Syn Z: 1.42

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSPRED1-related Legius syndromeLOFAD

This gene — mechanism propensity

0.4091th %ile

GOF

0.4381th %ile

LOF

0.64top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 88% of P/LP variants are LoF · LOEUF 0.32 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFGermline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 17704776 ↗

ClinVar Variant Classifications

1235 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic116

Likely Pathogenic61

VUS621

Likely Benign317

Benign46

Conflicting63

116

Pathogenic

Likely Pathogenic

621

VUS

317

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	101	2	13	0	116
Likely Pathogenic	54	6	1	0	61
VUS	6	515	96	4	621
Likely Benign	0	15	88	214	317
Benign	0	1	43	2	46
Conflicting	—				63
Total	161	539	241	220	1,224

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap SPRED1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →