SGPL1

Chr 10AR

sphingosine-1-phosphate lyase 1

Also known as: NPHS14, RENI, S1PL, SPL

NCBI Gene: 8879ENSG00000166224UniProt: O95470

Enables sphinganine-1-phosphate aldolase activity. Involved in apoptotic signaling pathway; fatty acid metabolic process; and sphingolipid metabolic process. Located in endoplasmic reticulum. Implicated in nephrotic syndrome type 14. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

RENI syndromeMIM #617575
AR
390
ClinVar variants
42
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— SGPL1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
📋
ClinVar Variants
42 Pathogenic / Likely Pathogenic· 135 VUS of 390 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.55LOEUF
pLI 0.004
Z-score 3.45
OE 0.33 (0.20–0.55)
Moderately constrained

More LoF-intolerant than ~75% 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.
1.82Z-score
OE missense 0.71 (0.64–0.80)
227 obs / 318.5 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.0.33 (0.20–0.55)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.71 (0.64–0.80)
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.0.97
0≤1.21.6
LoF obs/exp: 10 / 30.6Missense obs/exp: 227 / 318.5Syn Z: 0.28

ClinVar Variant Classifications

390 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33
Likely Pathogenic9
VUS135
Likely Benign163
Benign25
Conflicting2
33
Pathogenic
9
Likely Pathogenic
135
VUS
163
Likely Benign
25
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
3
22
0
33
Likely Pathogenic
4
3
2
0
9
VUS
1
124
8
2
135
Likely Benign
0
4
61
98
163
Benign
0
1
19
5
25
Conflicting
—2
Total13135112105367

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

View in ClinVar →

Protein Context — Lollipop Plot

SGPL1 · 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

RENI syndrome

MIM #617575

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Combined novel homozygous variants in both SGPL1 and STAT1 presenting with severe combined immune deficiency: case report and literature review.
Roa-Bautista A et al.·Front Immunol
2023Review
A rare cause of nephrotic syndrome-sphingosine-1-phosphate lyase (SGPL1) deficiency: 6 cases and a review of the literature.
Tastemel Ozturk T et al.·Pediatr Nephrol
2023Review
Sphingosine phosphate lyase insufficiency syndrome: a systematic review.
Pournasiri Z et al.·World J Pediatr
2023Review
SGPL1(321) mutation: one main trigger for invasiveness of pediatric alveolar rhabdomyosarcoma.
Adamus A et al.·Cancer Gene Ther
2020
First evidence of SGPL1 expression in the cell membrane silencing the extracellular S1P siren in mammary epithelial cells.
Engel N et al.·PLoS One
2018
SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency.
Settas N et al.·J Clin Endocrinol Metab
2019
Sphingosine-1-phosphate lyase (SGPL1) deficiency is associated with mitochondrial dysfunction.
Maharaj A et al.·J Steroid Biochem Mol Biol
2020
Clinical presentation and management challenges of sphingosine-1-phosphate lyase insufficiency syndrome associated with an SGPL1 variant: a case report.
Saeedi V et al.·BMC Pediatr
2025Case report
Primary adrenal insufficiency: New genetic causes and their long-term consequences.
Buonocore F et al.·Clin Endocrinol (Oxf)
2020Review
Genotype/Phenotype Interactions and First Steps Toward Targeted Therapy for Sphingosine Phosphate Lyase Insufficiency Syndrome.
Saba JD et al.·Cell Biochem Biophys
2021Review
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
Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)

Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)

RECRUITING
NCT06669949University of California, San FranciscoStarted 2025-04-22
no intervention

External Resources

Links to major genomics databases and tools