SGPL1

protein-coding

sphingosine-1-phosphate lyase 1

Gene summary

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 RENI syndrome. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_003901.4

Inheritance

ClinVar variants

P:31U:138B:109

Top phenotype

RENI syndrome

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr10:70,815,905-70,958,701

External References & Databases

Ensembl (ENSG00000166224)

Transcript & Mutation Effects

hg38 • Region Span ~142.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nephrotic syndrome 14DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0033203

Submitter: ClinGen

*SGPL1* was first reported in relation to autosomal recessive nephrotic syndrome 14 in 2017 (Prasad et al., PMID: 28165343 and Lovric et al., PMID: 28165339). This condition can include steroid-resistant nephrotic syndrome, primary adrenal insufficiency, testicular insufficiency, hypothyroidism, ichthyosis, lymphopenia, immunodeficiency, developmental delay, and peripheral motor and sensory neuropathy. Prenatal features of this condition may include fetal hydrops, increased nuchal translucency, skin edema, polyhydramnios, and adrenal calcifications. Fifteen variants (missense, frameshift, nonsense, canonical splice site) that have been reported in 12 probands in five publications (PMIDs: 28165343, 28165339, 28181337, 29501407, 32855188, 32855188) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by animal models (PMIDs: 19119317, 28165343, 28165339). Null mouse models recapitulate the human renal and adrenal phenotype and knock-in of human S1PL in the heterozygous or homozygous state partially rescued enzyme activity. In summary, there is definitive evidence supporting the relationship between *SGPL1* and autosomal recessive nephrotic syndrome 14. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Prenatal GCEP on September 18, 2024 (SOP Version 11).

nephrotic syndrome 14MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0033203

Submitter: Ambry Genetics

nephrotic syndrome 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033203

Submitter: Labcorp Genetics (formerly Invitae)

nephrotic syndrome 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033203

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

RENI syndromeAR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Dermatologic; Endocrine; Genitourinary; Neurologic; Renal

Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Endocrine

Rationale: Individuals have been described with immunodeficiency, including recurrent bacterial infections, and awareness may allow preventative measures and early and aggressive treatment of infections; Individuals have been described with hearing loss, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Individuals have been described with adrenal insufficiency, and awareness may allow early diagnosis and management

Refs: 28165339; 28165343; 28181337; 36873630

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SGPL1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 272

Inborn genetic diseasesTotal: 57

Nephrotic syndrome 14Total: 32

not specifiedTotal: 20

SGPL1-related disorderTotal: 16

Nephrotic syndromeTotal: 2

Differences in sex developmentTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003901.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	99 clinvar	1 clinvar	102
missense	3 clinvar	4 clinvar	130 clinvar	9 clinvar		146
nonsense	7 clinvar	2 clinvar	1 clinvar			10
start loss						0
frameshift	7 clinvar	4 clinvar	1 clinvar			12
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	4 clinvar			8
Total	18	13	138	108	1	278

Highest pathogenic variant AF is 0.000026678998

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003901.4	RefSeq	NP_003892.2	14	MANE Select
ENST00000373202.8	Ensembl	ENSP00000362298.3	14	MANE Select
NM_001437828.1	RefSeq	NP_001424757.1	12	Standard
NM_001438353.1	RefSeq	NP_001425282.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Sphingolipid signaling pathway - Homo sapiens (human)
Sphingolipid metabolism - Homo sapiens (human)
Sphingolipid Metabolism
Gaucher Disease
Globoid Cell Leukodystrophy

Biological Process

luteinization
vasculogenesis
ameboidal-type cell migration
kidney development
fatty acid metabolic process

Molecular Function

protein binding
sphinganine-1-phosphate aldolase activity
carboxy-lyase activity
pyridoxal phosphate binding

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
integral component of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373202
Coding exons: 14
Length: 65214
Individuals with no LoFs: 125708
Homozygous LoFs: 0
Heterozygous LoFs: 40
Defined: 125748
p: 0.000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.82	227	318	0.713	0.0000170	3726
Missense (PolyPhen)		53	112.91	0.46941		1301
Synonymous	0.285	111	115	0.966	0.00000618	1072
Loss of Function	3.45	10	30.6	0.326	0.00000155	381

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000072	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.00088	0.00088	rare
European (Non-Finnish)	0.000099	0.000097	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cleaves phosphorylated sphingoid bases (PSBs), such as sphingosine-1-phosphate, into fatty aldehydes and phosphoethanolamine. Elevates stress-induced ceramide production and apoptosis. {ECO:0000269|PubMed:11018465, ECO:0000269|PubMed:14570870, ECO:0000269|PubMed:24809814, ECO:0000269|PubMed:28165339}.;

Recessive Scores

pRec: 0.432

Intolerance Scores

LoFtool: 0.593
RVIS EVS: -0.29
RVIS percentile EVS: 33.34

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.554

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium