SPNS2

protein-coding

SPNS lysolipid transporter 2, sphingosine-1-phosphate, the group of Solute carrier family 63, sphingosine phosphate transporters

Gene summary

The protein encoded by this gene is a transporter of sphingosine 1-phosphate, a secreted lipid that is important in cardiovascular, immunological, and neural development. Defects in this gene are a cause of early onset progressive hearing loss. [provided by RefSeq, Jul 2016]

MANE transcript

NM_001124758.3

Inheritance

ClinVar variants

P:3U:113B:32

Top phenotype

Deafness, autosomal recessive, 115

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr17:4,498,881-4,539,035

External References & Databases

Ensembl (ENSG00000183018)

Transcript & Mutation Effects

hg38 • Region Span ~40.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss, autosomal recessive 115MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032762

Submitter: PanelApp Australia

hearing loss, autosomal recessive 115LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032762

Submitter: ClinGen

SPNS2 was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2019 (Ingham et al., PMID: 30973865). Onset of this hearing loss is in infancy/early childhood and has been observed as downsloping and high-frequency. Four variants (missense, inframe deletion, frameshift, nonsense) that have been reported in two probands in two publications are included in this curation (PMIDs: 30973865, 36494063). The mechanism of pathogenicity appears to be loss of function (30973865). This gene-disease relationship is also supported by experimental evidence (mouse models, rescue evidence, expression level data; PMIDs: 25356849, 37552762). Homozygous knockout mice have progressive hearing loss, reduced endocochlear potential, and ocular anomalies (such as corneal opacity). The hearing phenotype was rescued in mice that received a recombinase allele and tamoxifen injection. Expression-level data shows strong expression of the gene in the cochlea (specifically the lateral wall and Organ of Corti) in wild-type mice, but significantly reduced expression in mutants. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 7/15/2026 (SOP Version 12).

hearing loss, autosomal recessive 115LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032762

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, autosomal recessive, 115AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 30973865

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPNS2 variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 105

SPNS2-related disorderTotal: 41

not providedTotal: 18

Hearing loss, autosomal recessive 115Total: 8

Inborn genetic diseasesTotal: 2

Sensorineural hearing loss disorderTotal: 2

Hearing impairmentTotal: 1

Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001124758.3. 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	21 clinvar	2 clinvar	25
missense			108 clinvar	7 clinvar	2 clinvar	117
nonsense		1 clinvar	1 clinvar			2
start loss						0
frameshift		2 clinvar				2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	3	113	28	4	148

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001124758.3	RefSeq	NP_001118230.1	12	MANE Select
ENST00000329078.8	Ensembl	ENSP00000333292.3	12	MANE Select
ENST00000571386.1	Ensembl	ENSP00000461410.1	6	Standard
ENST00000932033.1	Ensembl	ENSP00000602092.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
spns2	Danio rerio	Structure: median fin Quality: blistered abnormal

Gene / Model

Organism

Observed Phenotype

spns2

Danio rerio

Structure: median fin

Quality: blistered

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

B cell homeostasis
regulation of humoral immune response
sphingosine-1-phosphate receptor signaling pathway
sphingolipid metabolic process
lipid transport

Molecular Function

sphingolipid transporter activity

Cellular Component

integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000329078
Coding exons: 12
Length: 40198
Individuals with no LoFs: 124692
Homozygous LoFs: 0
Heterozygous LoFs: 33
Defined: 124725
p: 0.000132

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0679	315	312	1.01	0.0000203	3457
Missense (PolyPhen)		105	122.03	0.86043		1252
Synonymous	-4.15	203	140	1.45	0.0000100	1205
Loss of Function	2.31	12	24.3	0.494	0.00000128	260

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00017	0.00017	rare
Finnish	0.000093	0.000093	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.000098	0.000098	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Sphingolipid transporter required for migration of myocardial precursors. Transports sphingosine 1-phosphate (S1P), a secreted lipid mediator that plays critical roles in cardiovascular, immunological, and neural development and function. Mediates the export of S1P from cells in the extraembryonic yolk syncytial layer (YSL), thereby regulating myocardial precursor migration. {ECO:0000269|PubMed:19074308}.;

Recessive Scores

pRec: 0.110

Intolerance Scores

LoFtool: 0.572
RVIS EVS: -0.98
RVIS percentile EVS: 8.85

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.270

Gene Damage Prediction

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