SMPDL3A

protein-coding

sphingomyelin phosphodiesterase acid like 3A

Gene summary

Enables phosphoric diester hydrolase activity and zinc ion binding activity. Involved in negative regulation of cGAS/STING signaling pathway and nucleoside triphosphate catabolic process. Located in extracellular exosome. Is active in obsolete extracellular space. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_006714.5

Inheritance

ClinVar variants

U:58B:1

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 1.33

Max pathogenic AF

—

Genomic locus

chr6:122,789,049-122,809,720

External References & Databases

Ensembl (ENSG00000172594)

Transcript & Mutation Effects

hg38 • Region Span ~20.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

sensory peripheral neuropathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0002321

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMPDL3A variants in ClinVar

1 Conditions Cataloged

not specifiedTotal: 52

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006714.5. 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			2
missense			54 clinvar	1 clinvar		55
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	58	1	0	59

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006714.5	RefSeq	NP_006705.1	8	MANE Select
ENST00000368440.5	Ensembl	ENSP00000357425.4	8	MANE Select
NM_001286138.2	RefSeq	NP_001273067.1	6	Standard
ENST00000539041.5	Ensembl	ENSP00000442152.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

sphingomyelin catabolic process
nucleoside triphosphate catabolic process

Molecular Function

sphingomyelin phosphodiesterase activity
protein binding
phosphoric diester hydrolase activity
zinc ion binding

Cellular Component

extracellular space
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368440
Coding exons: 8
Length: 20551
Individuals with no LoFs: 125489
Homozygous LoFs: 0
Heterozygous LoFs: 259
Defined: 125748
p: 0.00103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.155	225	232	0.971	0.0000104	2986
Missense (PolyPhen)		89	98.316	0.90525		1242
Synonymous	0.607	80	87.2	0.917	0.00000417	836
Loss of Function	-1.36	27	20.4	1.33	8.60e-7	254

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.0011	0.0011	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0076	0.0076	notable
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00049	0.00048	rare
South Asian	0.00036	0.00036	rare
Other	0.0012	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Has in vitro nucleotide phosphodiesterase activity with nucleoside triphosphates, such as ATP (PubMed:25288789, PubMed:26783088). Has in vitro activity with p-nitrophenyl-TMP (PubMed:25288789). Has lower activity with nucleoside diphosphates, and no activity with nucleoside monophosphates (PubMed:25288789, PubMed:26783088). Has in vitro activity with CDP-choline, giving rise to CMP and phosphocholine. Has in vitro activity with CDP-ethanolamine (PubMed:26783088). Does not have sphingomyelin phosphodiesterase activity (PubMed:25288789, PubMed:26783088). {ECO:0000269|PubMed:25288789, ECO:0000269|PubMed:26783088}.;

Recessive Scores

pRec: 0.126

Intolerance Scores

LoFtool: 0.351
RVIS EVS: 0.57
RVIS percentile EVS: 82.08

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.000369

Gene Damage Prediction

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