SMPD1

Chr 11AR

sphingomyelin phosphodiesterase 1

Also known as: ASM, ASMASE, NPD

NCBI Gene: 6609 ENSG00000166311 UniProt: P17405 OMIM: 607608

The protein is a lysosomal acid sphingomyelinase that converts sphingomyelin to ceramide and has phospholipase C activity. Mutations cause Niemann-Pick disease types A and B through an autosomal recessive inheritance pattern. The pathogenic mechanism involves loss of function, leading to sphingomyelin accumulation in lysosomes.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a lysosomal acid sphingomyelinase that converts sphingomyelin to ceramide. The encoded protein also has phospholipase C activity. Defects in this gene are a cause of Niemann-Pick disease type A (NPA) and Niemann-Pick disease type B (NPB). Multiple transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.082 OMIM phenotypes

Clinical Summary— SMPD1

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Gene-Disease Validity (ClinGen)

acid sphingomyelinase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

386 unique Pathogenic / Likely Pathogenic· 277 VUS of 1202 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SMPD1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.08LOEUF

pLI 0.000

Z-score 1.23

OE 0.73 (0.51–1.08)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.10Z-score

OE missense 1.01 (0.93–1.10)

382 obs / 376.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.73 (0.51–1.08)

0≤0.351.4

Missense OE?1.01 (0.93–1.10)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 18 / 24.6Missense obs/exp: 382 / 376.7Syn Z: -1.00

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSMPD1-related Niemann-Pick diseaseLOFAR

Mechanism Note (expert annotation)

LOF

Acid sphingomyelinase. Biallelic LOF causes Niemann-Pick disease type A (severe, neuronopathic) or type B (milder, non-neuronopathic). GOF prediction is incorrect for this classic lysosomal storage disease.1

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.5575th %ile

GOF

0.6736th %ile

LOF

0.3355th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 2023319 ↗

ClinVar Variant Classifications

1202 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic133

Likely Pathogenic253

VUS277

Likely Benign394

Benign25

Conflicting114

133

Pathogenic

253

Likely Pathogenic

277

VUS

394

Likely Benign

Benign

114

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	108	22	3	0	133
Likely Pathogenic	122	127	3	1	253
VUS	6	249	13	9	277
Likely Benign	2	49	62	281	394
Benign	1	8	11	5	25
Conflicting	—				114
Total	239	455	92	296	1,196

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap SMPD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →