SMPD1

Chr 11AR

sphingomyelin phosphodiesterase 1

Also known as: ASM, ASMASE, NPD

NCBI Gene: 6609ENSG00000166311UniProt: P17405

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]

Primary Disease Associations & Inheritance

Niemann-Pick disease, type AMIM #257200
AR
Niemann-Pick disease, type BMIM #607616
AR
502
ClinVar variants
157
Pathogenic / LP
0.00
pLI score
3
Active trials
Clinical Summary— SMPD1
🧬
Gene-Disease Validity (ClinGen)
acid sphingomyelinase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
157 Pathogenic / Likely Pathogenic· 157 VUS of 502 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
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?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.
-0.10Z-score
OE missense 1.01 (0.93–1.10)
382 obs / 376.7 exp
Tolerant

Tolerant to missense variation

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.0.73 (0.51–1.08)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.01 (0.93–1.10)
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.1.10
0≤1.21.6
LoF obs/exp: 18 / 24.6Missense obs/exp: 382 / 376.7Syn Z: -1.00

ClinVar Variant Classifications

502 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic50
Likely Pathogenic107
VUS157
Likely Benign158
Benign12
Conflicting18
50
Pathogenic
107
Likely Pathogenic
157
VUS
158
Likely Benign
12
Benign
18
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
20
12
18
0
50
Likely Pathogenic
38
59
9
1
107
VUS
1
137
13
6
157
Likely Benign
1
17
26
114
158
Benign
0
0
10
2
12
Conflicting
—18
Total6022576123502

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

View in ClinVar →

Protein Context — Lollipop Plot

SMPD1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SMPD1-related Niemann-Pick disease

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Niemann-Pick disease, type A

MIM #257200

Molecular basis of disorder known

Autosomal recessive

Niemann-Pick disease, type B

MIM #607616

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — SMPD1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical, biochemical, and genotype-phenotype correlations of 118 patients with Niemann-Pick disease Types A/B.
Hu J et al.·Hum Mutat
2021Cohort
Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug.
Bi J et al.·Cell Rep
2021
The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann-Pick Disease: A Comprehensive Review.
Tirelli C et al.·Biomolecules
2024Review
Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease.
Robak LA et al.·Brain
2017
Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann-Pick disease types A, B and A/B).
Geberhiwot T et al.·Orphanet J Rare Dis
2023Guideline
Niemann-Pick diseases.
Vanier MT·Handb Clin Neurol
2013Review
SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants.
Zampieri S et al.·Hum Mutat
2016Review
The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations.
Simonaro CM et al.·Am J Hum Genet
2002
Linking autism spectrum disorders and parkinsonism: clinical and genetic association.
Mai AS et al.·Ann Clin Transl Neurol
2023Review
SMPD1 expression profile and mutation landscape help decipher genotype-phenotype association and precision diagnosis for acid sphingomyelinase deficiency.
Wang R et al.·Hereditas
2023
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
Actinic KeratosisImipraminePhotodynamic Therapy

The Effect of Topical Imipramine on Photodynamic Therapy-Mediated Immunosuppression on Forearms or Face on US Veterans

RECRUITING
NCT06778434Phase PHASE2VA Office of Research and DevelopmentStarted 2025-04-01
ImipramineControl Vehicle
Gaucher Disease

Screening for Gaucher Disease and Acid Sphingomyelinase Deficiency

NOT YET RECRUITING
NCT06258577Chung-Hsing WangStarted 2024-05-01
Acid Sphingomyelinase DeficiencyCeroid Lipofuscinosis, Neuronal, 2Cerebrotendinous Xanthomatosis

ScreenPlus: A Comprehensive, Flexible, Multi-disorder Newborn Screening Program

ENROLLING BY INVITATION
NCT05368038Albert Einstein College of MedicineStarted 2021-05-10
Confirmatory Testing

External Resources

Links to major genomics databases and tools