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…

Primary Disease Associations & Inheritance

Niemann-Pick disease, type AMIM #257200

Niemann-Pick disease, type BMIM #607616

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · acid sphingomyelinase deficiency · AR · ClinGen 2022
Definitive · Niemann-Pick disease · AR · Myriad Women's Health
Definitive · Niemann-Pick disease type A · AR · G2P
Strong · Niemann-Pick disease type B · AR · Genomics England PanelApp

Interpreting a novel variant

Loss of function is the established mechanism, though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.08

LOEUF

LOF

Mechanism· annotated

📖

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

Background carrier burden — how many people carry a rare variant somewhere in SMPD1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 49

875 rare PASS variants

Rare truncating (LoF)

1 in 790

171 rare PASS variants

Rare synonymous (reference)

1 in 130

350 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SMPD1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 76	1 in 810
South Asian	~43k	1 in 51	1 in 530
Remaining (unassigned)	~30k	1 in 41	1 in 810
European (Finnish)	~27k	1 in 110	1 in 1,700
Admixed American	~22k	1 in 39	1 in 2,000
African / African American	~21k	1 in 45	1 in 1,200
East Asian	~20k	1 in 77	1 in 960
Ashkenazi Jewish	~13k	1 in 190	1 in 2,200
Middle Eastern	~2,884	1 in 49	≈ 1 in 720

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓