SMPD4

Chr 2AR

sphingomyelin phosphodiesterase 4

Also known as: NEDMABA, NEDMEBA, NET13, NSMASE-3, NSMASE3, SKNY

NCBI Gene: 55627ENSG00000136699UniProt: Q9NXE4

The protein encoded by this gene is a sphingomyelinase that catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide. This gene is activated by DNA damage, cellular stress, and tumor necrosis factor, but it is downregulated by wild-type p53. The encoded protein localizes to the endoplasmic reticulum and Golgi network. [provided by RefSeq, Mar 2017]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomaliesMIM #618622
AR
0
Active trials
45
Pathogenic / LP
279
ClinVar variants
5
Pubs (1 yr)
0.9
Missense Z
1.02
LOEUF
Clinical Summary— SMPD4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
45 Pathogenic / Likely Pathogenic· 188 VUS of 279 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.02LOEUF
pLI 0.000
Z-score 1.43
OE 0.77 (0.59–1.02)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.86Z-score
OE missense 0.90 (0.83–0.97)
474 obs / 529.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.77 (0.59–1.02)
0≤0.351.4
Missense OE0.90 (0.83–0.97)
0≤0.61.4
Synonymous OE1.12
0≤1.21.6
LoF obs/exp: 35 / 45.4Missense obs/exp: 474 / 529.5Syn Z: -1.42

ClinVar Variant Classifications

279 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic24
VUS188
Likely Benign28
Benign12
Conflicting6
21
Pathogenic
24
Likely Pathogenic
188
VUS
28
Likely Benign
12
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
0
13
0
21
Likely Pathogenic
14
1
9
0
24
VUS
1
158
29
0
188
Likely Benign
0
8
2
18
28
Benign
0
1
7
4
12
Conflicting
—6
Total231686022279

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

View in ClinVar →

SMPD4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SMPD4-related developmental disorder with microcephaly and arthrogryposis

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients