SMPD4

Chr 2AR

sphingomyelin phosphodiesterase 4

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

NCBI Gene: 55627 ENSG00000136699 UniProt: Q9NXE4 OMIM: 610457

The protein catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide, playing a critical role in membrane sphingolipid homeostasis and endoplasmic reticulum function. Biallelic mutations cause a neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies with autosomal recessive inheritance. The gene shows minimal constraint against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.021 OMIM phenotype

Clinical Summary— SMPD4

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

31 unique Pathogenic / Likely Pathogenic· 167 VUS of 257 total submissions

Explore recent and relevant literature in Research Assistant →

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 OE?0.77 (0.59–1.02)

0≤0.351.4

Missense OE?0.90 (0.83–0.97)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 35 / 45.4Missense obs/exp: 474 / 529.5Syn Z: -1.42

ClinVar Variant Classifications

257 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic22

VUS167

Likely Benign29

Benign8

Conflicting6

Pathogenic

Likely Pathogenic

167

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	0	1	0	9
Likely Pathogenic	20	1	1	0	22
VUS	2	161	4	0	167
Likely Benign	0	8	2	19	29
Benign	0	1	3	4	8
Conflicting	—				6
Total	30	171	11	23	241

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap SMPD4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →