SMPD4

Summary

SMPD4 (sphingomyelin phosphodiesterase 4, HGNC:32949) is a protein-coding gene on chromosome 2q21.1, encoding Sphingomyelin phosphodiesterase 4 (Q9NXE4). Catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide.

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.

Source: NCBI Gene 55627 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (Strong, GenCC)
• Clinical variants (ClinVar): 256 total — 9 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 45
• Druggable target: yes
• MANE Select transcript: NM_017951

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:32949
Approved symbol	SMPD4
Name	sphingomyelin phosphodiesterase 4
Location	2q21.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20297, FLJ20756, nSMase-3, KIAA1418, NSMASE3, NET13
Ensembl gene	ENSG00000136699
Ensembl biotype	protein_coding
OMIM	610457
Entrez	55627

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 17 protein_coding, 8 nonsense_mediated_decay, 5 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000351288, ENST00000409031, ENST00000412570, ENST00000430682, ENST00000431183, ENST00000433118, ENST00000435455, ENST00000439029, ENST00000439886, ENST00000441135, ENST00000449159, ENST00000451542, ENST00000454468, ENST00000455548, ENST00000457039, ENST00000461187, ENST00000473720, ENST00000482171, ENST00000491128, ENST00000491319, ENST00000680196, ENST00000680298, ENST00000680401, ENST00000680679, ENST00000680810, ENST00000680987, ENST00000681660, ENST00000883567, ENST00000883568, ENST00000883569, ENST00000883570, ENST00000951021

RefSeq mRNA: 3 — MANE Select: NM_017951 NM_001171083, NM_017751, NM_017951

CCDS: CCDS2156, CCDS42751, CCDS54398

Canonical transcript exons

ENST00000680298 — 20 exons

Exon	Start	End
ENSE00003465102	130153043	130153171
ENSE00003484532	130173514	130173656
ENSE00003493171	130167458	130167590
ENSE00003501797	130161186	130161272
ENSE00003511881	130153319	130153450
ENSE00003525118	130164374	130164445
ENSE00003527812	130172787	130172895
ENSE00003537172	130172625	130172677
ENSE00003552623	130153702	130153935
ENSE00003562292	130173279	130173354
ENSE00003594366	130156585	130156675
ENSE00003611259	130174914	130175000
ENSE00003613641	130156035	130156135
ENSE00003626863	130157251	130157396
ENSE00003637444	130172349	130172500
ENSE00003646709	130176554	130176637
ENSE00003685899	130151408	130152884
ENSE00003785178	130154277	130154482
ENSE00003786948	130155096	130155259
ENSE00003914625	130181530	130181602

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 96.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.8231 / max 357.2765, expressed in 1814 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
30615	42.6803	1808
30616	3.1131	1528
30614	0.0297	6

Top tissues by expression

134 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pituitary gland	UBERON:0000007	96.74	gold quality
adenohypophysis	UBERON:0002196	96.37	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.69	gold quality
left lobe of thyroid gland	UBERON:0001120	95.55	gold quality
endocervix	UBERON:0000458	95.51	gold quality
right lobe of thyroid gland	UBERON:0001119	95.45	gold quality
cerebellar hemisphere	UBERON:0002245	95.41	gold quality
thyroid gland	UBERON:0002046	95.39	gold quality
cerebellum	UBERON:0002037	95.37	gold quality
cerebellar cortex	UBERON:0002129	95.36	gold quality
apex of heart	UBERON:0002098	95.31	gold quality
body of uterus	UBERON:0009853	94.93	gold quality
right uterine tube	UBERON:0001302	94.85	gold quality
left ovary	UBERON:0002119	94.82	gold quality
right ovary	UBERON:0002118	94.66	gold quality
ovary	UBERON:0000992	94.29	gold quality
skin of leg	UBERON:0001511	94.27	gold quality
tibial nerve	UBERON:0001323	94.25	gold quality
left uterine tube	UBERON:0001303	94.20	gold quality
zone of skin	UBERON:0000014	94.06	gold quality
mucosa of stomach	UBERON:0001199	94.04	gold quality
skin of abdomen	UBERON:0001416	93.92	gold quality
ectocervix	UBERON:0012249	93.85	gold quality
prostate gland	UBERON:0002367	93.83	gold quality
bone marrow	UBERON:0002371	93.73	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.69	gold quality
fundus of stomach	UBERON:0001160	93.67	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.58	gold quality
myometrium	UBERON:0001296	93.51	gold quality
uterine cervix	UBERON:0000002	93.48	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	28.20
E-CURD-112	yes	15.07
E-ANND-3	yes	10.16
E-CURD-11	no	167.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

25 targeting SMPD4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-499A-3P	99.18	69.20	1392
HSA-MIR-499B-3P	99.18	69.27	1391
HSA-MIR-5100	99.11	67.52	1098
HSA-MIR-3124-3P	98.87	68.95	2123
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-6819-5P	97.96	66.59	1071
HSA-MIR-4469	97.93	65.81	1319
HSA-MIR-4432	97.80	67.87	705
HSA-MIR-6737-5P	97.75	66.54	1044
HSA-MIR-647	97.73	67.79	927
HSA-MIR-6812-5P	97.56	65.39	1059
HSA-MIR-4703-3P	96.68	68.61	545
HSA-MIR-551A	93.83	70.97	38
HSA-MIR-551B-3P	93.83	70.97	38

Literature-anchored findings (GeneRIF, showing 5)

• nSMase3 is an important molecule that is linked to tumorigenesis and cellular stress response (PMID:18505924)
• Data show DA remarkably increased the NSMase2 message and protein, whereas little change in NSMase1 and NSMase3 mRNAs. (PMID:19698806)
• data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the endoplasmic reticulum and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly (PMID:31495489)
• Proximity Ligation Mapping of Microcephaly Associated SMPD4 Shows Association with Components of the Nuclear Pore Membrane. (PMID:35203325)
• Two novel cases of biallelic SMPD4 variants with brain structural abnormalities. (PMID:37882972)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	smpd4	ENSDARG00000020730
mus_musculus	Smpd4	ENSMUSG00000005899
rattus_norvegicus	Smpd4	ENSRNOG00000001875
drosophila_melanogaster	CG6962	FBGN0037958
caenorhabditis_elegans	R05D11.9	WBGENE00011037

Protein

Protein identifiers

Sphingomyelin phosphodiesterase 4 — Q9NXE4 (reviewed: Q9NXE4)

Alternative names: Neutral sphingomyelinase 3, Neutral sphingomyelinase III

All UniProt accessions (17): A0A7P0T8J0, A0A7P0T9J6, A0A7P0TAZ0, A0A7P0TB24, A0A7P0TB44, A0A7P0Z453, C9J647, Q9NXE4, F2Z2I0, F2Z2W5, F8WEQ5, F8WF03, H7C0W5, H7C1Q6, H7C235, H7C2E2, H7C2J2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide. It has a relevant role in the homeostasis of membrane sphingolipids, thereby influencing membrane integrity, and endoplasmic reticulum organization and function. May sensitize cells to DNA damage-induced apoptosis. In skeletal muscle, mediates TNF-stimulated oxidant production.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane. Nucleus envelope. Cell membrane. Sarcolemma.

Tissue specificity. Widely expressed, with highest levels in heart and skeletal muscle. Expressed in skeletal muscle (at protein level). Expressed in skeletal muscle but a lower levels than isoform 1 (at protein level).

Disease relevance. Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (NEDMABA) [MIM:618622] An autosomal recessive disorder characterized by severe global developmental delay, severely impaired intellectual development with poor or absent speech, severe encephalopathy, microcephaly with simplified gyral pattern, hypomyelination, thin corpus callosum, mild cerebellar hypoplasia, brainstem hypoplasia, congenital arthrogryposis, dysmorphic features, and respiratory problems often leading to early demise. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by phosphatidylserine and tumor necrosis factor (TNF). Inhibited by scyphostatin.

Induction. Expression is induced by DNA-damage and TNF.

Isoforms (10)

UniProt ID	Names	Canonical?
Q9NXE4-1	1, nSMase3a	yes
Q9NXE4-2	2, nSMase3b
Q9NXE4-3	3
Q9NXE4-4	4
Q9NXE4-5	5
Q9NXE4-6	6
Q9NXE4-7	7
Q9NXE4-8	8
Q9NXE4-9	9
Q9NXE4-10	10

RefSeq proteins (3): NP_001164554, NP_060221, NP_060421* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024129	Sphingomy_SMPD4	Family

Pfam: PF14724

Enzyme classification (BRENDA):

• EC 3.1.4.12 — sphingomyelin phosphodiesterase (BRENDA: 30 organisms, 220 substrates, 319 inhibitors, 54 Km, 10 kcat entries)

Substrate kinetics (BRENDA)

18 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
SPHINGOMYELIN	0.0006–13	30
2-N-HEXADECANOYLAMINO-4-NITROPHENYLPHOSPHORYLCHO	0.034–0.34	2
4-(4-NITROPHENOXY)-2-HYDROXY-BUTYL-1-PHOSPHORYLC	12.6–39.6	2
1-ALKYL-LYSO-PLATELET ACTIVATING FACTOR	0.048	1
2-(N-HEXADECANOYLAMINO)-4-NITROPHENYLPHOSPHORYLC	1.7	1
2N-HEXADECANOYLAMINO-4-NITROPHENYLPHOSPHORYLCHOL	0.027	1
4-NITROPHENYL PHOSPHORYLCHOLINE	11.6	1
ADP	0.306	1
ADP-RIBOSE	0.348	1
ATP	0.327	1
BIS-P-NITROPHENYL PHOSPHATE	14.5	1
BODIPYFL-C12-SPHINGOMYELIN	0.06	1
CDP-CHOLINE	0.262	1
CDP-ETHANOLAMINE	0.391	1
HEXADECANOYL-P-NITROPHENYL PHOSPHORYLCHOLINE	0.174	1

Catalyzed reactions (Rhea), 1 shown:

• a sphingomyelin + H2O = phosphocholine + an N-acylsphing-4-enine + H(+) (RHEA:19253)

UniProt features (31 total): splice variant 12, sequence variant 6, sequence conflict 6, modified residue 4, chain 1, transmembrane region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NXE4-F1	72.01	0.30

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (4): 169, 285, 708, 792

Mutagenesis-validated functional residues (1):

Position	Phenotype
862–865	no effect on endoplasmic reticulum location.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9840310	Glycosphingolipid catabolism

MSigDB gene sets: 253 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, KAAB_FAILED_HEART_ATRIUM_DN, GOBP_RESPONSE_TO_PEPTIDE, GOBP_SPHINGOMYELIN_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MEMBRANE_LIPID_CATABOLIC_PROCESS, PUJANA_CHEK2_PCC_NETWORK, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOCC_TRANS_GOLGI_NETWORK, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_AMIDE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_CATABOLIC_PROCESS

GO Biological Process (7): sphingomyelin catabolic process (GO:0006685), endoplasmic reticulum organization (GO:0007029), glycerophospholipid catabolic process (GO:0046475), ceramide biosynthetic process (GO:0046513), cellular response to tumor necrosis factor (GO:0071356), in utero embryonic development (GO:0001701), lipid metabolic process (GO:0006629)

GO Molecular Function (4): sphingomyelin phosphodiesterase activity (GO:0004767), metal ion binding (GO:0046872), sphingomyelin phosphodiesterase D activity (GO:0050290), hydrolase activity (GO:0016787)

GO Cellular Component (11): Golgi membrane (GO:0000139), nuclear envelope (GO:0005635), nuclear outer membrane (GO:0005640), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), sarcolemma (GO:0042383), nucleus (GO:0005634), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glycosphingolipid metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endomembrane system	3
intracellular membrane-bounded organelle	3
phospholipid catabolic process	2
nuclear outer membrane-endoplasmic reticulum membrane network	2
cytoplasm	2
sphingomyelin metabolic process	1
sphingolipid catabolic process	1
organelle organization	1
endomembrane system organization	1
glycerophospholipid metabolic process	1
glycerolipid catabolic process	1
ceramide metabolic process	1
sphingolipid biosynthetic process	1
response to tumor necrosis factor	1
cellular response to cytokine stimulus	1
chordate embryonic development	1
primary metabolic process	1
phosphoric diester hydrolase activity	1
sphingophospholipase activity	1
cation binding	1
sphingomyelin phosphodiesterase activity	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
nucleus	1
organelle envelope	1
nuclear membrane	1
organelle outer membrane	1
organelle membrane	1
endoplasmic reticulum subcompartment	1
Golgi apparatus subcompartment	1
plasma membrane	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1008 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMPD4	SMPD3	Q9NY59	969
SMPD4	SMPD2	O60906	948
SMPD4	SMPD1	P17405	707
SMPD4	SGMS1	Q86VZ5	649
SMPD4	ENPP7	Q6UWV6	609
SMPD4	SGMS2	Q8NHU3	552
SMPD4	ACER3	Q9NUN7	545
SMPD4	CERS6	Q6ZMG9	542
SMPD4	DEGS1	O15121	538
SMPD4	ASAH1	Q13510	533
SMPD4	NCLN	Q969V3	532
SMPD4	DEGS2	Q6QHC5	532
SMPD4	CERS2	Q96G23	531
SMPD4	LPCAT1	Q8NF37	516
SMPD4	SPTLC1	O15269	507

IntAct

79 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
UNC93B1	GPR89A	psi-mi:“MI:0914”(association)	0.530
ERBB2	SMPD4	psi-mi:“MI:0915”(physical association)	0.370
FOXA3	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXB1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXE1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXH1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXI1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXI2	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXL1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXL2	DDX39A	psi-mi:“MI:0914”(association)	0.350
TEAD2	DDX39A	psi-mi:“MI:0914”(association)	0.350
PB1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ISG15	SURF4	psi-mi:“MI:0914”(association)	0.350
CLN6	SCAMP3	psi-mi:“MI:0914”(association)	0.350
	TSPO	psi-mi:“MI:0914”(association)	0.350
UNC93B1		psi-mi:“MI:0914”(association)	0.350
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	FAM20B	psi-mi:“MI:0914”(association)	0.350
STYK1	XPO1	psi-mi:“MI:0914”(association)	0.350
CCDC47	ESYT2	psi-mi:“MI:0914”(association)	0.350
MAGEA8	METTL15	psi-mi:“MI:0914”(association)	0.350
GPR182	METTL15	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
PIGH	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (228): SMPD4 (Affinity Capture-MS), SMPD4 (Affinity Capture-MS), SMPD4 (Proximity Label-MS), SMPD4 (Proximity Label-MS), SMPD4 (Proximity Label-MS), SMPD4 (Proximity Label-MS), SMPD4 (Affinity Capture-MS), SMPD4 (Affinity Capture-MS), SMPD4 (Affinity Capture-MS), SMPD4 (Affinity Capture-MS), SMPD4 (Affinity Capture-MS), SMPD4 (Affinity Capture-MS), SMPD4 (Affinity Capture-MS), SMPD4 (Affinity Capture-MS), SMPD4 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GUX5, A0A571BF63, A0A8M9QN10, A1L1K1, A2ARM1, A2AVJ5, A7YDW0, O08576, O60268, P0C6P5, P97433, Q08E29, Q0V9V7, Q0VDN7, Q17QK1, Q2NKQ1, Q2NL11, Q3B7K9, Q3SYZ9, Q4R7B9, Q561Q8, Q59EK9, Q5E9L4, Q5E9R0, Q5EB20, Q5NVC2, Q5PQS0, Q5R565, Q5U3W3, Q5XHG1, Q61194, Q6AYK4, Q6MZQ0, Q6NXJ0, Q6P047, Q6P7D5, Q6ZUJ8, Q80ZQ3, Q8BPQ7, Q8N1W1

Diamond homologs: Q5XHG1, Q6PFJ7, Q6ZPR5, Q9NXE4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
anatomical structure morphogenesis	7	11.1×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

256 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	20
Uncertain significance	166
Likely benign	29
Benign	8

Top pathogenic / likely-pathogenic (29)

Variant ID	HGVS	Classification
1686221	NM_017951.5(SMPD4):c.792+2T>G	Pathogenic
1701387	NM_017951.5(SMPD4):c.1487del (p.Ile496fs)	Pathogenic
1805741	NM_017951.5(SMPD4):c.-43del	Pathogenic
2271385	NM_017951.5(SMPD4):c.-67_-66del	Pathogenic
2498125	NM_017951.5(SMPD4):c.270-1G>A	Pathogenic
3251837	NC_000002.11:g.(?130908980)(130939176_?)del	Pathogenic
691969	NM_017951.5(SMPD4):c.1453+1G>A	Pathogenic
691970	NM_017951.5(SMPD4):c.345+1G>T	Pathogenic
691973	NM_017951.5(SMPD4):c.1356_1362del (p.Leu453fs)	Pathogenic
1030617	NM_017951.5(SMPD4):c.1893+2T>C	Likely pathogenic
1684150	NM_017951.5(SMPD4):c.546_547del (p.Ala183fs)	Likely pathogenic
2433653	NM_017951.5(SMPD4):c.2074G>T (p.Glu692Ter)	Likely pathogenic
2433656	NM_017951.5(SMPD4):c.1961_1962delinsC (p.Lys654fs)	Likely pathogenic
3027157	NM_017951.5(SMPD4):c.2068del (p.Asp690fs)	Likely pathogenic
3062305	NM_017951.5(SMPD4):c.2242_2260del (p.Ser748fs)	Likely pathogenic
3062306	NM_017951.5(SMPD4):c.202dup (p.Leu68fs)	Likely pathogenic
3064542	NM_017951.5(SMPD4):c.1660-28_1666del	Likely pathogenic
3065042	NM_017951.5(SMPD4):c.127-2A>G	Likely pathogenic
3342595	NM_017951.5(SMPD4):c.2063del (p.Gln688fs)	Likely pathogenic
3362584	NM_017951.5(SMPD4):c.273_289del (p.Pro92fs)	Likely pathogenic
3584370	NM_017951.5(SMPD4):c.1971del (p.Asp658fs)	Likely pathogenic
3780652	NM_017951.5(SMPD4):c.1098-2A>G	Likely pathogenic
4082515	NM_017951.5(SMPD4):c.1504C>T (p.Arg502Ter)	Likely pathogenic
4292369	NM_017951.5(SMPD4):c.525_550dup (p.Tyr184fs)	Likely pathogenic
4293856	NM_017951.5(SMPD4):c.1612C>T (p.Gln538Ter)	Likely pathogenic
4849354	NM_017951.5(SMPD4):c.1446del (p.Gln483fs)	Likely pathogenic
691971	NM_017951.5(SMPD4):c.82C>T (p.Gln28Ter)	Likely pathogenic
870337	NM_017951.5(SMPD4):c.253G>T (p.Glu85Ter)	Likely pathogenic
870338	NM_017951.5(SMPD4):c.575T>C (p.Leu192Pro)	Likely pathogenic

SpliceAI

3921 predictions. Top by Δscore:

Variant	Effect	Δscore
2:130152881:CAAA:C	acceptor_gain	1.0000
2:130152883:AA:A	acceptor_gain	1.0000
2:130152885:C:CC	acceptor_gain	1.0000
2:130153038:CTCA:C	donor_gain	1.0000
2:130153041:A:AC	donor_gain	1.0000
2:130153042:C:CT	donor_gain	1.0000
2:130153042:CT:C	donor_gain	1.0000
2:130153042:CTCTG:C	donor_gain	1.0000
2:130153168:TGAT:T	acceptor_gain	1.0000
2:130153169:GAT:G	acceptor_gain	1.0000
2:130153169:GATC:G	acceptor_loss	1.0000
2:130153170:ATCTA:A	acceptor_loss	1.0000
2:130153171:TCTAG:T	acceptor_loss	1.0000
2:130153172:C:CC	acceptor_gain	1.0000
2:130153173:T:G	acceptor_loss	1.0000
2:130153694:G:C	donor_gain	1.0000
2:130153696:TCGTA:T	donor_loss	1.0000
2:130153697:CGTAC:C	donor_loss	1.0000
2:130153698:GTACC:G	donor_loss	1.0000
2:130153699:TACC:T	donor_loss	1.0000
2:130153700:A:AC	donor_gain	1.0000
2:130153700:A:AG	donor_loss	1.0000
2:130153700:AC:A	donor_gain	1.0000
2:130153701:C:CC	donor_gain	1.0000
2:130153701:CC:C	donor_gain	1.0000
2:130153725:C:CA	donor_gain	1.0000
2:130153936:C:CA	acceptor_loss	1.0000
2:130153937:T:A	acceptor_loss	1.0000
2:130154273:TCACC:T	donor_loss	1.0000
2:130154274:CAC:C	donor_loss	1.0000

AlphaMissense

5393 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:130156102:A:G	W447R	1.000
2:130156102:A:T	W447R	1.000
2:130156119:A:G	L441P	1.000
2:130156123:A:G	W440R	1.000
2:130156123:A:T	W440R	1.000
2:130157343:C:A	K374N	1.000
2:130157343:C:G	K374N	1.000
2:130155146:C:G	R507P	0.999
2:130155248:A:T	V473D	0.999
2:130156100:C:A	W447C	0.999
2:130156100:C:G	W447C	0.999
2:130156104:G:T	P446Q	0.999
2:130156115:G:C	S442R	0.999
2:130156115:G:T	S442R	0.999
2:130156117:T:G	S442R	0.999
2:130156119:A:T	L441Q	0.999
2:130156127:C:A	E438D	0.999
2:130156127:C:G	E438D	0.999
2:130156128:T:A	E438V	0.999
2:130156129:C:T	E438K	0.999
2:130156611:A:G	W427R	0.999
2:130156611:A:T	W427R	0.999
2:130157253:T:A	K404N	0.999
2:130157253:T:G	K404N	0.999
2:130157328:A:C	F379L	0.999
2:130157328:A:T	F379L	0.999
2:130157330:A:G	F379L	0.999
2:130157338:A:G	L376P	0.999
2:130157345:T:C	K374E	0.999
2:130164430:A:G	W309R	0.999

dbSNP variants (sampled 300 via entrez): RS1000136066 (2:130180891 G>T), RS1000285877 (2:130154163 G>A,T), RS1000387399 (2:130154602 C>T), RS1000536099 (2:130182056 G>A,C), RS1001043467 (2:130181863 T>A,C), RS1001355324 (2:130164275 C>G), RS1001372660 (2:130154667 A>G), RS1001427051 (2:130176491 C>T), RS1001444612 (2:130154822 G>A), RS1001531497 (2:130175797 G>A), RS1001758608 (2:130181300 C>A,G,T), RS1001812883 (2:130176852 CT>C,CTT), RS1002147837 (2:130182399 G>A), RS1002167213 (2:130165156 C>A,T), RS1002221008 (2:130165473 A>G)

Disease associations

OMIM: gene MIM:610457 | disease phenotypes: MIM:618622

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies	Strong	Autosomal recessive

Mondo (1): neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (MONDO:0032838)

Orphanet (1): Congenital arthrogryposis-microcephaly-facial dysmorphism-severe neurodevelopmental delay syndrome (Orphanet:664923)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000193	Bifid uvula
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000303	Mandibular prognathia
HP:0000319	Smooth philtrum
HP:0000322	Short philtrum
HP:0000340	Sloping forehead
HP:0000341	Narrow forehead
HP:0000358	Posteriorly rotated ears
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000470	Short neck
HP:0000494	Downslanted palpebral fissures
HP:0000601	Hypotelorism
HP:0000819	Diabetes mellitus
HP:0000954	Single transverse palmar crease
HP:0001181	Adducted thumb
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001321	Cerebellar hypoplasia
HP:0001511	Intrauterine growth retardation
HP:0001522	Death in infancy
HP:0001622	Premature birth

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066252 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Sphingomyelin phosphodiesterase

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.05	Kd	89.56	nM	CHEMBL5653589
7.05	ED50	89.56	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149449: Binding affinity to human SMPD4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0896	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases expression	3
Arsenic	affects methylation, decreases expression, increases abundance	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
bisphenol A	decreases expression	1
trichostatin A	affects expression	1
beta-lapachone	decreases expression, increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
Vehicle Emissions	increases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Caffeine	decreases phosphorylation	1
Catechin	decreases expression, affects cotreatment	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Lead	affects splicing	1
Ribonucleotides	affects binding	1
Smoke	decreases expression	1
Dronabinol	increases expression	1
Valproic Acid	increases methylation	1
Vitamin E	increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652491	Binding	Binding affinity to human SMPD4 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.