CERS1

Summary

CERS1 (ceramide synthase 1, HGNC:14253) is a protein-coding gene on chromosome 19p13.11, encoding Ceramide synthase 1 (P27544). Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward stearoyl-CoA (octadecanoyl-CoA; C18:0-CoA).

This gene encodes a ceramide synthase enzyme, which catalyzes the synthesis of ceramide, the hydrophobic moiety of sphingolipids. The encoded enzyme synthesizes 18-carbon (C18) ceramide in brain neurons. Elevated expression of this gene may be associated with increased longevity, while decreased expression of this gene may be associated with myoclonus epilepsy with dementia in human patients. This protein is transcribed from a monocistronic mRNA as well as a bicistronic mRNA, which also encodes growth differentiation factor 1.

Source: NCBI Gene 10715 — RefSeq curated summary.

At a glance

• Gene–disease (curated): progressive myoclonic epilepsy type 8 (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 529 total — 12 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes
• MANE Select transcript: NM_021267

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14253
Approved symbol	CERS1
Name	ceramide synthase 1
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	LAG1, UOG1
Ensembl gene	ENSG00000223802
Ensembl biotype	protein_coding
OMIM	606919
Entrez	10715

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000429504, ENST00000542296, ENST00000596048, ENST00000623882

RefSeq mRNA: 10 — MANE Select: NM_021267 NM_001290265, NM_001387439, NM_001387440, NM_001387441, NM_001387442, NM_001387443, NM_001387444, NM_001387445, NM_021267, NM_198207

CCDS: CCDS46020, CCDS46021, CCDS77267

Canonical transcript exons

ENST00000623882 — 8 exons

Exon	Start	End
ENSE00003478394	18879241	18879388
ENSE00003562809	18893416	18893575
ENSE00003567449	18880274	18880435
ENSE00003601441	18878930	18879039
ENSE00003623505	18884087	18884267
ENSE00003756060	18895824	18896158
ENSE00003758602	18868545	18869390
ENSE00003759162	18869983	18870619

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 98.48.

FANTOM5 (CAGE): breadth broad, TPM avg 4.9800 / max 434.1932, expressed in 731 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180104	11.0664	983
180103	4.1256	597
180105	1.2490	464
180101	0.5919	253
180096	0.1520	68
180102	0.0852	40
180106	0.0254	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	98.48	gold quality
right frontal lobe	UBERON:0002810	97.61	gold quality
spinal cord	UBERON:0002240	97.54	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.33	gold quality
anterior cingulate cortex	UBERON:0009835	97.20	gold quality
amygdala	UBERON:0001876	97.01	gold quality
putamen	UBERON:0001874	96.90	gold quality
hypothalamus	UBERON:0001898	96.89	gold quality
nucleus accumbens	UBERON:0001882	96.86	gold quality
caudate nucleus	UBERON:0001873	96.80	gold quality
prefrontal cortex	UBERON:0000451	96.01	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.83	gold quality
medial globus pallidus	UBERON:0002477	94.68	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.63	gold quality
substantia nigra	UBERON:0002038	94.60	gold quality
neocortex	UBERON:0001950	94.44	gold quality
frontal cortex	UBERON:0001870	94.12	gold quality
Ammon’s horn	UBERON:0001954	93.80	gold quality
cerebral cortex	UBERON:0000956	93.45	gold quality
cortical plate	UBERON:0005343	93.34	gold quality
cerebellar hemisphere	UBERON:0002245	93.31	gold quality
cerebellar cortex	UBERON:0002129	93.30	gold quality
midbrain	UBERON:0001891	93.15	gold quality
forebrain	UBERON:0001890	92.94	gold quality
brain	UBERON:0000955	92.69	gold quality
globus pallidus	UBERON:0001875	92.29	gold quality
cerebellum	UBERON:0002037	92.21	gold quality
temporal lobe	UBERON:0001871	91.63	gold quality
ventricular zone	UBERON:0003053	91.53	gold quality
primary visual cortex	UBERON:0002436	90.62	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.68

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CCDC3

miRNA regulators (miRDB)

17 targeting CERS1, 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-345-3P	99.89	70.23	1421
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-324-3P	99.26	66.31	1034
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-3117-5P	99.04	67.93	618
HSA-MIR-3130-5P	98.14	66.00	711
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-4288	97.11	67.23	1636
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-10396A-3P	93.99	62.06	94
HSA-MIR-10396B-3P	93.99	62.06	94

Literature-anchored findings (GeneRIF, showing 9)

• regulates N-stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian cel (PMID:12105227)
• LAG1 and C18-ceramide have roles in the regulation of growth of HNSCC (PMID:15317812)
• The study suggests that diverse stresses initiate responses through different signaling pathways, which ultimately converge to regulate CerS1 localization. (PMID:19800881)
• The variation in LASS1 is functional, causing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. (PMID:20569235)
• Moreover, an alternatively spliced variant CerS1 mRNA (CerS1-2) was detected mainly in cancer cells or primary tumour tissues compared to controls, which was targeted by miR-574-5p for degradation (PMID:22180294)
• This study highlights a close interaction between CLN5/CLN8 proteins, and their role in sphingolipid metabolism. Our findings suggest that CLN5p/CLN8p most likely are positive modulators of CerS1 and/or CerS2. (PMID:23160995)
• Single nucleotide polymorphisms in the gene LASS1 associated with programmed cell death, providing a potential cellular mechanism for the effects on tissue damage and circulating Creatine kinase. (PMID:26913518)
• The Potential Role of CERS1 in Autophagy Through PI3K/AKT Signaling Pathway in Hypophysoma. (PMID:33267708)
• Inhibition of CERS1 in skeletal muscle exacerbates age-related muscle dysfunction. (PMID:38506902)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cers1	ENSDARG00000063412
mus_musculus	Cers1	ENSMUSG00000087408
rattus_norvegicus	Gdf1	ENSRNOG00000070518
caenorhabditis_elegans	lagr-1	WBGENE00006505

Paralogs (5): CERS4 (ENSG00000090661), CERS5 (ENSG00000139624), CERS2 (ENSG00000143418), CERS3 (ENSG00000154227), CERS6 (ENSG00000172292)

Protein

Protein identifiers

Ceramide synthase 1 — P27544 (reviewed: P27544)

Alternative names: LAG1 longevity assurance homolog 1, Longevity assurance gene 1 protein homolog 1, Protein UOG-1, Sphingoid base N-stearoyltransferase CERS1

All UniProt accessions (3): P27544, M0R0T2, Q5XG75

UniProt curated annotations — full annotation on UniProt →

Function. Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward stearoyl-CoA (octadecanoyl-CoA; C18:0-CoA). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively. Plays a predominant role in skeletal muscle in regulating C18 ceramide and dihydroceramide levels with an impact on whole-body glucose metabolism and insulin sensitivity. Protects from diet-induced obesity by suppressing the uptake of glucose in multiple organs in a FGF21-dependent way. Generates C18 ceramides in the brain, playing a critical role in cerebellar development and Purkinje cell function. In response to cellular stress mediates mitophagy, a known defense mechanism against cell transformation and aging. Upon mitochondria fission, generates C18 ceramides that anchor lipidated MAP1LC3B/LC3B-II autophagolysosomes to outer mitochondrial membranes to eliminate damaged mitochondria.

Subcellular location. Endoplasmic reticulum membrane.

Post-translational modifications. Acetylated. Deacetylation by SIRT3 increases enzyme activity and promotes mitochondrial ceramide accumulation.

Disease relevance. Epilepsy, progressive myoclonic 8 (EPM8) [MIM:616230] A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. EPM8 is an autosomal recessive form characterized by myoclonus, generalized tonic-clonic seizures and moderate to severe cognitive impairment. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by fumonisin B1.

Pathway. Lipid metabolism; sphingolipid metabolism.

Miscellaneous. This protein is produced by a bicistronic gene which also produces the GDF1 protein from a non-overlapping reading frame.

Similarity. Belongs to the sphingosine N-acyltransferase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P27544-1	1	yes
P27544-2	2

RefSeq proteins (10): NP_001277194, NP_001374368, NP_001374369, NP_001374370, NP_001374371, NP_001374372, NP_001374373, NP_001374374, NP_067090, NP_937850 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006634	TLC-dom	Domain
IPR016439	Lag1/Lac1-like	Family

Pfam: PF03798

Enzyme classification (BRENDA):

• EC 2.3.1.299 — sphingoid base N-stearoyltransferase (BRENDA: 4 organisms, 36 substrates, 12 inhibitors, 4 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
D-ERYTHRO-SPHINGANINE	0.035	1
DIHYDROSPHINGOSINE	0.0025	1
STEAROYL-COA	0.003	1

Catalyzed reactions (Rhea), 7 shown:

• sphinganine + octadecanoyl-CoA = N-(octadecanoyl)-sphinganine + CoA + H(+) (RHEA:36547)
• eicosanoyl-CoA + sphinganine = N-eicosanoylsphinganine + CoA + H(+) (RHEA:36555)
• 2-hydroxyoctadecanoyl-CoA + sphinganine = N-(2-hydroxyoctadecanoyl)-sphinganine + CoA + H(+) (RHEA:36615)
• sphing-4-enine + octadecanoyl-CoA = N-octadecanoylsphing-4-enine + CoA + H(+) (RHEA:36691)
• hexadecasphinganine + octadecanoyl-CoA = N-octadecanoylhexadecasphinganine + CoA + H(+) (RHEA:43044)
• a sphingoid base + octadecanoyl-CoA = an N-octadecanoyl-sphingoid base + CoA + H(+) (RHEA:61476)
• heptadecasphing-4-enine + octadecanoyl-CoA = N-octadecanoyl-heptadecasphing-4-enine + CoA + H(+) (RHEA:67596)

UniProt features (16 total): transmembrane region 6, sequence variant 3, initiator methionine 1, chain 1, splice variant 1, mutagenesis site 1, sequence conflict 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P27544-F1	88.95	0.74

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 (1): 2

Mutagenesis-validated functional residues (1):

Position	Phenotype
183	loss of ceramide synthase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis

MSigDB gene sets: 134 (showing top): GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_CELLULAR_RESPONSE_TO_UV, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_MACROAUTOPHAGY, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (12): brain development (GO:0007420), negative regulation of cardiac muscle hypertrophy (GO:0010614), sphingolipid biosynthetic process (GO:0030148), cellular response to mycotoxin (GO:0036146), negative regulation of D-glucose import across plasma membrane (GO:0046325), ceramide biosynthetic process (GO:0046513), cellular response to xenobiotic stimulus (GO:0071466), cellular response to UV-A (GO:0071492), cellular response to dithiothreitol (GO:0072721), positive regulation of mitophagy (GO:1901526), lipid metabolic process (GO:0006629), sphingolipid metabolic process (GO:0006665)

GO Molecular Function (3): sphingosine N-acyltransferase activity (GO:0050291), obsolete N-acyltransferase activity (GO:0016410), transferase activity (GO:0016740)

GO Cellular Component (3): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sphingolipid metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
central nervous system development	1
animal organ development	1
head development	1
cardiac muscle hypertrophy	1
regulation of cardiac muscle hypertrophy	1
negative regulation of muscle hypertrophy	1
sphingolipid metabolic process	1
lipid biosynthetic process	1
response to mycotoxin	1
cellular response to toxic substance	1
negative regulation of D-glucose transmembrane transport	1
regulation of D-glucose import across plasma membrane	1
D-glucose import across plasma membrane	1
ceramide metabolic process	1
sphingolipid biosynthetic process	1
response to xenobiotic stimulus	1
cellular response to chemical stimulus	1
cellular response to UV	1
response to UV-A	1
response to dithiothreitol	1
cellular response to oxygen-containing compound	1
mitophagy	1
positive regulation of macroautophagy	1
regulation of mitophagy	1
positive regulation of autophagy of mitochondrion	1
primary metabolic process	1
lipid metabolic process	1
acyltransferase activity, transferring groups other than amino-acyl groups	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

29 interactions, top by confidence:

A	B	Type	Score
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
CERS1	BDKRB1	psi-mi:“MI:0915”(physical association)	0.370
CERS1	DRD2	psi-mi:“MI:0915”(physical association)	0.370
CERS1	HTR4	psi-mi:“MI:0915”(physical association)	0.370
CERS1	LTB4R2	psi-mi:“MI:0915”(physical association)	0.370
MAPK6	CERS1	psi-mi:“MI:0915”(physical association)	0.370
G	PGRMC2	psi-mi:“MI:0914”(association)	0.350
POMK	ESYT2	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
VCAM1	ATP2A1	psi-mi:“MI:0914”(association)	0.350
GPR182	TMEM120B	psi-mi:“MI:0914”(association)	0.350
HTR1E	ESYT2	psi-mi:“MI:0914”(association)	0.350
MFSD8	STXBP3	psi-mi:“MI:0914”(association)	0.350
NIPA1	UNC119B	psi-mi:“MI:0914”(association)	0.350
NPC1	SURF4	psi-mi:“MI:0914”(association)	0.350
SLC15A2	LGALS8	psi-mi:“MI:0914”(association)	0.350
SLC19A2	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC30A7	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC35F1	C15orf61	psi-mi:“MI:0914”(association)	0.350
SLC39A14	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC5A3	PGRMC1	psi-mi:“MI:0914”(association)	0.350
SLC5A9	RER1	psi-mi:“MI:0914”(association)	0.350
SLC6A11	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC6A12	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC7A3	ILVBL	psi-mi:“MI:0914”(association)	0.350
1C		psi-mi:“MI:0914”(association)	0.350
TCTN3	TMEM120B	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (47): CERS1 (Proximity Label-MS), ACTG1 (Affinity Capture-Western), CERS1 (Affinity Capture-MS), CERS1 (Proximity Label-MS), CERS1 (Two-hybrid), CERS1 (Two-hybrid), CERS1 (Two-hybrid), CERS1 (Two-hybrid), CERS1 (Proximity Label-MS), CERS1 (Proximity Label-MS), CERS1 (Proximity Label-MS), CERS1 (Proximity Label-MS), CERS1 (Proximity Label-MS), CERS1 (Proximity Label-MS), CERS1 (Proximity Label-MS)

ESM2 similar proteins: A6NGC4, A6NKX4, A6NM10, F1NZP5, O96011, P0C242, P27544, P27545, Q0VCY6, Q2TBI8, Q3SYU3, Q4V8E5, Q5F2F2, Q5JZQ7, Q5RFI0, Q5U2T1, Q5U419, Q6AYM9, Q6GQT6, Q6PIS1, Q6TCG5, Q6UXD7, Q6UXT9, Q71RH2, Q7TNV1, Q7Z403, Q80ZE4, Q863Y8, Q86WI3, Q8BMT9, Q8CHK3, Q8IU68, Q8IXF9, Q8N9H8, Q8TBR7, Q8VC26, Q8WUG5, Q96N66, Q99640, Q99JT6

Diamond homologs: A6ZSP9, A6ZZV7, G5ED45, O59735, P27544, P27545, P28496, P38703, P78970, Q5E9R6, Q8J2Q2, Q9D6J1, W7LKY5, Q1A3B0, Q6EUN0, Q6NQI8, Q6YWS8, Q6ZMG9, Q7Z139, Q84QC0, Q8C172, Q8N5B7, Q8W4Y5, Q9D6K9, Q9HA82, Q9LJK3, Q9XWE9, Q15035, Q15629, Q3ZBF8, Q5R7Z3, Q5XI41, Q8IU89, Q91V04, Q924Z4, Q924Z5, Q96G23, Q9LDF2, Q9M6A3, G1UJF5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CERS1	“up-regulates quantity”	ceramide	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 41 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
SLC-mediated transmembrane transport	5	10.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	12
Uncertain significance	269
Likely benign	205
Benign	10

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1074441	NM_001492.6(GDF1):c.742dup (p.Leu248fs)	Pathogenic
1322994	NM_001492.6(GDF1):c.264dup (p.Pro89fs)	Pathogenic
3018188	NM_001492.6(GDF1):c.933dup (p.Pro312fs)	Pathogenic
3776097	NM_021267.5(CERS1):c.269del (p.Cys90fs)	Pathogenic
4531712	NM_001492.6(GDF1):c.653dup (p.Leu219fs)	Pathogenic
4722046	NM_001492.6(GDF1):c.609G>A (p.Trp203Ter)	Pathogenic
4736658	NM_001492.6(GDF1):c.808_809del (p.Arg270fs)	Pathogenic
522570	NM_001492.6(GDF1):c.1090_1092del (p.Met364del)	Pathogenic
664346	NM_001492.6(GDF1):c.189G>A (p.Trp63Ter)	Pathogenic
665854	NM_001492.6(GDF1):c.523_586dup (p.Ala196fs)	Pathogenic
850258	NM_001492.6(GDF1):c.289del (p.Val97fs)	Pathogenic
915273	NM_001492.6(GDF1):c.667dup (p.Ala223fs)	Pathogenic
1301764	NM_021267.5(CERS1):c.*1120G>A	Likely pathogenic
1324461	NM_001492.6(GDF1):c.579_678del (p.Val194fs)	Likely pathogenic
1507891	NM_001492.6(GDF1):c.1092G>A (p.Met364Ile)	Likely pathogenic
2687842	NM_001492.6(GDF1):c.768_823del (p.Pro257fs)	Likely pathogenic
3377285	NM_001492.6(GDF1):c.91_98dup (p.Gly34fs)	Likely pathogenic
392938	NM_001492.6(GDF1):c.371G>T (p.Cys124Phe)	Likely pathogenic
4056383	NM_001492.6(GDF1):c.822del (p.Ser275fs)	Likely pathogenic
4086170	NM_001492.6(GDF1):c.968_969dup (p.Met324fs)	Likely pathogenic
418231	NM_001492.6(GDF1):c.401C>G (p.Ser134Trp)	Likely pathogenic
418232	NM_001492.6(GDF1):c.776_801del (p.Leu259fs)	Likely pathogenic
418233	NM_001492.6(GDF1):c.952G>A (p.Ala318Thr)	Likely pathogenic
977094	NM_001492.6(GDF1):c.380G>A (p.Trp127Ter)	Likely pathogenic

SpliceAI

1535 predictions. Top by Δscore:

Variant	Effect	Δscore
19:18878928:A:AC	donor_gain	1.0000
19:18878929:C:CC	donor_gain	1.0000
19:18878929:CT:C	donor_gain	1.0000
19:18878929:CTCGG:C	donor_gain	1.0000
19:18879035:ATGTA:A	acceptor_gain	1.0000
19:18879036:TGTA:T	acceptor_gain	1.0000
19:18879038:TA:T	acceptor_gain	1.0000
19:18879039:AC:A	acceptor_loss	1.0000
19:18879039:ACT:A	acceptor_loss	1.0000
19:18879040:C:CC	acceptor_gain	1.0000
19:18879040:CTG:C	acceptor_loss	1.0000
19:18879237:TCA:T	donor_loss	1.0000
19:18879237:TCACC:T	donor_loss	1.0000
19:18879238:CACCA:C	donor_loss	1.0000
19:18879239:A:AC	donor_gain	1.0000
19:18879239:ACCAG:A	donor_loss	1.0000
19:18879240:C:CC	donor_gain	1.0000
19:18879240:C:G	donor_loss	1.0000
19:18879387:ACCTG:A	acceptor_loss	1.0000
19:18880266:CCA:C	donor_gain	1.0000
19:18880269:CTCA:C	donor_loss	1.0000
19:18880270:TCAC:T	donor_loss	1.0000
19:18880271:CA:C	donor_loss	1.0000
19:18880272:A:AC	donor_gain	1.0000
19:18880272:AC:A	donor_gain	1.0000
19:18880273:C:CA	donor_gain	1.0000
19:18880273:CC:C	donor_gain	1.0000
19:18880273:CCAG:C	donor_gain	1.0000
19:18880398:CG:C	acceptor_gain	1.0000
19:18880433:TAC:T	acceptor_gain	1.0000

AlphaMissense

2269 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:18884133:G:C	H182D	0.999
19:18884206:G:C	S157R	0.999
19:18884206:G:T	S157R	0.999
19:18884208:T:G	S157R	0.999
19:18884133:G:T	H182N	0.997
19:18884193:A:G	S162P	0.997
19:18880366:C:A	K220N	0.996
19:18880366:C:G	K220N	0.996
19:18880397:T:A	D210V	0.996
19:18884099:G:A	S193F	0.996
19:18880397:T:G	D210A	0.995
19:18880398:C:A	D210Y	0.995
19:18880401:G:C	H209D	0.995
19:18884111:A:T	L189H	0.995
19:18884154:C:G	D175H	0.995
19:18884159:C:G	R173P	0.995
19:18893488:A:G	W113R	0.995
19:18893488:A:T	W113R	0.995
19:18879256:G:C	N295K	0.994
19:18879256:G:T	N295K	0.994
19:18880398:C:G	D210H	0.994
19:18880422:C:G	G202R	0.994
19:18884099:G:T	S193Y	0.994
19:18884128:G:C	H183Q	0.994
19:18884128:G:T	H183Q	0.994
19:18884153:T:G	D175A	0.994
19:18884160:G:T	R173S	0.994
19:18884203:G:C	F158L	0.994
19:18884203:G:T	F158L	0.994
19:18884205:A:G	F158L	0.994

dbSNP variants (sampled 300 via entrez): RS1000062904 (19:18868605 A>AG), RS1000168129 (19:18880936 C>T), RS1000275000 (19:18885438 C>T), RS1000287033 (19:18897391 C>CCCGCCA), RS1000292527 (19:18877606 G>C,T), RS1000371339 (19:18898172 T>G), RS1000450783 (19:18897161 AC>A,ACC), RS1000542322 (19:18873265 T>C), RS1000573480 (19:18873010 C>G,T), RS1000606848 (19:18891486 C>G,T), RS1000660977 (19:18892680 C>G), RS1000663212 (19:18885795 G>A), RS1000744427 (19:18886617 C>T), RS1000770254 (19:18879177 G>A,T), RS1000815859 (19:18875900 G>A,C)

Disease associations

OMIM: gene MIM:606919 | disease phenotypes: MIM:616230, MIM:613854, MIM:208530, MIM:306955, MIM:187500

GenCC curated gene-disease

Disease	Classification	Inheritance
progressive myoclonic epilepsy type 8	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
progressive myoclonus epilepsy	Moderate	AR

Mondo (8): progressive myoclonic epilepsy type 8 (MONDO:0014545), congenital heart defects, multiple types, 6 (MONDO:0013463), right atrial isomerism (MONDO:0008832), congenital heart defects, multiple types (MONDO:0000119), visceral heterotaxy (MONDO:0018677), transposition of the great arteries (MONDO:0000153), double outlet right ventricle (MONDO:0018089), tetralogy of fallot (MONDO:0008542)

Orphanet (8): Progressive myoclonic epilepsy type 8 (Orphanet:424027), Congenitally uncorrected transposition of the great arteries (Orphanet:860), Right isomerism (Orphanet:97548), Visceral heterotaxy (Orphanet:450), Transposition of the great arteries (Orphanet:216675), Double outlet right ventricle (Orphanet:3426), Tetralogy of Fallot (Orphanet:3303), Situs ambiguus (Orphanet:157769)

HPO phenotypes

21 total (22 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000639	Nystagmus
HP:0000726	Dementia
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001336	Myoclonus
HP:0002069	Bilateral tonic-clonic seizure
HP:0002070	Limb ataxia
HP:0002078	Truncal ataxia
HP:0002344	Progressive neurologic deterioration
HP:0002527	Falls
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0007366	Atrophy/Degeneration affecting the brainstem
HP:0010852	EEG with photoparoxysmal response
HP:0034360	Action myoclonus
HP:0011536	Right atrial isomerism

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D004310	Double Outlet Right Ventricle	C14.240.400.560.540.500; C14.240.400.915.300; C14.280.400.560.540.500; C14.280.400.915.300; C16.131.240.400.560.540.500; C16.131.240.400.915.300
D013771	Tetralogy of Fallot	C14.240.400.849; C14.280.400.849; C16.131.240.400.849
D014188	Transposition of Great Vessels	C14.240.400.915; C14.280.400.915; C16.131.240.400.915

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291526 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Ceramide synthase

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.27	IC50	540	nM	CHEMBL5268405

PubChem BioAssay actives

1 with measured affinity, of 4 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
(2S)-2-amino-4-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2-methylbutan-1-ol	1923490: Inhibition of human CerS1	ic50	0.5400	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases expression, increases expression	2
Valproic Acid	affects expression, increases methylation	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, increases methylation	1
TAK-243	decreases sumoylation	1
methylmercuric chloride	increases expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
bisphenol S	increases methylation	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	increases abundance, increases expression	1
Aldehydes	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Dronabinol	increases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5226571	Binding	Inhibition of CerS1 (unknown origin) at 10 uM relative to control	Small Molecule Inhibitors Targeting Biosynthesis of Ceramide, the Central Hub of the Sphingolipid Network. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00703352	PHASE4	COMPLETED	Eplerenone in Systemic Right Ventricle
NCT01971593	PHASE4	TERMINATED	The Effects of Eplerenone on Markers of Myocardial Fibrosis in Adult Congenital Heart Disease
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00006183	PHASE3	COMPLETED	Comparison of Hematocrit Levels in Infant Heart Surgery
NCT03661385	PHASE3	COMPLETED	Nitric Oxide During Bypass for Arterial Switch Operation
NCT00564993	PHASE3	TERMINATED	Cardiac Function Under Stress for Early Detection of the Right Ventricular Insufficiency After Repair of Tetralogy of Fallot
NCT00199771	PHASE2	COMPLETED	Hypertonic Saline Dextran in Pediatric Cardiac Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT04467671	PHASE2	RECRUITING	Two-Year Study of the Safety and Efficacy of the Second-Generation Tissue Engineered Vascular Grafts
NCT00848393	PHASE2	COMPLETED	Measures to Lower the Stress Response in Pediatric Cardiac Surgery
NCT02010905	PHASE2	UNKNOWN	Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System
NCT01915277	PHASE1	COMPLETED	A Phase I Study of Dexmedetomidine Bolus and Infusion in Corrective Infant Cardiac Surgery: Safety and Pharmacokinetics
NCT04713657	PHASE1	RECRUITING	Beta-blocker Administration for Cardiomyocyte Division
NCT00573066	PHASE1	COMPLETED	Understanding Dexmedetomidine In Infants Post-Operative From Cardiac Surgery
NCT04009863	Not specified	COMPLETED	HIFU Ablation vs Fixed-dose RAI-131 Therapy in Moderate-sized Non-toxic MNG
NCT01591928	Not specified	COMPLETED	Heterotaxy Syndrome and Intestinal Rotation Abnormalities - A Prospective Study
NCT01929967	Not specified	COMPLETED	Defining Immunodeficiency in Heterotaxy Syndrome: Pilot Study Data
NCT02432079	Not specified	RECRUITING	Molecular Genetics of Heterotaxy and Related Congenital Heart Defects
NCT00513240	PHASE1/PHASE2	COMPLETED	Erythropoetin Neuroprotection for Neonatal Cardiac Surgery
NCT00005190	Not specified	COMPLETED	Reproduction and Survival After Cardiac Defect Repair
NCT00837603	Not specified	COMPLETED	Physical Training in Transposition of the Great Arteries
NCT01916499	Not specified	COMPLETED	MRI Study After Arterial Switch Operation in Patients With Transposition of the Great Arteries
NCT02161471	Not specified	COMPLETED	Haemodynamics and Function of the Atria in Congenital Heart Disease by Cardiovascular Magnetic Resonance
NCT02184169	Not specified	COMPLETED	Oxygen Consumption-based Assessments of Hemodynamics in Neonates Following Congenital Heart Surgery (Oxy-CAHN Study)
NCT02415491	Not specified	UNKNOWN	Cardiovascular MRI and Cardiopulmonary Exercise Capacity After Neonatal ASO) in Young Adults
NCT02588989	Not specified	ACTIVE_NOT_RECRUITING	Fibrosis, Valvular and Ventricular Function in Patients With TGA
NCT03078413	Not specified	COMPLETED	Late Function After Surgery for Transposition of the Great Arteries
NCT03469843	Not specified	COMPLETED	Characterization of the Cardiac Reinnervation of Patients With Transposition of the Great Arteries Long After Repair With the Arterial Switch Operation. Correlation With Electrocardiographic and Exercise Test Parameters
NCT03833843	Not specified	COMPLETED	Sudden Cardiac Death in Systemic Right Ventricle
NCT04106479	Not specified	RECRUITING	NIRS in Congenital Heart Defects - Correlation With Echocardiography
NCT04288596	Not specified	NOT_YET_RECRUITING	Canadian Adult Congenital Heart Disease Intervention Registry
NCT04335448	Not specified	ACTIVE_NOT_RECRUITING	Comprehensive Long-term Follow up of Adults With Arterial Switch Operation
NCT04452188	Not specified	COMPLETED	Targeting Normoxia in Neonates With Cyanotic Congenital Heart Disease in the Intra-operative and Immediate Post-operative Period
NCT04616222	Not specified	UNKNOWN	A Retrospective Comparison of the Efficacy and Safety of Celsior® in Pediatric Cardiac Surgery for Transposition of the Great Vessels
NCT04788082	Not specified	WITHDRAWN	Clinical Impact of Rapid Prototyping 3D Models for Surgical Management
NCT05089773	Not specified	COMPLETED	Outcomes of Transposition of the Great Arteries After Arterial Switch Operation
NCT05160116	Not specified	COMPLETED	Influence of Timing of Switch Operation in Transposition of Great Arteries
NCT05452720	Not specified	RECRUITING	MASA Valve Early Feasibility Study
NCT05524324	Not specified	RECRUITING	Cardiac Resynchronization Therapy in Adult Congenital Heart Disease With Systemic Right Ventricle: RIGHT-CRT
NCT05809310	Not specified	RECRUITING	Effects Branch PA Stenting d-TGA, ToF and TA