DEGS1

Summary

DEGS1 (delta 4-desaturase, sphingolipid 1, HGNC:13709) is a protein-coding gene on chromosome 1q42.11, encoding Sphingolipid delta(4)-desaturase DES1 (O15121). Has sphingolipid-delta-4-desaturase activity.

This gene encodes a member of the membrane fatty acid desaturase family which is responsible for inserting double bonds into specific positions in fatty acids. This protein contains three His-containing consensus motifs that are characteristic of a group of membrane fatty acid desaturases. It is predicted to be a multiple membrane-spanning protein localized to the endoplasmic reticulum. Overexpression of this gene inhibited biosynthesis of the EGF receptor, suggesting a possible role of a fatty acid desaturase in regulating biosynthetic processing of the EGF receptor.

Source: NCBI Gene 8560 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukodystrophy, hypomyelinating, 18 (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 109 total — 8 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 28
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003676

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13709
Approved symbol	DEGS1
Name	delta 4-desaturase, sphingolipid 1
Location	1q42.11
Locus type	gene with protein product
Status	Approved
Aliases	MLD, Des-1, DES1, FADS7, DEGS-1
Ensembl gene	ENSG00000143753
Ensembl biotype	protein_coding
OMIM	615843
Entrez	8560

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000323699, ENST00000415210, ENST00000465848, ENST00000498813, ENST00000910544

RefSeq mRNA: 3 — MANE Select: NM_003676 NM_001321541, NM_001321542, NM_003676

CCDS: CCDS1540

Canonical transcript exons

ENST00000323699 — 3 exons

Exon	Start	End
ENSE00000961810	224189577	224190319
ENSE00001354168	224192332	224193441
ENSE00001866625	224183240	224183418

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 71.6692 / max 495.3202, expressed in 1825 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8782	67.6511	1825
8783	2.8128	1422
8784	0.4732	267
8781	0.3455	165
8779	0.2351	57
8780	0.1363	56
201964	0.0153	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of hip	UBERON:0001554	99.78	gold quality
upper leg skin	UBERON:0004262	99.77	gold quality
penis	UBERON:0000989	99.58	gold quality
cervix squamous epithelium	UBERON:0006922	99.41	gold quality
mammalian vulva	UBERON:0000997	99.38	gold quality
skin of abdomen	UBERON:0001416	99.25	gold quality
zone of skin	UBERON:0000014	99.21	gold quality
skin of leg	UBERON:0001511	99.14	gold quality
nipple	UBERON:0002030	99.07	gold quality
endothelial cell	CL:0000115	98.92	gold quality
upper arm skin	UBERON:0004263	98.92	gold quality
choroid plexus epithelium	UBERON:0003911	98.60	gold quality
hair follicle	UBERON:0002073	98.58	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.22	gold quality
gingival epithelium	UBERON:0001949	98.21	gold quality
gingiva	UBERON:0001828	98.00	gold quality
placenta	UBERON:0001987	97.55	gold quality
saphenous vein	UBERON:0007318	97.52	gold quality
visceral pleura	UBERON:0002401	97.44	gold quality
cranial nerve II	UBERON:0000941	97.34	gold quality
cauda epididymis	UBERON:0004360	97.25	gold quality
trabecular bone tissue	UBERON:0002483	97.14	gold quality
tongue squamous epithelium	UBERON:0006919	97.04	gold quality
parietal pleura	UBERON:0002400	97.01	gold quality
stromal cell of endometrium	CL:0002255	97.00	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.00	gold quality
cervix epithelium	UBERON:0004801	96.99	gold quality
pleura	UBERON:0000977	96.89	gold quality
seminal vesicle	UBERON:0000998	96.81	gold quality
mammary duct	UBERON:0001765	96.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

70 targeting DEGS1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-7844-5P	99.55	68.56	1428

Literature-anchored findings (GeneRIF, showing 21)

• identification of sphingolipid delta 4-desaturase family (PMID:11937514)
• partial loss of DEGS-1 inhibited cell growth, with cell cycle arrest at G(0)/G(1). This was accompanied by a significant decrease in the amount of phosphorylated retinoblastoma protein (PMID:17283068)
• oxidative stress leads to potent inhibition of dihydroceramide desaturase resulting in significant elevation in dihydroceramide levels in vivo (PMID:20105137)
• overexpression of DEGS1 or DEGS2 attenuates the DHC accumulation and increased cell proliferation during hypoxia (PMID:21914808)
• a role of the sphingolipid pathway, dihydroceramides desaturase in particular, in confluence-induced growth arrest in neuroblastoma cells (PMID:22377532)
• changes in lipid homeostasis and gene expression in Huh7 hepatocytes when the synthesis of ceramide is perturbed by knocking down serine pal mitoyltransferase subunits 1, 2, and 3 (SPTLC123) or dihydroceramide desaturase 1 (DEGS1) (PMID:22628619)
• Dihydroceramide desaturase 1 (DES) is a potential molecular target for regulating apoptotic resistance to photodynamic therapy (PMID:23267130)
• SKI II is a noncompetitive inhibitor (Ki = 0.3 muM) of Des1 activity with effect also in intact cells without modifying Des1 protein levels. Molecular modeling studies support that the SKI II-induced decrease in Des1 activity could result from inhibition of NADH-cytochrome b5 reductase. (PMID:24875537)
• ABC294640 may reduce the proliferative capacity of castration-resistant prostate cancer cells through inhibition of both sphingosine kinase 2 and dihydroceramide desaturase. (PMID:26494858)
• DES1 plays a key role in palmitic acid-mediated caspase 9 and caspase 3 activation. (PMID:27364952)
• Pratensein induced both FADS1 and FADS2 in differentiated 3T3-L1 cells and DEGS1 was increased by treatment with apigenin, genistein, luteolin, orobol, and quercetin. In conclusion, pratensein may be an interesting test compound for further studies in vitro and in vivo on omega-3 synthesis since it induces its rate-limiting enzyme FADS2 (PMID:30365230)
• DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems. (PMID:30620338)
• DEGS1 variant causes neurological disorder. (PMID:31186544)
• Sphingolipid Modulation Activates Proteostasis Programs to Govern Human Hematopoietic Stem Cell Self-Renewal. (PMID:31631013)
• Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress. (PMID:33852856)
• N-(4-Hydroxyphenyl) Retinamide Suppresses SARS-CoV-2 Spike Protein-Mediated Cell-Cell Fusion by a Dihydroceramide Delta4-Desaturase 1-Independent Mechanism. (PMID:34106748)
• Dihydroceramide desaturase 1 (DES1) promotes anchorage-independent survival downstream of HER2-driven glucose uptake and metabolism. (PMID:36165222)
• Dihydroceramide Delta4-Desaturase 1 Is Not Involved in SARS-CoV-2 Infection. (PMID:36184516)
• Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity. (PMID:36951944)
• The atypical sphingolipid SPB 18:1(14Z);O2 is a biomarker for DEGS1 related hypomyelinating leukodystrophy. (PMID:37890668)
• Loss of function and reduced levels of sphingolipid desaturase DEGS1 variants are both relevant in disease mechanism. (PMID:38342436)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	degs1	ENSDARG00000007347
mus_musculus	Degs1	ENSMUSG00000038633
mus_musculus	Degs1l	ENSMUSG00000038768
rattus_norvegicus	Degs1	ENSRNOG00000003223
rattus_norvegicus	Degs1l2	ENSRNOG00000003601
rattus_norvegicus	Degs1l1	ENSRNOG00000050163
drosophila_melanogaster	ifc	FBGN0001941
caenorhabditis_elegans	ttm-5	WBGENE00013197
caenorhabditis_elegans		WBGENE00017996

Paralogs (1): DEGS2 (ENSG00000168350)

Protein

Protein identifiers

Sphingolipid delta(4)-desaturase DES1 — O15121 (reviewed: O15121)

Alternative names: Cell migration-inducing gene 15 protein, Degenerative spermatocyte homolog 1, Dihydroceramide desaturase-1, Membrane lipid desaturase, Retinol isomerase

All UniProt accessions (2): O15121, E7EMA0

UniProt curated annotations — full annotation on UniProt →

Function. Has sphingolipid-delta-4-desaturase activity. Converts D-erythro-sphinganine to D-erythro-sphingosine (E-sphing-4-enine). Catalyzes the equilibrium isomerization of retinols.

Subunit / interactions. Interacts with RLBP1; the interaction increases synthesis of chromophore-precursors by DEGS1.

Subcellular location. Mitochondrion membrane. Endoplasmic reticulum membrane.

Tissue specificity. Ubiquitous.

Post-translational modifications. Myristoylation can target the enzyme to the mitochondria leading to an increase in ceramide levels.

Disease relevance. Leukodystrophy, hypomyelinating, 18 (HLD18) [MIM:618404] An autosomal recessive disorder characterized by hypomyelinating leukodystrophy with progressive atrophy of the corpus callosum, thalami and cerebellum, and peripheral neuropathy. Clinical features include very poor psychomotor development, dystonia, severe spasticity, seizures, and failure to thrive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the fatty acid desaturase type 1 family. DEGS subfamily.

RefSeq proteins (3): NP_001308470, NP_001308471, NP_003667* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005804	FA_desaturase_dom	Domain
IPR011388	DES1/DES2	Family
IPR013866	Sphingolipid_d4-desaturase_N	Domain

Pfam: PF00487, PF08557

Enzyme classification (BRENDA):

• EC 1.14.19.17 — sphingolipid 4-desaturase (BRENDA: 10 organisms, 25 substrates, 75 inhibitors, 3 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
N-OCTANOYL-D-ERYTHRO-C18-SPHINGANINE	0.34	1
N-OCTANOYLDIHYDROCERAMIDE	0.0015	1
NADH	0.12	1

Catalyzed reactions (Rhea), 6 shown:

• all-trans-retinol = 11-cis-retinol (RHEA:19141)
• an N-acylsphinganine + 2 Fe(II)-[cytochrome b5] + O2 + 2 H(+) = an N-acylsphing-4-enine + 2 Fe(III)-[cytochrome b5] + 2 H2O (RHEA:46544)
• all-trans-retinol = 9-cis-retinol (RHEA:55348)
• all-trans-retinol = 13-cis-retinol (RHEA:55352)
• 11-cis-retinol = 13-cis-retinol (RHEA:55356)
• 11-cis-retinol = 9-cis-retinol (RHEA:55360)

UniProt features (23 total): sequence variant 10, transmembrane region 6, short sequence motif 3, initiator methionine 1, chain 1, modified residue 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15121-F1	96.93	0.96

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 (2): 307, 2

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 282 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, GOCC_SECRETORY_GRANULE, BOYAULT_LIVER_CANCER_SUBCLASS_G2, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_PLASMA_MEMBRANE_ORGANIZATION, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, CHANG_IMMORTALIZED_BY_HPV31_DN, GALE_APL_WITH_FLT3_MUTATED_DN, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS

GO Biological Process (8): unsaturated fatty acid biosynthetic process (GO:0006636), glycosphingolipid biosynthetic process (GO:0006688), sphingolipid biosynthetic process (GO:0030148), myelin maintenance (GO:0043217), ceramide biosynthetic process (GO:0046513), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631), fatty acid biosynthetic process (GO:0006633)

GO Molecular Function (6): electron transfer activity (GO:0009055), sphingolipid delta-4 desaturase activity (GO:0042284), retinol isomerase activity (GO:0050251), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), isomerase activity (GO:0016853)

GO Cellular Component (9): mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020), mitochondrial membrane (GO:0031966), specific granule membrane (GO:0035579), cytoplasmic side of endoplasmic reticulum membrane (GO:0098554), endomembrane system (GO:0012505)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Sphingolipid metabolism	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sphingolipid biosynthetic process	2
lipid biosynthetic process	2
catalytic activity	2
cytoplasm	2
intracellular membrane-bounded organelle	2
organelle membrane	2
cellular anatomical structure	2
fatty acid biosynthetic process	1
unsaturated fatty acid metabolic process	1
glycosphingolipid metabolic process	1
glycolipid biosynthetic process	1
sphingolipid metabolic process	1
plasma membrane organization	1
myelination	1
ceramide metabolic process	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
fatty acid metabolic process	1
monocarboxylic acid biosynthetic process	1
molecular_function	1
oxidoreductase activity, acting on paired donors, with oxidation of a pair of donors resulting in the reduction of molecular oxygen to two molecules of water	1
cis-trans isomerase activity	1
binding	1
endomembrane system	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
mitochondrion	1
mitochondrial envelope	1
secretory granule membrane	1
specific granule	1
endoplasmic reticulum membrane	1
cytoplasmic side of membrane	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

840 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DEGS1	SPTLC1	O15269	810
DEGS1	SPTLC2	O15270	768
DEGS1	SPTLC3	Q9NUV7	767
DEGS1	CERS6	Q6ZMG9	740
DEGS1	UGCG	Q16739	732
DEGS1	CERS2	Q96G23	696
DEGS1	KDSR	Q06136	688
DEGS1	CERS5	Q8N5B7	675
DEGS1	CERS4	Q9HA82	659
DEGS1	GDF1	P27539	630
DEGS1	SMPD2	O60906	619
DEGS1	CERS3	Q8IU89	608
DEGS1	SPHK1	Q9NYA1	607
DEGS1	ASAH1	Q13510	607
DEGS1	SGMS1	Q86VZ5	605
DEGS1	SPHK2	Q9NRA0	605

IntAct

69 interactions, top by confidence:

A	B	Type	Score
DEGS1	SEMA4G	psi-mi:“MI:0915”(physical association)	0.560
DEGS1	ARLN	psi-mi:“MI:0915”(physical association)	0.560
CD79A	METTL15	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
NCR3LG1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
CPLX2	DEGS1	psi-mi:“MI:0914”(association)	0.530
ARLN	DEGS1	psi-mi:“MI:0914”(association)	0.530
DEGS1	EIF5B	psi-mi:“MI:0915”(physical association)	0.400
DEGS1	ZFTRAF1	psi-mi:“MI:0915”(physical association)	0.400
NAGPA	DEGS1	psi-mi:“MI:0915”(physical association)	0.370
DEGS1	CFTR	psi-mi:“MI:0915”(physical association)	0.370
CFTR	DEGS1	psi-mi:“MI:0915”(physical association)	0.370
PSEN1	PGRMC1	psi-mi:“MI:0914”(association)	0.350
PACC1	DEGS1	psi-mi:“MI:0914”(association)	0.350
SLC17A2	PSMD11	psi-mi:“MI:0914”(association)	0.350
OPRM1	EXOC5	psi-mi:“MI:0914”(association)	0.350
LPAR6	DEGS1	psi-mi:“MI:0914”(association)	0.350
PTH1R	DEGS1	psi-mi:“MI:0914”(association)	0.350
SCARA3	DEGS1	psi-mi:“MI:0914”(association)	0.350
SIRT2	DEGS1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
DEGS1	SURF6	psi-mi:“MI:0914”(association)	0.350
VAPA	ESYT2	psi-mi:“MI:0914”(association)	0.350
VAPB	ESYT2	psi-mi:“MI:0914”(association)	0.350
KCNA2	TMEM129	psi-mi:“MI:0914”(association)	0.350
IGHM	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (104): DEGS1 (Affinity Capture-MS), LSG1 (Affinity Capture-MS), EIF5B (Affinity Capture-MS), UFD1L (Affinity Capture-MS), HDGFRP2 (Affinity Capture-MS), SUPT6H (Affinity Capture-MS), CYHR1 (Affinity Capture-MS), GTF2F1 (Affinity Capture-MS), DEGS1 (Affinity Capture-MS), DEGS1 (Affinity Capture-MS), DEGS1 (Affinity Capture-MS), DEGS1 (Affinity Capture-MS), DEGS1 (Affinity Capture-MS), DEGS1 (Affinity Capture-MS), DEGS1 (Affinity Capture-MS)

ESM2 similar proteins: A3F5L2, A3F5L3, C8V7U7, O09005, O15121, O65797, O81931, P32291, P46313, P48618, P48623, P48624, P48625, P48626, P48630, P59668, Q0II71, Q12618, Q2KIA4, Q39287, Q3EBF7, Q3ZBY7, Q41131, Q564G3, Q594P3, Q5F3C1, Q5RE51, Q5XIF5, Q68FB8, Q6H5U3, Q6QHC5, Q6RS95, Q6UQ04, Q84UB8, Q84UB9, Q84UC0, Q8GZC2, Q8R2F2, Q94515, Q9AT72

Diamond homologs: C4R613, G5EC63, O09005, O15121, O44186, O59715, Q0II71, Q3ZBY7, Q564G3, Q5AJX2, Q5F3C1, Q5RE51, Q5XIF5, Q68FB8, Q6H5U3, Q6QHC5, Q6UQ04, Q8R2F2, Q94515, Q9ZPH4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	8
Uncertain significance	52
Likely benign	20
Benign	9

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1457673	NM_003676.4(DEGS1):c.252dup (p.Thr85fs)	Pathogenic
1954874	NM_003676.4(DEGS1):c.49C>T (p.Gln17Ter)	Pathogenic
2719969	NM_003676.4(DEGS1):c.22G>T (p.Glu8Ter)	Pathogenic
3604176	NM_003676.4(DEGS1):c.825+4_825+5delinsTT	Pathogenic
3770186	Single allele	Pathogenic
625852	NM_003676.4(DEGS1):c.764A>G (p.Asn255Ser)	Pathogenic
626327	NM_003676.4(DEGS1):c.341_342del (p.Leu114fs)	Pathogenic
626328	NM_003676.4(DEGS1):c.604del (p.Tyr202fs)	Pathogenic
1514221	NM_003676.4(DEGS1):c.82+1G>C	Likely pathogenic
2502429	NM_003676.4(DEGS1):c.826-1G>A	Likely pathogenic
2584783	NM_003676.4(DEGS1):c.2T>C (p.Met1Thr)	Likely pathogenic
3062080	NM_003676.4(DEGS1):c.775C>T (p.His259Tyr)	Likely pathogenic
4086265	NM_003676.4(DEGS1):c.201A>T (p.Lys67Asn)	Likely pathogenic
626324	NM_003676.4(DEGS1):c.839C>T (p.Ala280Val)	Likely pathogenic
805859	NM_003676.4(DEGS1):c.397C>T (p.Arg133Trp)	Likely pathogenic
985447	NM_003676.4(DEGS1):c.752dup (p.Leu251fs)	Likely pathogenic

SpliceAI

650 predictions. Top by Δscore:

Variant	Effect	Δscore
1:224189575:A:AG	acceptor_gain	1.0000
1:224189576:G:GG	acceptor_gain	1.0000
1:224189576:GC:G	acceptor_gain	1.0000
1:224189576:GCA:G	acceptor_gain	1.0000
1:224189576:GCAA:G	acceptor_gain	1.0000
1:224189576:GCAAA:G	acceptor_gain	1.0000
1:224192326:TTCTA:T	acceptor_loss	1.0000
1:224192327:TCTA:T	acceptor_loss	1.0000
1:224192328:CTAG:C	acceptor_loss	1.0000
1:224192329:TA:T	acceptor_loss	1.0000
1:224192331:G:GC	acceptor_loss	1.0000
1:224192331:GGT:G	acceptor_gain	1.0000
1:224183415:CTGG:C	donor_loss	0.9900
1:224183417:GG:G	donor_gain	0.9900
1:224183418:GG:G	donor_gain	0.9900
1:224183418:GGTGA:G	donor_loss	0.9900
1:224183419:G:C	donor_loss	0.9900
1:224183419:G:GG	donor_gain	0.9900
1:224183420:T:A	donor_loss	0.9900
1:224189572:TACA:T	acceptor_loss	0.9900
1:224189575:A:AC	acceptor_loss	0.9900
1:224189576:G:A	acceptor_loss	0.9900
1:224192330:A:AG	acceptor_gain	0.9900
1:224192331:G:GG	acceptor_gain	0.9900
1:224192331:GGTGA:G	acceptor_gain	0.9900
1:224183358:G:GT	donor_gain	0.9800
1:224183358:G:T	donor_gain	0.9800
1:224183369:G:GG	donor_gain	0.9800
1:224183408:G:GT	donor_gain	0.9800
1:224192330:AGGT:A	acceptor_gain	0.9800

AlphaMissense

2159 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:224190281:C:G	H263D	0.999
1:224183401:G:C	R22P	0.998
1:224183404:G:C	R23P	0.998
1:224189885:C:G	H131D	0.998
1:224189887:T:A	H131Q	0.998
1:224189887:T:G	H131Q	0.998
1:224189888:C:G	H132D	0.998
1:224190192:A:T	H233L	0.998
1:224190193:T:A	H233Q	0.998
1:224190193:T:G	H233Q	0.998
1:224190269:C:G	H259D	0.998
1:224190282:A:C	H263P	0.998
1:224190283:T:A	H263Q	0.998
1:224190283:T:G	H263Q	0.998
1:224190284:G:C	D264H	0.998
1:224183391:C:G	H19D	0.997
1:224189876:C:G	H128D	0.997
1:224189890:T:A	H132Q	0.997
1:224189890:T:G	H132Q	0.997
1:224189915:G:C	D141H	0.997
1:224190191:C:G	H233D	0.997
1:224190192:A:C	H233P	0.997
1:224190280:T:A	H262Q	0.997
1:224190280:T:G	H262Q	0.997
1:224190285:A:G	D264G	0.997
1:224190285:A:T	D264V	0.997
1:224190288:T:C	F265S	0.997
1:224192345:C:A	A280E	0.997
1:224189864:T:C	F124L	0.996
1:224189866:T:A	F124L	0.996

dbSNP variants (sampled 300 via entrez): RS1000246865 (1:224189207 CT>C), RS1000268830 (1:224183902 C>T), RS1000998578 (1:224185285 A>T), RS1001284834 (1:224188827 C>A,T), RS1001338742 (1:224189154 A>G), RS1001466783 (1:224184196 G>T), RS1001493513 (1:224183662 A>C), RS1001612056 (1:224183838 G>C,T), RS1002287154 (1:224190619 A>G), RS1002339503 (1:224190988 C>G,T), RS1002881037 (1:224183121 G>A,T), RS1002903146 (1:224184648 A>G,T), RS1002973213 (1:224181609 G>A), RS1003002744 (1:224187641 A>C,T), RS1003563053 (1:224182863 G>A,C)

Disease associations

OMIM: gene MIM:615843 | disease phenotypes: MIM:618404, MIM:312080

GenCC curated gene-disease

Disease	Classification	Inheritance
leukodystrophy, hypomyelinating, 18	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
leukodystrophy, hypomyelinating, 18	Definitive	AR

Mondo (2): leukodystrophy, hypomyelinating, 18 (MONDO:0032730), leukodystrophy (MONDO:0019046)

Orphanet (1): Leukodystrophy (Orphanet:68356)

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000639	Nystagmus
HP:0000750	Delayed speech and language development
HP:0000762	Decreased nerve conduction velocity
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001310	Dysmetria
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001371	Flexion contracture
HP:0001508	Failure to thrive
HP:0002191	Progressive spasticity
HP:0002510	Spastic tetraplegia
HP:0002518	Abnormal periventricular white matter morphology
HP:0002650	Scoliosis
HP:0003487	Babinski sign
HP:0003676	Progressive
HP:0003828	Variable expressivity
HP:0005484	Secondary microcephaly
HP:0007108	Demyelinating peripheral neuropathy
HP:0007366	Atrophy/Degeneration affecting the brainstem
HP:0011344	Severe global developmental delay
HP:0011471	Gastrostomy tube feeding in infancy
HP:0011968	Feeding difficulties
HP:0040131	Abnormal motor nerve conduction velocity

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002403_66	Red blood cell count	1.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2021749 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 23,935 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL7301	FENRETINIDE	3	23,935

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Sphingolipid Δ⁴-desaturase

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
SKI II	Inhibition	6.52	pKi
RBM2-1B	Inhibition	4.74	pIC50

ChEMBL bioactivities

49 potent at pChembl≥5 of 51 total, top 45 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL5283631
9.00	IC50	1	nM	CHEMBL5267102
8.70	IC50	2	nM	CHEMBL6049628
8.52	IC50	3	nM	CHEMBL5898757
8.41	IC50	3.9	nM	CHEMBL5982554
8.40	IC50	4	nM	CHEMBL5280582
8.40	IC50	4	nM	CHEMBL5958435
8.30	IC50	5	nM	CHEMBL5844152
8.30	IC50	5	nM	CHEMBL5996966
8.30	IC50	5	nM	CHEMBL5758107
8.22	IC50	6	nM	CHEMBL5818984
8.00	IC50	10	nM	CHEMBL6022617
7.96	IC50	11	nM	CHEMBL5978910
7.89	IC50	13	nM	CHEMBL5779518
7.85	IC50	14	nM	CHEMBL5814299
7.80	IC50	16	nM	CHEMBL5741100
7.72	IC50	19	nM	CHEMBL5879916
7.68	IC50	21	nM	CHEMBL5995818
7.68	IC50	21	nM	CHEMBL5921115
7.66	Ki	22	nM	CHEMBL5275998
7.64	IC50	23	nM	CHEMBL5926409
7.30	IC50	50	nM	CHEMBL5905982
7.30	IC50	50	nM	CHEMBL6055350
7.28	IC50	52	nM	CHEMBL5275998
7.22	IC50	60	nM	CHEMBL6046751
7.20	IC50	63	nM	CHEMBL6044915
7.18	IC50	66	nM	CHEMBL5795081
7.06	IC50	88	nM	CHEMBL5991060
7.05	IC50	90	nM	CHEMBL5275806
7.00	IC50	100	nM	FENRETINIDE
6.89	IC50	130	nM	CHEMBL5800233
6.89	IC50	130	nM	CHEMBL5948642
6.85	IC50	140	nM	CHEMBL6044725
6.81	IC50	155	nM	CHEMBL5268107
6.75	IC50	180	nM	CHEMBL5766465
6.64	IC50	230	nM	CHEMBL5771889
6.62	IC50	240	nM	CHEMBL5825938
6.60	IC50	250	nM	CHEMBL5811619
6.52	Ki	300	nM	CHEMBL1076555
6.36	IC50	440	nM	CHEMBL229844
6.23	IC50	590	nM	CHEMBL6032998
6.08	IC50	840	nM	CHEMBL5951726
5.35	IC50	4460	nM	CHEMBL5999731
5.35	IC50	4500	nM	CHEMBL5841378
5.09	IC50	8200	nM	CHEMBL5828025

PubChem BioAssay actives

9 with measured affinity, of 29 total; 8 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-(4-chlorophenyl)-N-(5-hydroxy-2-pyridinyl)cyclohexane-1-carboxamide	1923482: Inhibition of DES1 (unknown origin)	ic50	0.0010	uM
N-(5-hydroxy-2-pyridinyl)-7-methyloctanamide	1923482: Inhibition of DES1 (unknown origin)	ic50	0.0010	uM
4-cyclohexyl-N-(5-hydroxy-2-pyridinyl)benzamide	1923482: Inhibition of DES1 (unknown origin)	ic50	0.0040	uM
N-[(1R,2S)-1,3-dihydroxy-1-(2-tridecylcyclopropen-1-yl)propan-2-yl]octanamide	1923479: Binding affinity to DES1 in human HGC-27 cell lysates assessed as inhibition constant	ki	0.0220	uM
4-cyclohexyl-N-(4-hydroxyphenyl)benzamide	1923482: Inhibition of DES1 (unknown origin)	ic50	0.0900	uM
(2E,4E,6E,8E)-N-(4-hydroxyphenyl)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenamide	1923482: Inhibition of DES1 (unknown origin)	ic50	0.1000	uM
N-[(E,2S,3R)-1,3-dihydroxyoctadec-6-en-2-yl]octanamide	1923478: Inhibition of DES1 in human HGC-27 cell lysates	ic50	0.1550	uM
4-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino]phenol	1923472: Noncompetitive inhibition of DES1 in human HGC-27 cell lysates assessed as inhibition constant	ki	0.3000	uM

CTD chemical–gene interactions

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	decreases expression, decreases reaction, increases expression	3
entinostat	increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Tretinoin	decreases expression, increases expression	2
Valproic Acid	increases expression	2
ABTL0812	decreases activity	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression, increases abundance	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
nickel chloride	decreases expression	1
aflatoxin B2	decreases methylation	1
resorcinol	increases expression	1
dihydroceramide	decreases activity, decreases reduction	1
K 7174	increases expression	1
abrine	decreases expression	1
N-((1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl)octanamide	decreases chemical synthesis, decreases reduction, decreases activity	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Biological Factors	decreases expression	1
Ceramides	decreases chemical synthesis, decreases activity	1
Cycloheximide	decreases expression, decreases reaction	1
Dimethyl Sulfoxide	increases expression	1
Methylcholanthrene	affects binding, increases reaction	1
Piroxicam	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Selenium	decreases expression	1

ChEMBL screening assays

17 unique, capped per target: 15 binding, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2026163	Binding	Inhibition of Des1 in human A549 cells assessed as formation of CerC6NBD from dhCerC6NBD after 4 hrs by HPLC-FD analysis	3-Deoxy-3,4-dehydro analogs of XM462. Preparation and activity on sphingolipid metabolism and cell fate. — Bioorg Med Chem
CHEMBL3767373	ADMET	Drug metabolism in human Jurkat cells assessed as DES1-mediated (2E,4E,6E,8E)-3,7-dimethyl-N-(4-oxocyclohexa-2,5-dienylidene)-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenamide formation	From Sphingosine Kinase to Dihydroceramide Desaturase: A Structure-Activity Relationship (SAR) Study of the Enzyme Inhibitory and Anticancer Activity of 4-((4-(4-Chlorophenyl)thiazol-2-yl)amino)phenol (SKI-II). — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2VT	Abcam HEK293T DEGS1 KO	Transformed cell line	Female
CVCL_E1VH	HAP1 DEGS1 (-)	Cancer cell line	Male
CVCL_F1Q5	HyCyte Hep-G2 KO-hDEGS1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00889174	Not specified	COMPLETED	The Nosology and Etiology of Leukodystrophies of Unknown Causes
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02843555	Not specified	COMPLETED	Natural History of the Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03639285	Not specified	RECRUITING	Natural History, Diagnosis, and Outcomes for Leukodystrophies
NCT05443906	Not specified	RECRUITING	Home Exercise for Individuals with Neurodegenerative Disease