ORMDL1

Summary

ORMDL1 (ORMDL sphingolipid biosynthesis regulator 1, HGNC:16036) is a protein-coding gene on chromosome 2q32.2, encoding ORM1-like protein 1 (Q9P0S3). Plays an essential role in the homeostatic regulation of sphingolipid de novo biosynthesis by modulating the activity of the serine palmitoyltransferase (SPT) in response to ceramide levels.

Involved in ceramide metabolic process. Acts upstream of or within negative regulation of ceramide biosynthetic process. Located in endoplasmic reticulum membrane.

Source: NCBI Gene 94101 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 26 total
• MANE Select transcript: NM_016467

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16036
Approved symbol	ORMDL1
Name	ORMDL sphingolipid biosynthesis regulator 1
Location	2q32.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000128699
Ensembl biotype	protein_coding
OMIM	610073
Entrez	94101

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 45 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000325795, ENST00000392349, ENST00000392350, ENST00000409519, ENST00000442547, ENST00000458355, ENST00000496543, ENST00000850615, ENST00000853746, ENST00000853747, ENST00000853748, ENST00000853749, ENST00000853750, ENST00000853751, ENST00000853752, ENST00000853753, ENST00000853754, ENST00000853755, ENST00000853756, ENST00000853757, ENST00000853758, ENST00000853759, ENST00000853760, ENST00000853761, ENST00000853762, ENST00000853763, ENST00000853764, ENST00000853765, ENST00000853766, ENST00000921292, ENST00000921293, ENST00000921294, ENST00000921295, ENST00000921296, ENST00000921297, ENST00000921298, ENST00000921299, ENST00000921300, ENST00000921301, ENST00000961246, ENST00000961247, ENST00000961248, ENST00000961249, ENST00000961250, ENST00000961251, ENST00000961252

RefSeq mRNA: 7 — MANE Select: NM_016467 NM_001128150, NM_001371384, NM_001371385, NM_001371386, NM_001371387, NM_001371388, NM_016467

CCDS: CCDS2301

Canonical transcript exons

ENST00000392349 — 5 exons

Exon	Start	End
ENSE00000883225	189782422	189782602
ENSE00001001149	189784269	189784339
ENSE00001824545	189770267	189771902
ENSE00003789988	189775565	189775716
ENSE00004282335	189783014	189783123

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 98.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 53.7282 / max 273.6108, expressed in 1824 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32879	38.0138	1817
32878	11.2781	1757
32880	4.3776	1616
32881	0.0587	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	98.06	gold quality
granulocyte	CL:0000094	97.93	gold quality
spleen	UBERON:0002106	97.92	gold quality
monocyte	CL:0000576	97.61	gold quality
adenohypophysis	UBERON:0002196	97.49	gold quality
leukocyte	CL:0000738	97.48	gold quality
mucosa of stomach	UBERON:0001199	97.33	gold quality
right lung	UBERON:0002167	97.31	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.31	gold quality
metanephros cortex	UBERON:0010533	97.29	gold quality
ileal mucosa	UBERON:0000331	97.21	gold quality
gall bladder	UBERON:0002110	97.09	gold quality
right uterine tube	UBERON:0001302	96.96	gold quality
vermiform appendix	UBERON:0001154	96.95	gold quality
rectum	UBERON:0001052	96.91	gold quality
pituitary gland	UBERON:0000007	96.88	gold quality
right testis	UBERON:0004534	96.88	gold quality
right adrenal gland cortex	UBERON:0035827	96.84	gold quality
lymph node	UBERON:0000029	96.79	gold quality
right coronary artery	UBERON:0001625	96.78	gold quality
adrenal tissue	UBERON:0018303	96.77	gold quality
skin of abdomen	UBERON:0001416	96.76	gold quality
endocervix	UBERON:0000458	96.73	gold quality
right adrenal gland	UBERON:0001233	96.59	gold quality
upper lobe of left lung	UBERON:0008952	96.57	gold quality
left lobe of thyroid gland	UBERON:0001120	96.56	gold quality
smooth muscle tissue	UBERON:0001135	96.56	gold quality
body of stomach	UBERON:0001161	96.56	gold quality
left uterine tube	UBERON:0001303	96.54	gold quality
left testis	UBERON:0004533	96.53	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)

59 targeting ORMDL1, 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-6758-5P	100.00	66.21	1470
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-154-3P	99.50	70.05	831
HSA-MIR-487A-3P	99.50	69.95	840

Literature-anchored findings (GeneRIF, showing 5)

• Adoplin-1/ORMDL-1 displays reduced expression in association with presenilin mutations; Adoplin-1 & two highly homologous genes (adoplin-2, -3) are a gene family that encodes transmembrane proteins that may play roles in gamma-secretase complex maturation (PMID:17928364)
• ORMDL1, ORMDL2 and ORMDL3 mediate the feedback response in ceramide biosynthesis. (PMID:23066021)
• Expression of the ORMDLS, modulators of serine palmitoyltransferase, is regulated by sphingolipids in mammalian cells. (PMID:25395622)
• ORMDL1 downregulation modestly increased levels of sphingosine, S1P, and ceramide in HepG2 cells. (PMID:27313060)
• Expression Patterns and Prognostic Values of ORMDL1 in Different Cancers. (PMID:33145351)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ormdl1	ENSDARG00000014333
mus_musculus	Ormdl1	ENSMUSG00000026097
rattus_norvegicus	Ormdl1	ENSRNOG00000064999
drosophila_melanogaster	ORMDL	FBGN0037110

Paralogs (2): ORMDL2 (ENSG00000123353), ORMDL3 (ENSG00000172057)

Protein

Protein identifiers

ORM1-like protein 1 — Q9P0S3 (reviewed: Q9P0S3)

Alternative names: Adoplin-1

All UniProt accessions (3): Q9P0S3, A0A1B0GXE7, F6WST4

UniProt curated annotations — full annotation on UniProt →

Function. Plays an essential role in the homeostatic regulation of sphingolipid de novo biosynthesis by modulating the activity of the serine palmitoyltransferase (SPT) in response to ceramide levels. When complexed to SPT, the binding of ceramides to its N-terminus stabilizes a conformation that block SPT substrate entry, hence preventing SPT catalytic activity. Through this mechanism, maintains ceramide levels at sufficient concentrations for the production of complex sphingolipids, but which prevents the accumulation of ceramides to levels that trigger apoptosis.

Subunit / interactions. Ceramide-sensitive subunit of the serine palmitoyltransferase (SPT) complex, which is also composed of SPTLC1, SPTLC2/3 and SPTSSA/B.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Widely expressed. Expressed in adult and fetal heart, brain, lung, liver, skeletal muscle and kidney. Expressed in adult pancreas and placenta and in fetal spleen abd thymus. Expressed at intermediate level in pancreas, placenta and brain but low in skeletal muscle and lung.

Domain organisation. Ceramides bind to ORMDL3 N-terminus and stabilize it in a conformation that physically restricts the accessibility of the substrates to their binding sites in the serine palmitoyltransferase (SPT) complex, hence inhibiting SPT catalytic activity. In the absence of ceramides, the N-terminus is flexible and permits substrate binding, thus liberating SPT from inhibition.

Similarity. Belongs to the ORM family.

RefSeq proteins (7): NP_001121622, NP_001358313, NP_001358314, NP_001358315, NP_001358316, NP_001358317, NP_057551* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007203	ORMDL	Family

Pfam: PF04061

UniProt features (9 total): topological domain 4, transmembrane region 4, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P0S3-F1	93.70	0.86

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis

MSigDB gene sets: 151 (showing top): GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_NEGATIVE_REGULATION_OF_AMIDE_METABOLIC_PROCESS, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, GOBP_LIPID_HOMEOSTASIS, GOBP_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_AMIDE_BIOSYNTHETIC_PROCESS, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_LIPID_METABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS

GO Biological Process (10): ceramide metabolic process (GO:0006672), sphingomyelin biosynthetic process (GO:0006686), sphingolipid biosynthetic process (GO:0030148), myelination (GO:0042552), motor behavior (GO:0061744), intracellular sphingolipid homeostasis (GO:0090156), negative regulation of ceramide biosynthetic process (GO:1900060), sphingolipid metabolic process (GO:0006665), regulation of sphingolipid biosynthetic process (GO:0090153), regulation of ceramide biosynthetic process (GO:2000303)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), serine palmitoyltransferase complex (GO:0017059), 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
sphingolipid metabolic process	2
sphingolipid biosynthetic process	2
ceramide biosynthetic process	2
sphingomyelin metabolic process	1
phospholipid biosynthetic process	1
lipid biosynthetic process	1
axon ensheathment	1
behavior	1
intracellular chemical homeostasis	1
lipid homeostasis	1
negative regulation of sphingolipid biosynthetic process	1
regulation of ceramide biosynthetic process	1
lipid metabolic process	1
regulation of macromolecule biosynthetic process	1
regulation of cellular component biogenesis	1
regulation of lipid biosynthetic process	1
regulation of sphingolipid biosynthetic process	1
binding	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
palmitoyltransferase complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

728 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ORMDL1	SPTLC1	O15269	899
ORMDL1	SPTLC3	Q9NUV7	875
ORMDL1	SPTLC2	O15270	874
ORMDL1	ORM1	P02763	873
ORMDL1	ORM2	P19652	851
ORMDL1	SPTSSA	Q969W0	637
ORMDL1	ANKAR	Q7Z5J8	605
ORMDL1	SPTSSB	Q8NFR3	546
ORMDL1	NEMP2	A6NFY4	479
ORMDL1	OSGEPL1	Q9H4B0	418
ORMDL1	MFSD6	Q6ZSS7	407
ORMDL1	PMS1	P54277	383
ORMDL1	OR11L1	Q8NGX0	378
ORMDL1	RSL24D1	Q9UHA3	375
ORMDL1	HIBCH	Q6NVY1	374

IntAct

135 interactions, top by confidence:

A	B	Type	Score
SPTLC1	SPTLC2	psi-mi:“MI:0914”(association)	0.680
ORMDL1	RNF5	psi-mi:“MI:0915”(physical association)	0.560
ORMDL1	LEPROTL1	psi-mi:“MI:0915”(physical association)	0.560
ORMDL1	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
RNF5	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
ZDHHC15	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
LEPROTL1	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
SAR1A	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
ORMDL1	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
ASGR2	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
LNX1	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
EHHADH	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
TMEM143	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
REEP4	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
VMA21	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
PCNX2	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
TMEM14B	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
COQ9	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
TMEM52B	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
CREB3L1	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
GPR152	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
SLC10A1	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
STOM	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
CPLX4	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
ZFYVE27	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
ARL13B	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560
SLC10A6	ORMDL1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (74): ORMDL1 (Two-hybrid), ORMDL1 (Affinity Capture-MS), ORMDL1 (Affinity Capture-MS), ORMDL1 (Affinity Capture-MS), DCUN1D5 (Affinity Capture-MS), ORMDL1 (Affinity Capture-MS), NEMF (Affinity Capture-MS), TTC33 (Affinity Capture-MS), ORMDL1 (Two-hybrid), ORMDL1 (Two-hybrid), ORMDL1 (Two-hybrid), ORMDL1 (Two-hybrid), ORMDL1 (Two-hybrid), ORMDL1 (Two-hybrid), ORMDL1 (Two-hybrid)

ESM2 similar proteins: A0A0E3D8L0, A0A0E3D8M3, A0A0M4KRN2, A0A0N0DCA4, A0A140JWS9, A0A194XJW1, A0A1U8QW16, A0A1V6NWP3, A0A1V6NYL5, A0A1W5T1Y3, A0A2H3E985, A0A384XG60, A0A3G9JTR4, A0A3G9JYH7, A0A3G9K3N1, A0A455LLV4, A0A455LLW3, A0A455LLW7, A0A455R4Z0, A0A7L9EYL3, A0A8F4NWB9, A0A8F4S8P5, A6QS12, A9JPE4, D2E9W6, E3UBL5, G0LET6, J7FJH0, O13912, P0C148, P0CU77, P0DXW0, P0DXW1, P78980, P9WEG7, Q0C9L5, Q0U2R3, Q10255, Q4HXT5, Q55E32

Diamond homologs: D2I2F3, O42901, P53224, Q06144, Q0VD15, Q29RQ9, Q53FV1, Q5E972, Q5R570, Q5R8X5, Q5XH57, Q5XJR6, Q5ZIU0, Q6QI25, Q8JFB7, Q8N138, Q921I0, Q96495, Q9CPZ6, Q9CQZ0, Q9P0S3, Q9VP04

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 75 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
Transport of small molecules	9	5.4×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	0
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

968 predictions. Top by Δscore:

Variant	Effect	Δscore
2:189775563:A:AC	donor_gain	1.0000
2:189775564:C:CC	donor_gain	1.0000
2:189775593:T:TA	donor_gain	1.0000
2:189775594:C:A	donor_gain	1.0000
2:189775713:TCCC:T	acceptor_gain	1.0000
2:189775714:CCC:C	acceptor_gain	1.0000
2:189775714:CCCC:C	acceptor_gain	1.0000
2:189775715:CCC:C	acceptor_gain	1.0000
2:189775716:CCTGG:C	acceptor_loss	1.0000
2:189775717:C:A	acceptor_loss	1.0000
2:189775717:C:CC	acceptor_gain	1.0000
2:189775718:T:A	acceptor_loss	1.0000
2:189782598:TTGCT:T	acceptor_gain	1.0000
2:189782599:TGCT:T	acceptor_gain	1.0000
2:189782601:CT:C	acceptor_gain	1.0000
2:189782603:C:CC	acceptor_gain	1.0000
2:189775564:CAG:C	donor_gain	0.9900
2:189775564:CAGA:C	donor_gain	0.9900
2:189775564:CAGAA:C	donor_gain	0.9900
2:189775616:C:CA	donor_gain	0.9900
2:189775715:CC:C	acceptor_gain	0.9900
2:189775716:CC:C	acceptor_gain	0.9900
2:189782600:GCT:G	acceptor_gain	0.9900
2:189782601:CTC:C	acceptor_gain	0.9900
2:189782602:TCT:T	acceptor_gain	0.9900
2:189782602:TCTGT:T	acceptor_loss	0.9900
2:189782603:CT:C	acceptor_loss	0.9900
2:189782604:T:C	acceptor_loss	0.9900
2:189783120:CATG:C	acceptor_gain	0.9900
2:189775560:CT:C	donor_loss	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000100836 (2:189773956 G>C), RS1000223144 (2:189780942 G>T), RS1000377268 (2:189785935 G>A,C), RS1000451351 (2:189774230 T>C), RS1000613129 (2:189769396 A>AG), RS1000671751 (2:189774757 A>C), RS1000728928 (2:189786139 A>T), RS1000891989 (2:189768584 T>C), RS1000942637 (2:189768308 G>A), RS1001056441 (2:189776068 A>G), RS1001157224 (2:189782722 C>T), RS1001267074 (2:189780049 T>C), RS1001416479 (2:189785603 CAG>C), RS1001491377 (2:189785939 A>G), RS1001890715 (2:189770144 A>T)

Disease associations

OMIM: gene MIM:610073 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000730_10	Bilirubin levels	2.000000e-06
GCST002578_1	Ferritin levels	2.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004570	bilirubin measurement
EFO:0004459	ferritin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs5742933	ORMDL1, PMS1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, affects expression	3
bisphenol A	decreases methylation, affects cotreatment, increases expression	2
Smoke	increases abundance, decreases expression	2
dicrotophos	decreases expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression	1
ICG 001	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects expression	1
Coal	decreases expression, increases abundance	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Mercuric Chloride	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Sodium Selenite	increases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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