ORMDL2

Summary

ORMDL2 (ORMDL sphingolipid biosynthesis regulator 2, HGNC:16037) is a protein-coding gene on chromosome 12q13.2, encoding ORM1-like protein 2 (Q53FV1). 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.

Source: NCBI Gene 29095 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 26 total
• MANE Select transcript: NM_014182

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16037
Approved symbol	ORMDL2
Name	ORMDL sphingolipid biosynthesis regulator 2
Location	12q13.2
Locus type	gene with protein product
Status	Approved
Aliases	HSPC160, adoplin-2, MST095, MSTP095
Ensembl gene	ENSG00000123353
Ensembl biotype	protein_coding
OMIM	610074
Entrez	29095

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 8 protein_coding, 1 retained_intron

ENST00000243045, ENST00000546645, ENST00000548974, ENST00000550836, ENST00000552672, ENST00000851416, ENST00000851417, ENST00000851418, ENST00000920546

RefSeq mRNA: 1 — MANE Select: NM_014182 NM_014182

CCDS: CCDS8893

Canonical transcript exons

ENST00000243045 — 4 exons

Exon	Start	End
ENSE00000838546	55818999	55819173
ENSE00001310110	55820260	55821879
ENSE00001420525	55818041	55818112
ENSE00003631179	55819342	55819493

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 96.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.9676 / max 125.1835, expressed in 1820 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125987	34.3603	1820
125988	2.6074	1253

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	96.63	gold quality
mucosa of transverse colon	UBERON:0004991	96.54	gold quality
tongue squamous epithelium	UBERON:0006919	96.07	gold quality
esophagus squamous epithelium	UBERON:0006920	96.06	gold quality
epithelium of esophagus	UBERON:0001976	95.73	gold quality
esophagus mucosa	UBERON:0002469	95.51	gold quality
oral cavity	UBERON:0000167	95.28	gold quality
ileal mucosa	UBERON:0000331	95.05	gold quality
lower esophagus mucosa	UBERON:0035834	94.99	gold quality
ileum	UBERON:0002116	94.94	silver quality
rectum	UBERON:0001052	94.51	gold quality
gingiva	UBERON:0001828	94.51	gold quality
gingival epithelium	UBERON:0001949	94.08	gold quality
colonic mucosa	UBERON:0000317	93.96	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.55	gold quality
granulocyte	CL:0000094	93.47	gold quality
pharyngeal mucosa	UBERON:0000355	93.25	gold quality
squamous epithelium	UBERON:0006914	92.92	gold quality
mammalian vulva	UBERON:0000997	92.77	gold quality
left testis	UBERON:0004533	92.65	gold quality
right testis	UBERON:0004534	92.65	gold quality
esophagus	UBERON:0001043	92.62	gold quality
right adrenal gland	UBERON:0001233	92.61	gold quality
decidua	UBERON:0002450	92.60	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.47	gold quality
mouth mucosa	UBERON:0003729	92.41	gold quality
thoracic aorta	UBERON:0001515	92.22	gold quality
left coronary artery	UBERON:0001626	92.18	gold quality
ascending aorta	UBERON:0001496	92.17	gold quality
upper lobe of left lung	UBERON:0008952	92.08	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.97
E-HCAD-13	yes	7.54

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting ORMDL2, 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-4531	99.99	69.70	3181
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-3128	99.50	67.85	1258
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-4641	99.28	66.64	744
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-1843	98.97	66.07	838
HSA-MIR-4802-5P	98.97	66.26	833
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-3149	98.77	67.13	1639

Literature-anchored findings (GeneRIF, showing 2)

• 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)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ormdl2	ENSDARG00000058022
mus_musculus	Ormdl2	ENSMUSG00000025353
rattus_norvegicus	Ormdl2	ENSRNOG00000030120
drosophila_melanogaster	ORMDL	FBGN0037110

Paralogs (2): ORMDL1 (ENSG00000128699), ORMDL3 (ENSG00000172057)

Protein

Protein identifiers

ORM1-like protein 2 — Q53FV1 (reviewed: Q53FV1)

Alternative names: Adoplin-2

All UniProt accessions (3): F8VWV8, F8VXD5, Q53FV1

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.

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 (1): NP_054901* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007203	ORMDL	Family

Pfam: PF04061

UniProt features (11 total): sequence conflict 4, topological domain 3, transmembrane region 3, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53FV1-F1	94.37	0.89

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis

MSigDB gene sets: 179 (showing top): GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, AAGCCAT_MIR135A_MIR135B, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_NEGATIVE_REGULATION_OF_AMIDE_METABOLIC_PROCESS, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, CREB_Q4, GOBP_LIPID_HOMEOSTASIS, GOBP_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, ONKEN_UVEAL_MELANOMA_UP, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS

GO Biological Process (6): ceramide metabolic process (GO:0006672), sphingolipid biosynthetic process (GO:0030148), intracellular sphingolipid homeostasis (GO:0090156), negative regulation of ceramide biosynthetic process (GO:1900060), sphingolipid metabolic process (GO:0006665), 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
ceramide biosynthetic process	2
lipid biosynthetic process	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 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

604 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ORMDL2	SPTLC1	O15269	886
ORMDL2	SPTLC2	O15270	855
ORMDL2	SPTLC3	Q9NUV7	853
ORMDL2	ORM1	P02763	847
ORMDL2	ORM2	P19652	820
ORMDL2	SPTSSA	Q969W0	632
ORMDL2	OR9Q1	Q8NGQ5	571
ORMDL2	OR1L8	Q8NGR8	571
ORMDL2	OR2T10	Q8NGZ9	571
ORMDL2	SARNP	P82979	526
ORMDL2	OR10V1	Q8NGI7	521
ORMDL2	OR2T11	Q8NH01	480
ORMDL2	OR52B6	Q8NGF0	479
ORMDL2	OR1J1	Q8NGS3	476
ORMDL2	SPTSSB	Q8NFR3	449

IntAct

94 interactions, top by confidence:

A	B	Type	Score
SPTLC1	SPTLC2	psi-mi:“MI:0914”(association)	0.680
	ORMDL2	psi-mi:“MI:0915”(physical association)	0.600
ORMDL2		psi-mi:“MI:0915”(physical association)	0.600
ORMDL2	SCN3B	psi-mi:“MI:0915”(physical association)	0.560
ORMDL2	CYB561	psi-mi:“MI:0915”(physical association)	0.560
ORMDL2	GJA8	psi-mi:“MI:0915”(physical association)	0.560
ORMDL2	TMX2	psi-mi:“MI:0915”(physical association)	0.560
ORMDL2	CREB3L1	psi-mi:“MI:0915”(physical association)	0.560
EBP	ORMDL2	psi-mi:“MI:0915”(physical association)	0.560
ORMDL2	TMEM120A	psi-mi:“MI:0915”(physical association)	0.560
ORMDL2	MMGT1	psi-mi:“MI:0915”(physical association)	0.560
CYB5R3	ORMDL2	psi-mi:“MI:0915”(physical association)	0.560
ORMDL2	FAM210B	psi-mi:“MI:0915”(physical association)	0.560
KCNJ6	ORMDL2	psi-mi:“MI:0915”(physical association)	0.560
ORMDL2	ELOVL4	psi-mi:“MI:0915”(physical association)	0.560
ORMDL2	TMEM86B	psi-mi:“MI:0915”(physical association)	0.560
CYB561	ORMDL2	psi-mi:“MI:0915”(physical association)	0.560
SLC10A1	ORMDL2	psi-mi:“MI:0915”(physical association)	0.560
GJA8	ORMDL2	psi-mi:“MI:0915”(physical association)	0.560
ORMDL2	RETREG3	psi-mi:“MI:0915”(physical association)	0.560
ORMDL2	ZDHHC15	psi-mi:“MI:0915”(physical association)	0.560
AQP6	ORMDL2	psi-mi:“MI:0915”(physical association)	0.560
CD79A	ORMDL2	psi-mi:“MI:0915”(physical association)	0.560
	ORMDL2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (81): ORMDL2 (Affinity Capture-MS), ORMDL2 (Affinity Capture-MS), ORMDL2 (Proximity Label-MS), ORMDL2 (Affinity Capture-MS), ORMDL2 (Affinity Capture-MS), ORMDL2 (Affinity Capture-MS), ORMDL2 (Affinity Capture-MS), ORMDL2 (Affinity Capture-MS), ORMDL2 (Affinity Capture-MS), ORMDL2 (Affinity Capture-MS), ORMDL2 (Affinity Capture-RNA), ORMDL2 (Reconstituted Complex), ORMDL2 (Affinity Capture-MS), ORMDL2 (Two-hybrid), ORMDL2 (Two-hybrid)

ESM2 similar proteins: A0A0E3D8L0, A0A0E3D8M3, A0A0M4KRN2, A0A0N0DCA4, A0A140JWS9, A0A194XJW1, A0A1U8QW16, A0A1V6NYL5, A0A1W5T1Y3, A0A384XG60, A0A455LLV4, A0A455LLW3, A0A455R4Z0, A6QS12, A9JPE4, D2E9W6, E3UBL5, G0LET6, J7FJH0, O13909, O13912, P0C148, P0CU77, P0DXW0, P0DXW1, P9WEG7, Q0C9L5, Q0U2R3, Q10255, Q29RQ9, Q4HXT5, Q53FV1, Q55E32, Q5E972, Q5R8X5, Q5XH57, Q5ZIU0, Q60M68, Q6BZU7, Q6QI25

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.

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	19
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

715 predictions. Top by Δscore:

Variant	Effect	Δscore
12:55819489:GTGCT:G	donor_gain	1.0000
12:55819490:TGCT:T	donor_gain	1.0000
12:55819491:GCT:G	donor_gain	1.0000
12:55819491:GCTG:G	donor_gain	1.0000
12:55819494:G:GG	donor_gain	1.0000
12:55820257:CAGCT:C	acceptor_loss	1.0000
12:55820258:A:AG	acceptor_gain	1.0000
12:55820258:A:AT	acceptor_loss	1.0000
12:55820259:G:GG	acceptor_gain	1.0000
12:55820259:GC:G	acceptor_gain	1.0000
12:55820259:GCT:G	acceptor_gain	1.0000
12:55820259:GCTA:G	acceptor_gain	1.0000
12:55820259:GCTAT:G	acceptor_gain	1.0000
12:55818110:C:T	donor_gain	0.9900
12:55818112:GG:G	donor_loss	0.9900
12:55818113:GTAG:G	donor_loss	0.9900
12:55818114:T:G	donor_loss	0.9900
12:55818992:C:CA	acceptor_gain	0.9900
12:55819339:CAGGC:C	acceptor_loss	0.9900
12:55819340:A:AG	acceptor_gain	0.9900
12:55819341:G:GG	acceptor_gain	0.9900
12:55819364:C:CA	acceptor_gain	0.9900
12:55819464:C:T	donor_gain	0.9900
12:55819494:GTGA:G	donor_loss	0.9900
12:55819495:T:A	donor_loss	0.9900
12:55820256:CCAG:C	acceptor_gain	0.9900
12:55820257:CAGC:C	acceptor_gain	0.9900
12:55820258:AGCT:A	acceptor_gain	0.9900
12:55820259:G:T	acceptor_gain	0.9900
12:55818988:A:AG	acceptor_gain	0.9800

AlphaMissense

997 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:55819144:T:A	W49R	0.991
12:55819144:T:C	W49R	0.991
12:55819425:G:C	W86C	0.985
12:55819425:G:T	W86C	0.985
12:55819381:T:C	F72L	0.983
12:55819383:T:A	F72L	0.983
12:55819383:T:G	F72L	0.983
12:55819371:A:C	K68N	0.981
12:55819371:A:T	K68N	0.981
12:55819427:A:T	E87V	0.981
12:55819423:T:A	W86R	0.980
12:55819423:T:C	W86R	0.980
12:55820273:A:C	S114R	0.976
12:55820275:C:A	S114R	0.976
12:55820275:C:G	S114R	0.976
12:55820314:C:A	N127K	0.976
12:55820314:C:G	N127K	0.976
12:55819428:G:C	E87D	0.975
12:55819428:G:T	E87D	0.975
12:55819431:A:C	Q88H	0.975
12:55819431:A:T	Q88H	0.975
12:55819114:A:C	S39R	0.973
12:55819116:C:A	S39R	0.973
12:55819116:C:G	S39R	0.973
12:55819372:G:A	G69R	0.973
12:55819372:G:C	G69R	0.973
12:55819372:G:T	G69W	0.973
12:55819170:C:A	N57K	0.971
12:55819170:C:G	N57K	0.971
12:55819158:C:A	N53K	0.968

dbSNP variants (sampled 300 via entrez): RS1000323363 (12:55818037 A>C), RS1000878438 (12:55818088 G>A,C), RS1001253250 (12:55817996 G>C), RS1002167516 (12:55818311 C>G,T), RS1002511602 (12:55818771 A>G), RS1002844851 (12:55821222 T>C), RS1002875932 (12:55821433 A>C), RS1003107904 (12:55820135 A>G), RS1003569683 (12:55819800 A>C), RS1004178422 (12:55817814 C>T), RS1004229331 (12:55817674 T>C,G), RS1004281686 (12:55817406 C>T), RS1004344845 (12:55817472 G>A), RS1005280661 (12:55818387 C>G,T), RS1006020877 (12:55816189 C>G,T)

Disease associations

OMIM: gene MIM:610074 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_217	Refractive error	6.000000e-174

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases methylation	4
Benzo(a)pyrene	increases expression	3
sodium arsenite	increases abundance, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Aflatoxin B1	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
bisphenol A	decreases expression	1
trichostatin A	affects expression	1
sodium bichromate	decreases expression	1
cobaltous chloride	decreases expression	1
ochratoxin A	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, increases expression	1
picoxystrobin	increases expression	1
Vorinostat	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Cadmium	increases expression	1
Cisplatin	increases expression	1
Diuron	decreases expression	1
Doxorubicin	decreases expression	1
Ivermectin	increases expression	1
Nickel	decreases expression	1
Ozone	affects expression, increases abundance	1

Clinical trials (associated diseases)

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