ORMDL3

Summary

ORMDL3 (ORMDL sphingolipid biosynthesis regulator 3, HGNC:16038) is a protein-coding gene on chromosome 17q21.1, encoding ORM1-like protein 3 (Q8N138). 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 several processes, including negative regulation of B cell apoptotic process; negative regulation of ceramide biosynthetic process; and positive regulation of protein localization to nucleus. Located in endoplasmic reticulum. Part of serine palmitoyltransferase complex.

Source: NCBI Gene 94103 — RefSeq curated summary.

At a glance

• GWAS associations: 42
• Clinical variants (ClinVar): 13 total
• Druggable target: yes
• MANE Select transcript: NM_139280

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16038
Approved symbol	ORMDL3
Name	ORMDL sphingolipid biosynthesis regulator 3
Location	17q21.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000172057
Ensembl biotype	protein_coding
OMIM	610075
Entrez	94103

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 27 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000304046, ENST00000394169, ENST00000579287, ENST00000579695, ENST00000581284, ENST00000582052, ENST00000584000, ENST00000584220, ENST00000889245, ENST00000889246, ENST00000889247, ENST00000889248, ENST00000889249, ENST00000889250, ENST00000889251, ENST00000889252, ENST00000889253, ENST00000889254, ENST00000889255, ENST00000889256, ENST00000889257, ENST00000889258, ENST00000889259, ENST00000889260, ENST00000889261, ENST00000889262, ENST00000889263, ENST00000889264, ENST00000934567, ENST00000934568

RefSeq mRNA: 4 — MANE Select: NM_139280 NM_001320801, NM_001320802, NM_001320803, NM_139280

CCDS: CCDS11355

Canonical transcript exons

ENST00000304046 — 4 exons

Exon	Start	End
ENSE00001159333	39923112	39923263
ENSE00001283878	39927484	39927601
ENSE00001283938	39924030	39924225
ENSE00003843134	39921043	39922685

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 98.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.5242 / max 520.9071, expressed in 1810 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
165652	26.5121	1788
165653	12.8501	1772
165651	0.1460	77
165650	0.0160	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.28	gold quality
bone marrow cell	CL:0002092	97.38	gold quality
granulocyte	CL:0000094	97.09	gold quality
liver	UBERON:0002107	97.04	gold quality
stromal cell of endometrium	CL:0002255	96.91	gold quality
body of pancreas	UBERON:0001150	96.23	gold quality
colonic epithelium	UBERON:0000397	95.72	gold quality
adenohypophysis	UBERON:0002196	95.25	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.17	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.00	gold quality
omental fat pad	UBERON:0010414	94.97	gold quality
peritoneum	UBERON:0002358	94.93	gold quality
apex of heart	UBERON:0002098	94.86	gold quality
adipose tissue	UBERON:0001013	94.74	gold quality
right testis	UBERON:0004534	94.74	gold quality
left testis	UBERON:0004533	94.71	gold quality
pancreas	UBERON:0001264	94.67	gold quality
pituitary gland	UBERON:0000007	94.39	gold quality
right lobe of thyroid gland	UBERON:0001119	94.33	gold quality
left lobe of thyroid gland	UBERON:0001120	94.33	gold quality
thyroid gland	UBERON:0002046	94.03	gold quality
lymph node	UBERON:0000029	94.01	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.99	gold quality
kidney epithelium	UBERON:0004819	93.74	silver quality
ileal mucosa	UBERON:0000331	93.69	gold quality
tonsil	UBERON:0002372	93.62	gold quality
body of stomach	UBERON:0001161	93.47	gold quality
testis	UBERON:0000473	93.32	gold quality
islet of Langerhans	UBERON:0000006	93.31	gold quality
mucosa of transverse colon	UBERON:0004991	93.27	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.90
E-CURD-53	no	946.52

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, ETS1, STAT6

miRNA regulators (miRDB)

102 targeting ORMDL3, 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-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606

Literature-anchored findings (GeneRIF, showing 40)

• results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma (PMID:17611496)
• a significant association between susceptibility to childhood atopic asthma and the polymorphism regulating ORMDL3 expression in a Japanese population (PMID:18155279)
• results confirm associations between two SNPs within ORMDL3 and asthma in Mexicans and African Americans, and a trend toward association in Puerto Ricans (PMID:18310477)
• A common genetic variation at a locus (rs7216389) controlling expression of the ORMDL3 gene increases patient susceptibility to asthma and is associated with poor control of asthma symptoms in children and young adults. (PMID:18395550)
• ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry. (PMID:18760456)
• polymorphisms in ORMDL3 and the adjacent GSDML may contribute to childhood asthma. (PMID:19133921)
• Childhood asthma and atopy are associated with chromosome 17q21 in Chinese, but such association may involve genes other than ORMDL3 in this region. (PMID:19175592)
• multiple SNP associations were replicated in both IRAK-3 and ORMDL3, these likely reflect a single disease susceptibility locus in each gene (PMID:19264973)
• The disease-linked haplotype and putative causal DNA variants of ZPBP2/GSDMB/ORMDL3 locus via a combination of genetic and functional analyses, were identified. (PMID:19732864)
• ORMDL3 binds and inhibits SERCA resulting in a reduced ER Ca(2+) concentration and increased unfolded-protein response. (PMID:19819884)
• Data indicat that Association analysis using risk variants for CD led to the identification of a new risk variant associated with AS, ORMDL3. (PMID:21072187)
• analysis of whole-genome SNP data in 986 self-reported asthma cases and 1846 controls confirms that variants in ORMDL3 associate with asthma in European and North American populations (PMID:21150878)
• Results suggest an association of 17q21 polymorphisms with ORMDL3, GSDMA expression, and IL-17 secretion early in life. These observations may imply a functional role of the 17q21 locus affecting T-cell development during immune maturation. (PMID:21546069)
• The TTAA haplotype of the ORMDL3 gene is marginally associated with asthma in the adult Czech population, and TCAG haplotype is significantly associated with asthma in males. (PMID:21843571)
• This study reveals the presence of a novel ORMDL3 splicing isoform, ORMDL3 V1 in human. (PMID:22015541)
• Several polymorphisms in ORMDL3, including rs7216389, rs4378650, rs8076131 and rs4795405, have been associated with childhood asthma risk. (PMID:22017802)
• allele-specific transcriptional regulation of genes in the asthma-associated chromosomal region 17q12-q21; rs4795397 influences activity of ZPBP2 promoter in an allele-dependent fashion; methylation of exon 1 of ZPBP2 masks the genetic effect on ZPBP2 promoter; ORMDL3 promoter is unmethylated (PMID:22271045)
• GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophil-mediated bronchial hyperresponsiveness. (PMID:22732088)
• results suggest that rs2872507 is associated with ORMDL3 gene expression and with inhaled corticosteroid treatment response in children with atopic asthma. (PMID:22986918)
• Data show that transfection of ORMDL3 in bronchial epithelial cells induced expression of MMP-9, ADAM-8, CCL-20, IL-8, CXCL-10, CXCL-11, oligoadenylate synthetases (OAS) genes, and selectively activated activating transcription factor 6 (ATF6). (PMID:23011799)
• ORMDL1, ORMDL2 and ORMDL3 mediate the feedback response in ceramide biosynthesis. (PMID:23066021)
• The ORMDL3 gene influences childhood asthma and that the TT genotype of the rs7216389 polymorphism is associated with childhood asthma in the Chinese population. (PMID:23096927)
• We have shown that ORMDL3 expression levels modify T-cell calcium signaling and lymphocyte activation. (PMID:23100328)
• ORMDL3 genetic variants in the 17q21 asthma susceptibility locus are significantly associated with AR in the Japanese population. (PMID:23157251)
• STAT6 plays important roles in regulating the expression of human ORMDL3 by directly binding to the promoter region. (PMID:23461825)
• signaling pathway cAMP/PKA/CREB plays an important role in regulating ORMDL3 expression (PMID:23577138)
• A polymorphism in ORMDL3 is associated not only with asthma without rhinitis but also with chronic obstructive pulmonary disease. (PMID:23964555)
• All-trans retinoic acid modulates ORMDL3 expression via transcriptional regulation. (PMID:24204796)
• Genetic variants of ORMDL3 on chromosome 17q21 are associated with ankylosing spondylitis susceptibility and severity in a Chinese Han population. (PMID:24219690)
• The ORMDL3 locus on chromosome 17q21 is a risk factor for childhood-onset asthma in the Northeastern Han Chinese population. (PMID:24649901)
• Studies indicate that genetic variation of the ORMDL3 rs7216389 polymorphism may be a major independent predisposing factor for asthma in ethnically diverse populations. (PMID:25167772)
• Results confirmed the genetic association between GSDMB/ ORMDL3 and childhood asthma and show significant differences in the DNA methylation levels of ORMDL3 promoter of asthmatic children. (PMID:25256354)
• Expression of the ORMDLS, modulators of serine palmitoyltransferase, is regulated by sphingolipids in mammalian cells. (PMID:25395622)
• the contribution of ORMDL3 to asthma risk may involve changes in sphingolipid metabolism (PMID:25691431)
• Pro-inflammatory gene ORMDL3 SNP rs12603332 may be associated with high LysoPC and apoB levels, which leads to the occurrence of childhood asthma. (PMID:25815492)
• genetic polymorphisms are associated with childhood asthma, and with changes in TH2 cytokines levels (PMID:25930191)
• results show that Cbl-b suppresses human ORMDL3 expression through STAT6 (PMID:26112603)
• The meta-analysis indicates that ORMDL3 rs7216389 may contribute to increasing susceptibility to asthma. (Meta-analysis) (PMID:26125920)
• ORMDL3 variants have been shown to be associated with Asthma in children with Rhinovirus infections -induced wheezing illnesses. (PMID:26270739)
• Two single nucleotide polymorphisms regulating ORMDL3 expression (rs7216389 and rs9303277) significantly associated with atherosclerosis risk and the evidence of increased ORMDL3 expression in AS cases compared to controls. (PMID:26603569)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ormdl3	ENSDARG00000025555
mus_musculus	Ormdl3	ENSMUSG00000038150
rattus_norvegicus	Ormdl3	ENSRNOG00000030445
drosophila_melanogaster	ORMDL	FBGN0037110

Paralogs (2): ORMDL2 (ENSG00000123353), ORMDL1 (ENSG00000128699)

Protein

Protein identifiers

ORM1-like protein 3 — Q8N138 (reviewed: Q8N138)

All UniProt accessions (3): Q8N138, J3KTF9, J3QRM9

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 and thymus.

Post-translational modifications. When hydroxylated at Pro-137, ubiquitinated via ‘Lys-48’-linkage, leading to proteasomal degradation. In endothelial cells, ORMDL3 proteasomal degradation is controlled by the sphingosine 1-phosphate receptor signaling pathway.

Disease relevance. Asthma (ASTHMA) [MIM:600807] The most common chronic disease affecting children and young adults. It is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. It is characterized by recurrent attacks of paroxysmal dyspnea, with wheezing due to spasmodic contraction of the bronchi. Disease susceptibility is associated with variants affecting the gene represented in this entry. SNPs on 17q21 locus that are associated with childhood asthma also show a consistent and strong association with transcript levels of ORMDL3, indicating that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.

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.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N138-1	1	yes
Q8N138-4	2

RefSeq proteins (4): NP_001307730, NP_001307731, NP_001307732, NP_644809* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007203	ORMDL	Family

Pfam: PF04061

UniProt features (41 total): helix 11, mutagenesis site 10, topological domain 4, transmembrane region 4, strand 4, turn 4, chain 1, modified residue 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
7YIY	ELECTRON MICROSCOPY	2.7
7K0M	ELECTRON MICROSCOPY	2.9
7YIU	ELECTRON MICROSCOPY	2.9
7YJ2	ELECTRON MICROSCOPY	2.9
7K0N	ELECTRON MICROSCOPY	3.1
7K0O	ELECTRON MICROSCOPY	3.1
7K0P	ELECTRON MICROSCOPY	3.1
7YJ1	ELECTRON MICROSCOPY	3.1
7CQI	ELECTRON MICROSCOPY	3.2
7CQK	ELECTRON MICROSCOPY	3.3
7K0Q	ELECTRON MICROSCOPY	3.3
6M4O	ELECTRON MICROSCOPY	3.4
6M4N	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N138-F1	94.26	0.85

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): 137

Mutagenesis-validated functional residues (10):

Position	Phenotype
2–17	impaired negative regulation of spt complex activity in the presence of ceramides.
2–8	impaired negative regulation of spt complex activity in the presence of ceramides.
2	impaired negative regulation of spt complex activity in the presence of ceramides.
13	disrupted ceramide binding; impaired negative regulation of spt complex activity in the presence of ceramides; in the ab
16	impaired negative regulation of spt complex activity in the presence of ceramides.
22	impaired negative regulation of spt complex activity in the presence of ceramides.
63	impaired negative regulation of spt complex activity in the presence of ceramides.
85	no effect on the negative regulation of spt complex activity in the presence of ceramides.
137	increased protein levels; decreased ubiquitination; increased negative regulation of spt complex activity.

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: 197 (showing top): RRAGTTGT_UNKNOWN, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOCC_SECRETORY_GRANULE, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LYMPHOCYTE_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_NEGATIVE_REGULATION_OF_AMIDE_METABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, GOBP_LIPID_HOMEOSTASIS

GO Biological Process (14): negative regulation of B cell apoptotic process (GO:0002903), ceramide metabolic process (GO:0006672), sphingomyelin biosynthetic process (GO:0006686), regulation of smooth muscle contraction (GO:0006940), positive regulation of autophagy (GO:0010508), 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), positive regulation of protein localization to nucleus (GO:1900182), 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 (7): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), serine palmitoyltransferase complex (GO:0017059), secretory granule membrane (GO:0030667), specific granule membrane (GO:0035579), membrane (GO:0016020)

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 metabolic process	2
sphingolipid biosynthetic process	2
ceramide biosynthetic process	2
B cell apoptotic process	1
regulation of B cell apoptotic process	1
negative regulation of lymphocyte apoptotic process	1
sphingomyelin metabolic process	1
phospholipid biosynthetic process	1
regulation of muscle contraction	1
smooth muscle contraction	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	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
protein localization to nucleus	1
regulation of protein localization to nucleus	1
positive regulation of protein localization	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
membrane	1
cell periphery	1
palmitoyltransferase complex	1
secretory granule	1
cytoplasmic vesicle membrane	1

Protein interactions and networks

STRING

1032 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ORMDL3	GSDMB	Q8TAX9	961
ORMDL3	ZPBP2	Q6X784	932
ORMDL3	SPTLC1	O15269	899
ORMDL3	SPTLC3	Q9NUV7	890
ORMDL3	ORM1	P02763	887
ORMDL3	SPTLC2	O15270	880
ORMDL3	IKZF3	Q9UKT9	799
ORMDL3	GSDMA	Q96QA5	792
ORMDL3	ORM2	P19652	774
ORMDL3	NPSR1	Q6W5P4	717
ORMDL3	DENND1B	Q6P3S1	680
ORMDL3	IL1RL1	Q01638	656
ORMDL3	ADAM33	Q9BZ11	635
ORMDL3	PGAP3	Q96FM1	634
ORMDL3	CHI3L1	P30923	626

IntAct

118 interactions, top by confidence:

A	B	Type	Score
ORMDL3	SPTLC1	psi-mi:“MI:0915”(physical association)	0.710
CRIPTO	AIP	psi-mi:“MI:0914”(association)	0.640
ORMDL3	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
ORMDL3	SLC10A1	psi-mi:“MI:0915”(physical association)	0.560
ORMDL3	TMEM237	psi-mi:“MI:0915”(physical association)	0.560
RETREG3	ORMDL3	psi-mi:“MI:0915”(physical association)	0.560
ORMDL3	RNF5	psi-mi:“MI:0915”(physical association)	0.560
ORMDL3	COQ8A	psi-mi:“MI:0915”(physical association)	0.560
EBP	ORMDL3	psi-mi:“MI:0915”(physical association)	0.560
FAM209A	ORMDL3	psi-mi:“MI:0915”(physical association)	0.560
SLC10A1	ORMDL3	psi-mi:“MI:0915”(physical association)	0.560
ORMDL3	GPR101	psi-mi:“MI:0915”(physical association)	0.560
ORMDL3	ELOVL4	psi-mi:“MI:0915”(physical association)	0.560
ARL13B	ORMDL3	psi-mi:“MI:0915”(physical association)	0.560
ORMDL3	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
SLC7A1	ORMDL3	psi-mi:“MI:0915”(physical association)	0.560
ORMDL3	GPR152	psi-mi:“MI:0915”(physical association)	0.560
ORMDL3	SYT2	psi-mi:“MI:0915”(physical association)	0.560
HSD17B13	ORMDL3	psi-mi:“MI:0915”(physical association)	0.560
ROM1	ORMDL3	psi-mi:“MI:0915”(physical association)	0.560
C10orf67	ORMDL3	psi-mi:“MI:0915”(physical association)	0.560
GET1	ORMDL3	psi-mi:“MI:0915”(physical association)	0.560
ORMDL3	MTIF3	psi-mi:“MI:0915”(physical association)	0.560
CERS3	ORMDL3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (67): ORMDL3 (Proximity Label-MS), ORMDL3 (Affinity Capture-MS), ORMDL3 (Affinity Capture-MS), SPRY4 (Affinity Capture-MS), ORMDL3 (Affinity Capture-MS), ORMDL3 (Two-hybrid), ORMDL3 (Two-hybrid), EEF1A1 (Two-hybrid), ORMDL3 (Two-hybrid), ORMDL3 (Two-hybrid), ORMDL3 (Two-hybrid), ORMDL3 (Two-hybrid), ORMDL3 (Two-hybrid), ORMDL3 (Two-hybrid), ORMDL3 (Two-hybrid)

ESM2 similar proteins: A0A0N0DCA4, A0A194XK05, A0A7L9EZ67, A0A8F4NUZ8, A0A8F4S726, C6Y4A4, D2I2F3, G5EEQ9, O94440, P0DXW0, P32564, P34296, P53748, Q0VD15, Q10255, Q10436, Q12155, Q29RQ9, Q3B8H0, Q53FV1, Q55E32, Q5E972, Q5R570, Q5R8X5, Q5RFN8, Q5VVB8, Q5XH57, Q5XJR6, Q5ZIU0, Q6NZZ4, Q6QI25, Q6UX40, Q74ZU2, Q86H65, Q8JFB7, Q8N138, Q8STK5, Q8SW90, Q91VP7, Q921I0

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

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to epidermal growth factor stimulus	5	23.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

907 predictions. Top by Δscore:

Variant	Effect	Δscore
17:39922555:A:AC	donor_gain	1.0000
17:39922556:C:CC	donor_gain	1.0000
17:39922559:A:AC	donor_gain	1.0000
17:39922686:CTGGG:C	acceptor_loss	1.0000
17:39923110:A:AC	donor_gain	1.0000
17:39923110:ACAG:A	donor_gain	1.0000
17:39923111:C:CC	donor_gain	1.0000
17:39923111:CAG:C	donor_gain	1.0000
17:39923111:CAGC:C	donor_gain	1.0000
17:39923111:CAGCA:C	donor_gain	1.0000
17:39923140:T:TA	donor_gain	1.0000
17:39923259:ATGCC:A	acceptor_gain	1.0000
17:39923260:TGCC:T	acceptor_gain	1.0000
17:39923261:GCC:G	acceptor_gain	1.0000
17:39923261:GCCC:G	acceptor_loss	1.0000
17:39923262:CC:C	acceptor_gain	1.0000
17:39923262:CCC:C	acceptor_gain	1.0000
17:39923263:CC:C	acceptor_gain	1.0000
17:39923264:C:CC	acceptor_gain	1.0000
17:39923264:C:T	acceptor_gain	1.0000
17:39923264:CTG:C	acceptor_loss	1.0000
17:39924024:TCTCA:T	donor_loss	1.0000
17:39924025:CTCA:C	donor_loss	1.0000
17:39924026:TCA:T	donor_loss	1.0000
17:39924027:CA:C	donor_loss	1.0000
17:39924029:C:CT	donor_loss	1.0000
17:39924076:A:AC	donor_gain	1.0000
17:39924077:C:CC	donor_gain	1.0000
17:39924077:CAAA:C	donor_gain	1.0000
17:39924221:CTGTT:C	acceptor_gain	1.0000

AlphaMissense

1009 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:39922631:G:C	N127K	0.999
17:39922631:G:T	N127K	0.999
17:39923142:C:G	R99P	0.999
17:39923180:C:A	W86C	0.999
17:39923180:C:G	W86C	0.999
17:39923182:A:G	W86R	0.999
17:39923182:A:T	W86R	0.999
17:39923232:C:T	G69E	0.999
17:39923233:C:A	G69W	0.999
17:39923233:C:G	G69R	0.999
17:39923233:C:T	G69R	0.999
17:39924059:A:G	W49R	0.999
17:39924059:A:T	W49R	0.999
17:39922670:G:C	S114R	0.998
17:39922670:G:T	S114R	0.998
17:39922672:T:G	S114R	0.998
17:39923121:G:C	P106R	0.998
17:39923174:C:A	Q88H	0.998
17:39923174:C:G	Q88H	0.998
17:39923175:T:G	Q88P	0.998
17:39923177:C:A	E87D	0.998
17:39923177:C:G	E87D	0.998
17:39923178:T:A	E87V	0.998
17:39923187:G:A	T84I	0.998
17:39923222:A:C	F72L	0.998
17:39923222:A:T	F72L	0.998
17:39923224:A:G	F72L	0.998
17:39923234:C:A	K68N	0.998
17:39923234:C:G	K68N	0.998
17:39922596:A:G	L139P	0.997

dbSNP variants (sampled 300 via entrez): RS1000912627 (17:39925210 G>A), RS1001178786 (17:39926998 G>C), RS1001261341 (17:39925538 C>G,T), RS1001268330 (17:39920923 C>T), RS1001630188 (17:39926700 C>T), RS1002884956 (17:39921835 T>G), RS1002902347 (17:39927769 G>C,T), RS1003269089 (17:39923605 G>A,C), RS1003523735 (17:39927592 C>T), RS1003644867 (17:39929339 T>A), RS1003753210 (17:39923466 G>T), RS1003903140 (17:39929371 AT>A,ATT), RS1004137698 (17:39927752 T>C), RS1004386940 (17:39921931 C>T), RS1004861843 (17:39927569 T>C,G)

Disease associations

OMIM: gene MIM:610075 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

42 associations (top):

Study	Trait	p-value
GCST000061_1	Asthma	9.000000e-11
GCST000207_25	Crohn’s disease	5.000000e-09
GCST000392_22	Type 1 diabetes	6.000000e-13
GCST000498_10	Hematological parameters	9.000000e-09
GCST000624_15	Ulcerative colitis	3.000000e-08
GCST000733_2	Primary biliary cholangitis	2.000000e-09
GCST000879_10	Crohn’s disease	2.000000e-09
GCST000910_1	Asthma	5.000000e-07
GCST000964_1	Ulcerative colitis	5.000000e-11
GCST001010_18	Primary biliary cholangitis	8.000000e-07
GCST001137_10	White blood cell count	9.000000e-35
GCST001137_8	White blood cell count	2.000000e-31
GCST001191_20	Type 1 diabetes	2.000000e-06
GCST001508_4	Asthma	1.000000e-08
GCST001685_2	Primary biliary cholangitis	4.000000e-09
GCST001725_54	Inflammatory bowel disease	4.000000e-38
GCST003589_1	Bronchial hyperresponsiveness in asthma	3.000000e-20
GCST003814_8	Selective IgA deficiency	7.000000e-07
GCST004131_33	Inflammatory bowel disease	2.000000e-26
GCST004132_116	Crohn’s disease	1.000000e-16
GCST004133_16	Ulcerative colitis	2.000000e-16
GCST004202_2	Systemic sclerosis	1.000000e-10
GCST004302_4	Primary biliary cholangitis	2.000000e-16
GCST004390_1	Asthma	4.000000e-12
GCST004610_154	White blood cell count	3.000000e-79
GCST005536_38	Type 1 diabetes	1.000000e-08
GCST005568_3	Rheumatoid arthritis (ACPA-positive)	3.000000e-09
GCST005568_9	Rheumatoid arthritis (ACPA-positive)	7.000000e-07
GCST005569_31	Rheumatoid arthritis	4.000000e-07
GCST005581_15	Primary biliary cirrhosis	6.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004267	biliary liver cirrhosis
EFO:0004833	neutrophil count
EFO:0010221	systemising measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066515 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2872507	ORMDL3		0.00	0

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.22	Kd	5955	nM	CHEMBL3752910
5.22	ED50	5955	nM	CHEMBL3752910
5.13	Kd	7465	nM	CHEMBL5653589
5.13	ED50	7465	nM	CHEMBL5653589

PubChem BioAssay actives

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

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148916: Binding affinity to human ORMDL3 incubated for 45 mins by Kinobead based pull down assay	kd	5.9547	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148916: Binding affinity to human ORMDL3 incubated for 45 mins by Kinobead based pull down assay	kd	7.4652	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases methylation, affects cotreatment, increases expression	3
sodium arsenite	affects binding, increases reaction, decreases expression, increases expression	3
Acetaminophen	decreases expression	2
potassium perchlorate	decreases expression	1
trichostatin A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
3-(4-methylphenylsulfonyl)-2-propenenitrile	decreases reaction, increases expression	1
torcetrapib	increases expression	1
thifluzamide	decreases expression	1
pyrachlostrobin	decreases expression	1
MitoTEMPO	decreases reaction, increases expression	1
picoxystrobin	decreases expression	1
Sunitinib	decreases expression	1
Acetylcysteine	decreases reaction, increases expression	1
Arsenic	affects methylation	1
Atrazine	decreases expression	1
Benomyl	decreases reaction, increases expression, affects reaction	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	increases abundance, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Potassium Dichromate	increases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Thiram	increases expression	1
Urethane	increases expression	1
Valproic Acid	affects expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651958	Binding	Binding affinity to human ORMDL3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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