OAS3

Summary

OAS3 (2’-5’-oligoadenylate synthetase 3, HGNC:8088) is a protein-coding gene on chromosome 12q24.13, encoding 2’-5’-oligoadenylate synthase 3 (Q9Y6K5). Interferon-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response.

This gene encodes an enzyme included in the 2’, 5’ oligoadenylate synthase family. This enzyme is induced by interferons and catalyzes the 2’, 5’ oligomers of adenosine in order to bind and activate RNase L. This enzyme family plays a significant role in the inhibition of cellular protein synthesis and viral infection resistance.

Source: NCBI Gene 4940 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 189 total
• MANE Select transcript: NM_006187

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8088
Approved symbol	OAS3
Name	2’-5’-oligoadenylate synthetase 3
Location	12q24.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000111331
Ensembl biotype	protein_coding
OMIM	603351
Entrez	4940

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 16 nonsense_mediated_decay, 15 protein_coding, 7 retained_intron

ENST00000228928, ENST00000546638, ENST00000546800, ENST00000548514, ENST00000549918, ENST00000551007, ENST00000679354, ENST00000679483, ENST00000679493, ENST00000679505, ENST00000679517, ENST00000679547, ENST00000679562, ENST00000679812, ENST00000679912, ENST00000680044, ENST00000680090, ENST00000680153, ENST00000680161, ENST00000680177, ENST00000680230, ENST00000680293, ENST00000680438, ENST00000680966, ENST00000681002, ENST00000681007, ENST00000681085, ENST00000681105, ENST00000681134, ENST00000681147, ENST00000681346, ENST00000681497, ENST00000681527, ENST00000681572, ENST00000681594, ENST00000681665, ENST00000681764, ENST00000877677

RefSeq mRNA: 2 — MANE Select: NM_006187 NM_001410984, NM_006187

CCDS: CCDS44981, CCDS91756

Canonical transcript exons

ENST00000228928 — 16 exons

Exon	Start	End
ENSE00000755375	112941570	112941852
ENSE00000755377	112946743	112946981
ENSE00000755379	112947946	112948099
ENSE00000755380	112948861	112949205
ENSE00000755381	112950693	112950975
ENSE00000755383	112962652	112962902
ENSE00000755384	112963313	112963457
ENSE00000755385	112964235	112964408
ENSE00000755388	112967936	112968174
ENSE00000834922	112965744	112966029
ENSE00000834923	112967418	112967593
ENSE00000834924	112969608	112969755
ENSE00001645238	112969962	112973251
ENSE00002344003	112938474	112938707
ENSE00002409457	112961071	112961246
ENSE00003576364	112944476	112944651

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 92.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.4446 / max 1484.6435, expressed in 1345 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128116	14.1730	1236
128117	1.3603	277
128115	0.7699	494
128118	0.1413	62

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	92.63	gold quality
mononuclear cell	CL:0000842	92.54	gold quality
leukocyte	CL:0000738	92.53	gold quality
granulocyte	CL:0000094	88.71	gold quality
decidua	UBERON:0002450	87.72	gold quality
gall bladder	UBERON:0002110	84.42	gold quality
apex of heart	UBERON:0002098	84.08	gold quality
esophagus mucosa	UBERON:0002469	83.42	gold quality
vermiform appendix	UBERON:0001154	83.32	gold quality
bone marrow cell	CL:0002092	82.18	gold quality
oral cavity	UBERON:0000167	81.69	gold quality
tongue squamous epithelium	UBERON:0006919	81.53	gold quality
colonic epithelium	UBERON:0000397	81.47	gold quality
rectum	UBERON:0001052	81.00	gold quality
smooth muscle tissue	UBERON:0001135	80.94	gold quality
palpebral conjunctiva	UBERON:0001812	80.48	gold quality
caecum	UBERON:0001153	80.36	gold quality
blood	UBERON:0000178	79.23	gold quality
nasal cavity epithelium	UBERON:0005384	79.15	silver quality
upper lobe of left lung	UBERON:0008952	79.12	gold quality
lymph node	UBERON:0000029	79.04	gold quality
urinary bladder	UBERON:0001255	79.03	gold quality
spleen	UBERON:0002106	78.81	gold quality
upper lobe of lung	UBERON:0008948	78.81	gold quality
sural nerve	UBERON:0015488	78.59	gold quality
esophagus	UBERON:0001043	78.46	gold quality
lower esophagus mucosa	UBERON:0035834	78.04	gold quality
lung	UBERON:0002048	77.85	gold quality
right lung	UBERON:0002167	77.83	gold quality
descending thoracic aorta	UBERON:0002345	77.57	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.51

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT1

Literature-anchored findings (GeneRIF, showing 28)

• OAS are interferon-inducible enzymes catalyzing 2’-5’ instead of 3’-5’ phosphodiester bond formation [review] (PMID:17408844)
• The data suggest a possible association between OAS2 and OAS3 single nucleotide polymorphisms and the outcome of tick-borne encephalitis virus infection in a Russian population. (PMID:21050126)
• among the members of the OAS family, OAS1 p46 and OAS3 p100 mediate the RNase L-dependent antiviral activity against HCV (PMID:23196181)
• The results suggest that OAS1-OAS3-OAS2 haplotypes are associated with differential susceptibility to clinical outcomes of dengue infection. (PMID:23337612)
• The combined high affinity for double-stranded RNA and the capability to produce 2’-5’-linked oligoadenylates of sufficient length to activate RNase L suggests that OAS3 is a potent activator of RNase L. (PMID:25275129)
• Common variation at 12q24.13 (OAS3 intron) influences chronic lymphocytic leukemia risk. (PMID:25363670)
• By means of an allelic association study of a cohort of 740 patients with dengue, the authors found a protective effect of OAS3_R381 against shock. (PMID:26063222)
• Preliminary study suggests that OAS gene cluster and CD209 gene polymorphisms influence the risk of developing clinical symptoms in Chikungunya virus-infected patients. (PMID:26398832)
• OAS3 displayed a higher affinity for dsRNA in intact cells than either OAS1 or OAS2, consistent with its dominant role in RNase L activation. (PMID:26858407)
• Here we report, to our knowledge, the first analysis of nuclear signal import in the pseudo enzymatic domain DI of human OAS3 (PMID:27379722)
• we characterized the functional consequences of the Neandertal haplotype in the transcriptional regulation of OAS genes at baseline and infected conditions. We found that cells from people with the Neandertal-like haplotype express lower levels of OAS3 upon infection, as well as distinct isoforms of OAS1 and OAS2 (PMID:27899133)
• Mitochondrial C11orf83 is a potent antiviral protein independent of interferon production; and knockdown of either OAS3 or RNase L impaired the antiviral capability of C11orf83. (PMID:28418037)
• The study findings suggest that the OAS3 rs1859330 G/A genetic polymorphism is associated with the severity of enterovirus 71 (EV71) infection, and that the A allele is a risk factor for the development of severe EV71 infection. (PMID:28444539)
• The carriage frequency of 2’-5’-oligoadenylate synthetase 3 (OAS3) S381R CC genotypes and the occurrence of C allele in severe EV71infected cases are higher than in mild cases. Severe cases have significant higher levels of Interferon-gamma in GC+GG genotypes compared to CC genotype. Carrying C allele of the OAS3 S381R gene is susceptibility factor in the development of severe EV71 infection among Chinese children. (PMID:29414184)
• Protein-coding rare variations on the OAS3 gene are associated with the coexistence of HBsAg and anti-HBs in patients with chronic hepatitis B infection in Chinese Han population. (PMID:29582521)
• Data suggest that OAS1 and OAS3 negatively regulate the expression of chemokines and interferon-responsive genes in human macrophages. (PMID:30078389)
• Genetic risk scores were calculated by summing the risk alleles of 4 selected single nucleotide polymorphisms, CDKAL1 rs7754840 and rs9460546, HHEX rs5015480, and OAS3 (PMID:30207601)
• We propose the following model for the selective targeting of exogenous RNA; OAS3 activated by the exogenous RNA releases 2’-5’-oligoadenylates (2-5A), which in turn converts latent RNase L to an active dimer. (PMID:30395302)
• Protein and fat intake interacts with the haplotype of PTPN11_rs11066325, RPH3A_rs886477, and OAS3_rs2072134 to modulate serum HDL concentrations in middle-aged people. (PMID:31006500)
• The dependence on expression of ZAP antiviral protein (ZAP), 2’-5’-oligoadenylate synthetase (OAS3) and 2-5A-dependent ribonuclease (RNAseL) for CpG/UpA-mediated attenuation and the variable and often low level expression of these pathway proteins in certain cell types. (PMID:31276592)
• Our study revealed a heterozygous mutation in OAS3 from a Chinese Juvenile-onset open-angle glaucoma family. And this mutation showed a deleterious effect to the expression of OAS3. (PMID:31618764)
• Length dependent activation of OAS proteins by dsRNA. (PMID:31629990)
• Genetic analysis of a Taiwanese family identifies a DMRT3-OAS3 interaction that is involved in human sexual differentiation through the regulation of ESR1 expression. (PMID:32553473)
• Zika virus employs the host antiviral RNase L protein to support replication factory assembly. (PMID:34031250)
• OAS1, OAS2, and OAS3 Contribute to Epidermal Keratinocyte Proliferation by Regulating Cell Cycle and Augmenting IFN-1Induced Jak1Signal Transducer and Activator of Transcription 1 Phosphorylation in Psoriasis. (PMID:35305973)
• IFN-beta1b induces OAS3 to inhibit EV71 via IFN-beta1b/JAK/STAT1 pathway. (PMID:35934228)
• Integrative Multiomics and Regulatory Network Analyses Uncovers the Role of OAS3, TRAFD1, miR-222-3p, and miR-125b-5p in Hepatitis E Virus Infection. (PMID:36672782)
• TYK2, IFITM3, IFNAR2 and OAS3 single-nucleotide polymorphisms among severe COVID-19 ICU patients in Morocco. (PMID:38760017)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Oas3	ENSMUSG00000032661
rattus_norvegicus	Oas3	ENSRNOG00000059207

Paralogs (3): OAS1 (ENSG00000089127), OAS2 (ENSG00000111335), OASL (ENSG00000135114)

Protein

Protein identifiers

2’-5’-oligoadenylate synthase 3 — Q9Y6K5 (reviewed: Q9Y6K5)

Alternative names: p100 OAS

All UniProt accessions (24): A0A7P0T7V2, A0A7P0T884, A0A7P0T8J8, A0A7P0T8S7, A0A7P0T9J0, A0A7P0T9W6, A0A7P0T9Z5, A0A7P0TA44, A0A7P0TA50, Q9Y6K5, A0A7P0TAC0, A0A7P0TAC8, A0A7P0TAS0, A0A7P0TAT5, A0A7P0TAU8, A0A7P0TAV3, A0A7P0TB72, A0A7P0TB73, A0A7P0Z4D0, A0A7P0Z4F1, A0A7P0Z4F5, A0A7P0Z4Q3, F8VS35, F8VWK9

UniProt curated annotations — full annotation on UniProt →

Function. Interferon-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response. In addition, it may also play a role in other cellular processes such as apoptosis, cell growth, differentiation and gene regulation. Synthesizes preferentially dimers of 2’-5’-oligoadenylates (2-5A) from ATP which then bind to the inactive monomeric form of ribonuclease L (RNase L) leading to its dimerization and subsequent activation. Activation of RNase L leads to degradation of cellular as well as viral RNA, resulting in the inhibition of protein synthesis, thus terminating viral replication. Can mediate the antiviral effect via the classical RNase L-dependent pathway or an alternative antiviral pathway independent of RNase L. Displays antiviral activity against Chikungunya virus (CHIKV), Dengue virus, Sindbis virus (SINV) and Semliki forest virus (SFV).

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Present at high level in placenta trophoblast.

Activity regulation. Produced as a latent enzyme which is activated by dsRNA generated during the course of viral infection. Strongly activated by long dsRNAs at least 50 nucleotides in length. ssRNA does not activate the enzyme.

Domain organisation. OAS domain 3 is catalytically active. OAS domain 1 has no catalytic activity but is essential for recognition of long dsRNAs.

Induction. By type I interferon (IFN) and viruses.

Similarity. Belongs to the 2-5A synthase family.

RefSeq proteins (2): NP_001397913, NP_006178* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002934	Polymerase_NTP_transf_dom	Domain
IPR006116	NT_2-5OAS_ClassI-CCAase	Domain
IPR006117	2-5OAS_C_CS	Conserved_site
IPR018952	2-5-oligoAdlate_synth_1_dom2/C	Domain
IPR043518	2-5OAS_N_CS	Conserved_site
IPR043519	NT_sf	Homologous_superfamily

Pfam: PF01909, PF10421

Enzyme classification (BRENDA):

• EC 2.7.7.84 — 2’-5’ oligoadenylate synthase (BRENDA: 12 organisms, 43 substrates, 21 inhibitors, 5 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NAD+	0.0011–0.0014	3
ATP	0.0004–0.0017	2

Catalyzed reactions (Rhea), 1 shown:

• 3 ATP = 5’-triphosphoadenylyl-(2’->5’)-adenylyl-(2’->5’)-adenosine + 2 diphosphate (RHEA:34407)

UniProt features (65 total): helix 17, strand 9, binding site 7, sequence variant 7, sequence conflict 7, region of interest 6, mutagenesis site 5, site 2, modified residue 2, turn 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4S3N	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6K5-F1	87.15	0.63

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 155 (interaction with dsrna); 244 (interaction with dsrna)

Ligand- & substrate-binding residues (7): 888; 947; 950; 969; 804; 816; 818

Post-translational modifications (2): 1, 365

Mutagenesis-validated functional residues (5):

Position	Phenotype
30	impaired dsrna binding.
41	impaired dsrna binding.
76	no effect on catalytic activity; when associated with d-145.
145	no effect on catalytic activity. no effect on catalytic activity; when associated with d-76.
816–818	abolishes catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-877300	Interferon gamma signaling
R-HSA-8983711	OAS antiviral response
R-HSA-909733	Interferon alpha/beta signaling

MSigDB gene sets: 350 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_NEGATIVE_REGULATION_OF_VIRAL_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, RIZKI_TUMOR_INVASIVENESS_3D_DN, SHIRAISHI_PLZF_TARGETS_UP, GOBP_POSITIVE_REGULATION_OF_TUMOR_NECROSIS_FACTOR_SUPERFAMILY_CYTOKINE_PRODUCTION, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS

GO Biological Process (23): nucleobase-containing compound metabolic process (GO:0006139), response to virus (GO:0009615), positive regulation of interferon-beta production (GO:0032728), positive regulation of tumor necrosis factor production (GO:0032760), negative regulation of chemokine (C-X-C motif) ligand 9 production (GO:0035395), RIG-I signaling pathway (GO:0039529), MDA-5 signaling pathway (GO:0039530), defense response to bacterium (GO:0042742), negative regulation of viral genome replication (GO:0045071), defense response to virus (GO:0051607), type I interferon-mediated signaling pathway (GO:0060337), negative regulation of type I interferon-mediated signaling pathway (GO:0060339), regulation of ribonuclease activity (GO:0060700), interleukin-27-mediated signaling pathway (GO:0070106), cellular response to exogenous dsRNA (GO:0071360), positive regulation of monocyte chemotactic protein-1 production (GO:0071639), negative regulation of chemokine (C-C motif) ligand 5 production (GO:0071650), negative regulation of IP-10 production (GO:0071659), antiviral innate immune response (GO:0140374), negative regulation of chemokine (C-X-C motif) ligand 2 production (GO:2000342), immune system process (GO:0002376), innate immune response (GO:0045087), defense response to other organism (GO:0098542)

GO Molecular Function (9): 2’-5’-oligoadenylate synthetase activity (GO:0001730), double-stranded RNA binding (GO:0003725), ATP binding (GO:0005524), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), RNA binding (GO:0003723), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779)

GO Cellular Component (8): obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), intracellular membrane-bounded organelle (GO:0043231), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Interferon Signaling	2
Antimicrobial mechanism of IFN-stimulated genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of chemokine production	4
cellular anatomical structure	4
cytoplasmic pattern recognition receptor signaling pathway	2
defense response	2
intracellular anatomical structure	2
primary metabolic process	1
response to other organism	1
positive regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
chemokine (C-X-C motif) ligand 9 production	1
regulation of chemokine (C-X-C motif) ligand 9 production	1
response to bacterium	1
viral genome replication	1
regulation of viral genome replication	1
negative regulation of viral process	1
response to virus	1
cellular response to type I interferon	1
interferon-mediated signaling pathway	1
negative regulation of cytokine-mediated signaling pathway	1
negative regulation of innate immune response	1
type I interferon-mediated signaling pathway	1
regulation of type I interferon-mediated signaling pathway	1
RNA nuclease activity	1
regulation of catalytic activity	1
regulation of RNA metabolic process	1
cytokine-mediated signaling pathway	1
response to exogenous dsRNA	1
cellular response to dsRNA	1
positive regulation of chemokine production	1
monocyte chemotactic protein-1 production	1
regulation of monocyte chemotactic protein-1 production	1
chemokine (C-C motif) ligand 5 production	1
regulation of chemokine (C-C motif) ligand 5 production	1
IP-10 production	1
regulation of IP-10 production	1
innate immune response	1

Protein interactions and networks

STRING

1304 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OAS3	RNASEL	Q05823	908
OAS3	IFIT1	P09914	832
OAS3	MX1	P20591	825
OAS3	EIF2AK2	P19525	802
OAS3	IFI6	P09912	768
OAS3	ICA1	P78506	762
OAS3	IFI27	P40305	757
OAS3	STAT1	P42224	740
OAS3	STAT2	P52630	729
OAS3	IRF9	Q00978	728
OAS3	RIGI	O95786	724
OAS3	ISG15	P05161	723
OAS3	IFIT3	O14879	719
OAS3	IFIT2	P09913	694
OAS3	RSAD2	Q8WXG1	666

IntAct

16 interactions, top by confidence:

A	B	Type	Score
MAVS	RIPK2	psi-mi:“MI:0914”(association)	0.580
MAVS	OAS3	psi-mi:“MI:0915”(physical association)	0.500
OAS3	EIF6	psi-mi:“MI:0915”(physical association)	0.500
IFRD2	OAS3	psi-mi:“MI:0915”(physical association)	0.500
DHX30	OAS3	psi-mi:“MI:0915”(physical association)	0.500
FTSJ3	OAS3	psi-mi:“MI:0915”(physical association)	0.500
Eea1	WWP2	psi-mi:“MI:0914”(association)	0.350
CCDC22	VPS26C	psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
NUDCD1	DNAJB2	psi-mi:“MI:0914”(association)	0.350
OAS3	PTBP1	psi-mi:“MI:0914”(association)	0.350
rep	DDX3X	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
OAS3	PPM1G	psi-mi:“MI:0914”(association)	0.350
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350
rep	BRCA1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (85): OAS3 (Affinity Capture-MS), OAS3 (Affinity Capture-MS), OAS3 (Affinity Capture-MS), OAS3 (Affinity Capture-MS), OAS3 (Affinity Capture-MS), OAS3 (Affinity Capture-RNA), C11orf98 (Affinity Capture-MS), CAPRIN1 (Affinity Capture-MS), CDC5L (Affinity Capture-MS), CNP (Affinity Capture-MS), EXOSC10 (Affinity Capture-MS), EXOSC3 (Affinity Capture-MS), G3BP2 (Affinity Capture-MS), GLTSCR2 (Affinity Capture-MS), GNL2 (Affinity Capture-MS)

ESM2 similar proteins: A0A6J1SUS3, A4FV14, A4IIW0, A7SFB5, A8E4S7, E9Q9A9, F1N3B8, O70299, P00973, P11928, P29728, Q05961, Q0IES7, Q0IES8, Q0V9X7, Q13394, Q29599, Q29H55, Q29H56, Q3TNL8, Q4KMD7, Q567X9, Q5BKD0, Q5MYT7, Q5MYT9, Q5MYU0, Q5TW90, Q60856, Q6DCQ5, Q6GNM3, Q6GQ81, Q6GQD9, Q6NYB4, Q7QHX4, Q8AY65, Q8BPP1, Q8C6L5, Q8CI17, Q8N884, Q8N8X9

Diamond homologs: E9Q9A9, F1N3B8, G3V645, P00973, P11928, P29728, Q05961, Q15646, Q29599, Q5BKD0, Q5MYT7, Q5MYT9, Q5MYU0, Q60856, Q8VI93, Q8VI94, Q8VI95, Q924S2, Q9Y6K5, Q9Z2F2, G1SK22, P0C224, P0C273, P0C275, P0C276, P0DXC2, P14794, P14795, P14799, P15357, P16709, P18101, P19848, P29504, P46575, P49633, P62975, P62978, P62979, P62982

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	149
Likely benign	8
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

3081 predictions. Top by Δscore:

Variant	Effect	Δscore
12:112938707:GGTG:G	donor_loss	1.0000
12:112938709:T:A	donor_loss	1.0000
12:112946978:CCAGG:C	donor_loss	1.0000
12:112946979:CAGGT:C	donor_loss	1.0000
12:112946980:AGGTA:A	donor_loss	1.0000
12:112946981:GGTAC:G	donor_loss	1.0000
12:112946982:GT:G	donor_loss	1.0000
12:112946983:T:A	donor_loss	1.0000
12:112949201:GTAAA:G	donor_gain	1.0000
12:112949206:G:GG	donor_gain	1.0000
12:112950688:CACAG:C	acceptor_loss	1.0000
12:112950690:CAG:C	acceptor_loss	1.0000
12:112950691:AG:A	acceptor_gain	1.0000
12:112950691:AGG:A	acceptor_gain	1.0000
12:112950691:AGGG:A	acceptor_gain	1.0000
12:112950691:AGGGG:A	acceptor_gain	1.0000
12:112950692:G:A	acceptor_loss	1.0000
12:112950692:GG:G	acceptor_gain	1.0000
12:112950692:GGG:G	acceptor_gain	1.0000
12:112950692:GGGG:G	acceptor_gain	1.0000
12:112950692:GGGGG:G	acceptor_gain	1.0000
12:112950942:G:GT	donor_gain	1.0000
12:112961242:GCCAG:G	donor_gain	1.0000
12:112961247:G:GG	donor_gain	1.0000
12:112961248:T:A	donor_loss	1.0000
12:112966028:AGG:A	donor_loss	1.0000
12:112966029:GG:G	donor_loss	1.0000
12:112966030:GTG:G	donor_loss	1.0000
12:112966031:T:A	donor_loss	1.0000
12:112967926:C:CA	acceptor_gain	1.0000

AlphaMissense

7095 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:112969663:T:A	W1054R	0.995
12:112969663:T:C	W1054R	0.995
12:112969665:G:C	W1054C	0.993
12:112969665:G:T	W1054C	0.993
12:112967528:T:C	F934L	0.986
12:112967530:C:A	F934L	0.986
12:112967530:C:G	F934L	0.986
12:112965958:T:C	F873S	0.985
12:112965804:T:C	F822L	0.984
12:112965806:C:A	F822L	0.984
12:112965806:C:G	F822L	0.984
12:112967466:T:C	L913P	0.983
12:112965957:T:C	F873L	0.982
12:112965959:C:A	F873L	0.982
12:112965959:C:G	F873L	0.982
12:112965999:T:C	F887L	0.982
12:112966001:T:A	F887L	0.982
12:112966001:T:G	F887L	0.982
12:112967507:T:C	F927L	0.982
12:112967509:C:A	F927L	0.982
12:112967509:C:G	F927L	0.982
12:112964356:T:C	L784S	0.981
12:112965760:A:T	K807I	0.981
12:112965825:T:C	F829L	0.980
12:112965827:C:A	F829L	0.980
12:112965827:C:G	F829L	0.980
12:112967582:T:A	W952R	0.980
12:112967582:T:C	W952R	0.980
12:112965880:T:C	L847P	0.979
12:112966006:T:A	V889E	0.977

dbSNP variants (sampled 300 via entrez): RS1000034114 (12:112947776 C>A,G), RS1000269413 (12:112942211 A>G), RS1000404485 (12:112953184 G>A), RS1000578859 (12:112960197 A>G), RS1000760406 (12:112967884 G>A,C), RS1000954194 (12:112964873 T>C), RS1001242188 (12:112951394 A>G), RS1001276209 (12:112967633 G>A,C), RS1001341285 (12:112941536 A>C), RS1001416351 (12:112964716 T>G), RS1001550378 (12:112964473 G>A), RS1001559966 (12:112965732 T>C), RS1001611374 (12:112971219 A>G), RS1001667636 (12:112958706 G>T), RS1001743902 (12:112959321 G>A)

Disease associations

OMIM: gene MIM:603351 | disease phenotypes: MIM:142623

GenCC curated gene-disease

Mondo (1): Hirschsprung disease (MONDO:0018309)

Orphanet (1): Hirschsprung disease (Orphanet:388)

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000954_4	Alcohol consumption	6.000000e-17
GCST001237_8	HDL cholesterol	6.000000e-06
GCST001738_6	Response to fenofibrate (adiponectin levels)	5.000000e-08
GCST004146_17	Chronic lymphocytic leukemia	5.000000e-08
GCST004404_3	Alcohol consumption (drinkers vs non-drinkers)	3.000000e-16
GCST005951_2	Body mass index	9.000000e-09
GCST007438_5	High density lipoprotein cholesterol levels	1.000000e-06
GCST007840_3	Low HDL-cholesterol levels	6.000000e-12
GCST007921_2	Right-sided colonic diverticulosis	7.000000e-06
GCST010476_20	Myocardial infarction	5.000000e-07
GCST011141_10	Hypertension	1.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004329	alcohol drinking
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004340	body mass index

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	3
Cyclosporine	affects expression, decreases expression, increases expression	3
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression, increases expression	2
(+)-JQ1 compound	decreases expression	2
Arsenic	decreases expression, increases abundance	2
Estradiol	affects cotreatment, increases expression	2
Nickel	decreases expression, increases expression	2
Silicon Dioxide	increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
sotorasib	affects cotreatment, increases expression	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
alpha phellandrene	increases expression	1
bisphenol A	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
decabromobiphenyl ether	decreases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
epigallocatechin gallate	decreases expression	1
celastrol	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2PA	Abcam A-549 OAS3 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT03660176	PHASE3	UNKNOWN	Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung’s Disease
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT00671684	PHASE1/PHASE2	UNKNOWN	Endoscopic Mucosal Resection (EMR) for Diagnosis of Hirschsprung’s Disease
NCT01985646	EARLY_PHASE1	COMPLETED	A Trial on Conservative Treatment for Infants’ Hirschsprung Disease
NCT00478712	Not specified	RECRUITING	Hirschsprung Disease Genetic Study
NCT01515501	Not specified	COMPLETED	Endoscopic Mucosal Resection for the Diagnosis of a-Ganglionosis, a Controlled Prospective Trial (EDGE Trial)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01927809	Not specified	UNKNOWN	Genetic Mosaicism in Hirschsprung’s Disease
NCT02193685	Not specified	UNKNOWN	Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease
NCT02216994	Not specified	UNKNOWN	A New Scoring System Improves Diagnostic Accuracy of Intestinal Dysganglionosis –a Prospective Study
NCT02296008	Not specified	COMPLETED	3D High Resolution Anorectal Manometry in Children After Surgery for Anorectal Disorders
NCT02776176	Not specified	UNKNOWN	Enhanced Recovery After Surgery In Hirschsprung Disease
NCT02857205	Not specified	COMPLETED	MICROPRUNG : Intestinal Microbiota Analysis in Patients With or Without Hirschsprung’s Associated EnteroColitis
NCT03269812	Not specified	UNKNOWN	Laparoscopic Assisted Pull-through Versus Other Surgical Procedures for Treatment of Hirschsprung Disease
NCT03406741	Not specified	COMPLETED	Neuropsychological Development and Functional Outcome Sin Children With Hirschsprung Disease at School Age
NCT03626350	Not specified	ACTIVE_NOT_RECRUITING	Prospective Evaluation of the Efficacy and Safety of Submucosal Endoscopy
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT04020939	Not specified	COMPLETED	The Role of Indocyanine Green Angiography Fluorescence on Intestinal Resections in Pediatric Surgery.
NCT04106947	Not specified	UNKNOWN	Transition of Care for Patients With Hirschsprung Disease and Anorectal Malformations
NCT04149093	Not specified	UNKNOWN	The Association Between Calretinin and the Function of Ganglion Cells in Hirschsprung Disease
NCT04150120	Not specified	COMPLETED	eHealth as an Aid for Facilitating and Supporting Self-management in Families With Long-term Childhood Illness
NCT04213976	Not specified	UNKNOWN	Ostomy in Continuity or Conventional Ileostomy: a Retrospective Multicentric Analysis
NCT04476225	Not specified	COMPLETED	Induced Pluripotent Stem Cells for Disease Research
NCT04598841	Not specified	COMPLETED	Nutrition Support for Hirschsprung Disease
NCT04622410	Not specified	RECRUITING	Registry for Hirschsprung Disease of the BELAPS
NCT04624334	Not specified	TERMINATED	Non-invasive Assessment of Colonic Motility
NCT04713085	Not specified	COMPLETED	Sacral Neuromodulation in Children and Adolescents
NCT04730128	Not specified	COMPLETED	Translation and Validation of a Disease-specific Questionnaire for Hirschsprung’s Disease in Danish Patients
NCT04837963	Not specified	COMPLETED	Does Hirschsprung Disease Increase the Risk of Febrile Urinary Tract Infection in Children
NCT04957667	Not specified	COMPLETED	Scintigraphic Defecography for Evaluation of Functional Outcome in an Adult Hirschsprung Population
NCT05038345	Not specified	TERMINATED	Hirschsprung Disease Trends in the United States: Analysis of the National Inpatient Sample
NCT05044741	Not specified	COMPLETED	Risk Factors of Perforated HSCR in Neonates
NCT05293353	Not specified	UNKNOWN	Neokare Safety and Tolerability Assessment in Neonates With GI Problems
NCT05307419	Not specified	UNKNOWN	Full Thickness vs. Rectal Suction Biopsy in the Diagnosis of Hirschsprungs Disease
NCT05450991	Not specified	RECRUITING	Long-term Qualitative and Quantitative Outcomes of Children With Hirschsprung’s Disease and Anorectal Malformations
NCT05655845	Not specified	UNKNOWN	Risk Factors for Bowel Dysfunction at Preschool and Early Childhood Age in Children With Hirschsprung Disease
NCT06072976	Not specified	RECRUITING	The Influence of Feeding Source on the Gut Microbiome and Time to Full Feeds in Neonates With Congenital Gastrointestinal Pathologies