IER3

Summary

IER3 (immediate early response 3, HGNC:5392) is a protein-coding gene on chromosome 6p21.33, encoding Radiation-inducible immediate-early gene IEX-1 (P46695). May play a role in the ERK signaling pathway by inhibiting the dephosphorylation of ERK by phosphatase PP2A-PPP2R5C holoenzyme.

This gene functions in the protection of cells from Fas- or tumor necrosis factor type alpha-induced apoptosis. Partially degraded and unspliced transcripts are found after virus infection in vitro, but these transcripts are not found in vivo and do not generate a valid protein.

Source: NCBI Gene 8870 — RefSeq curated summary.

At a glance

• GWAS associations: 28
• Clinical variants (ClinVar): 23 total
• MANE Select transcript: NM_003897

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5392
Approved symbol	IER3
Name	immediate early response 3
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Aliases	IEX-1, DIF-2, PRG1, IEX-1L
Ensembl gene	ENSG00000137331
Ensembl biotype	protein_coding
OMIM	602996
Entrez	8870

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000259874, ENST00000376377, ENST00000917877

RefSeq mRNA: 1 — MANE Select: NM_003897 NM_003897

CCDS: CCDS4689

Canonical transcript exons

ENST00000259874 — 2 exons

Exon	Start	End
ENSE00001822780	30744309	30744547
ENSE00001857026	30743199	30744196

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 98.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 377.4966 / max 10502.5565, expressed in 1800 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72601	377.1144	1800
72600	0.3821	175

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory segment of nasal mucosa	UBERON:0005386	98.96	gold quality
islet of Langerhans	UBERON:0000006	98.32	gold quality
mucosa of stomach	UBERON:0001199	98.18	gold quality
metanephros cortex	UBERON:0010533	97.50	gold quality
lower esophagus mucosa	UBERON:0035834	97.47	gold quality
gall bladder	UBERON:0002110	97.10	gold quality
esophagus mucosa	UBERON:0002469	96.96	gold quality
body of stomach	UBERON:0001161	96.74	gold quality
granulocyte	CL:0000094	96.05	gold quality
bone marrow	UBERON:0002371	95.87	gold quality
left uterine tube	UBERON:0001303	95.62	gold quality
vagina	UBERON:0000996	95.31	gold quality
right atrium auricular region	UBERON:0006631	95.20	gold quality
pancreas	UBERON:0001264	95.19	gold quality
cortex of kidney	UBERON:0001225	95.00	gold quality
adult mammalian kidney	UBERON:0000082	94.71	gold quality
monocyte	CL:0000576	94.61	gold quality
leukocyte	CL:0000738	94.44	gold quality
stomach	UBERON:0000945	94.35	gold quality
vermiform appendix	UBERON:0001154	94.27	gold quality
omental fat pad	UBERON:0010414	94.27	gold quality
mucosa of transverse colon	UBERON:0004991	94.20	gold quality
body of pancreas	UBERON:0001150	94.19	gold quality
transverse colon	UBERON:0001157	94.05	gold quality
smooth muscle tissue	UBERON:0001135	93.78	gold quality
fundus of stomach	UBERON:0001160	93.71	gold quality
bone marrow cell	CL:0002092	93.63	gold quality
apex of heart	UBERON:0002098	93.61	gold quality
skin of abdomen	UBERON:0001416	93.54	gold quality
placenta	UBERON:0001987	93.48	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	78.45
E-MTAB-6701	yes	72.11
E-MTAB-10287	yes	56.10
E-CURD-46	yes	34.66
E-MTAB-9221	yes	18.02
E-GEOD-125970	yes	17.88
E-MTAB-9801	yes	2.98
E-MTAB-7249	no	1488.26
E-CURD-114	no	231.75
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
BCL2

Upstream regulators (CollecTRI, top): E2F1, FOXL2, HOXA1, MYC, NFKB1, NFKB, RARA, REL, RELA, RUNX1, RXRA, SOX17, SP1, TFAP4, TP53, VDR

miRNA regulators (miRDB)

16 targeting IER3, 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-4682	100.00	68.89	1258
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-7158-5P	99.25	67.95	796
HSA-MIR-4266	98.53	67.29	1035
HSA-MIR-6884-3P	98.05	65.32	750
HSA-MIR-450A-2-3P	97.91	67.56	1459
HSA-MIR-342-3P	96.44	67.48	1344
HSA-MIR-4484	96.35	64.08	382

Literature-anchored findings (GeneRIF, showing 40)

• Impaired apoptosis, extended duration of immune responses, and a lupus-like autoimmune disease in IEX-1-transgenic mice. (PMID:11782530)
• regulation by p53 tumor suppressor and Sp1 (PMID:11844788)
• mechanical strain increased IEX-1 gene expression in macrophages (PMID:11910304)
• Characterization of a novel hexameric repeat DNA sequence in the promoter of the immediate early gene, IEX-1, that mediates 1alpha,25-dihydroxyvitamin D(3)-associated IEX-1 gene repression. (PMID:12032839)
• IEX-1 is a new type of ERK substrate that has a dual role in ERK signaling by acting both as an ERK downstream effector mediating survival and as a regulator of ERK activation (PMID:12356731)
• IEX-1 has roles in regulation of cell death and oncogenesis [review] (PMID:12510147)
• Overexpression of IEX-1S results in acceleration of TNF-alpha-induced hepatocyte apoptosis through blockade of the PI3K/Akt survival pathway. (PMID:12682234)
• failure of IEX-1 to express its protein reflects the numerous mechanisms by which HSV-1 thwarts the cells from expressing its genes after infection (PMID:12743274)
• IEX-1 attenuates NF-kappaB activation, a possible counter-regulatory process leading to apoptosis. (PMID:12761504)
• IEX-1 expression was stimulated by hydroxytamoxifen, that the degree of increase was greater in resistant cells (four-fold versus 1.5-fold) and that this hydroxytamoxifen regulation was estrogen receptor dependent (PMID:15120418)
• Our data suggest that IEX-1 may regulate apoptosis by directly interacting with various proteins involved in the control of apoptotic pathways. (PMID:15451437)
• concluded that IEX-1 mRNA is not preferentially degraded during HSV-1 infection and that HSV-1 instead inhibits the normal turnover of this mRNA (PMID:15767410)
• We found that p73beta targets the apoptotic program at multiple levels: facilitating caspase activation through p53-dependent signals and inducing p57KIP2, while down-regulating c-IPA1 and IEX1 through a p53-independent mechanism. (PMID:15781630)
• IEX-1 is organized in subnuclear structures and partially co-localizes with promyelocytic leukemia protein in HeLa cells (PMID:15855159)
• sequence-targeting mutagenesis reveals a transmembrane-like integrated region of the protein that is critical for both pro-apoptotic and anti-apoptotic functions (PMID:16567805)
• IEX-1 plays an important role in astrocytic differentiation of human glioma cells and that IEX-1 functions at downstream of PKA. (PMID:16960879)
• ICP27 is essential for IEX-1 mRNA stabilization whereas virion host shut plays little if any role (PMID:16973576)
• Modulates NF-kappaB-dependent antiapoptotic protection and thereby exerts tumor-suppressive potential. (PMID:17704804)
• This study indicates that an evaulation of IEX-1 expression may be clinically useful for predicting patient prognosis in pancreatic cancer. (PMID:18026799)
• study showed that IEX-1 is involved in the radiation-induced apoptosis of human glioma cells and that its overexpression enhances the apoptotic sensitivity of these cells to gamma-radiation (PMID:18564103)
• down-regulation of IEX-1 gene was associated with short survival in myelodysplastic syndrome patients (PMID:19152102)
• This study demonstrated the physical association of the MCL-1 and IEX-1 proteins, the modulatory role of MCL-1 in IEX-1-induced apoptosis, and the role of BIM as an essential downstream molecule for IEX-1-induced cell death. (PMID:19285955)
• The small interfering RNA knockdown of BNIP3, IER3, and SEPW1 genes affected critical multiple myeloma endothelial cell functions correlated with the overangiogenic phenotype (PMID:19690192)
• Results suggest dysregulated expression of IER3 is common in MDS (61% >4-fold increase or decrease in expression with decreased expression primarily in early MDS and increased expression primarily in later MDS progressing toward leukemia). (PMID:19773435)
• Results suggest that hypertension in IEX-1 knockout mice may arise primarily from impaired cAMP signaling induced by overproduction of mitochondrial reactive oxygen species in vascular smooth muscle cells. (PMID:20713914)
• IER3 is upregulated in human PDLCs subjected to tensile stress related to mechano-induced cell cycle arrest. (PMID:20934684)
• IER3 plays a complex and to some extent contradictory role in cell cycle control and apoptosis. Effects of IER3 relate to an interference with certain signalling pathways (PMID:21112119)
• IEX-1 plays a role in suppression of apoptosis and protects cells by controlling sensitivity to TNFalpha under both normal and inflammatory conditions. (PMID:21250941)
• Changes of methylation status of gene IEX-1 promoter CpG island correlates with hematologic malignancies. (PMID:21518511)
• Altered IEX-1 expression can potentially be a new predictor of the malignant transformation and a prognostic indicator for cancer therapy. (PMID:22085302)
• Studied the binding effect of hcmv-miR-UL148D to the 3’ untranslated region (3’UTR) of IEX-1.Results showed that only one binding site in the 3’UTR of IEX-1 was completely complementary to an 11nt sequence in the 5’ terminus of hcmv-mir-UL148D. (PMID:23403649)
• IEX-1 expression levels correlate with the severity of preeclampsia (PMID:23725081)
• the interference of IER3 with the PI3K/Akt-Fyn pathway represents a novel mechanism of Nrf2 regulation that may get lost in tumors and by which IER3 exerts its stress-adaptive and tumor-suppressive activity. (PMID:24311782)
• In human samples removed from failed AVF, there was a significant increase in IEX-1 expression localized to the adventitia. (PMID:25036043)
• interleukin-1beta (IL-1beta)-induced IER3 expression is mediated by the ERK1/2 target, transcription factor Elk-1. (PMID:25066273)
• findings suggest that IER3 is a putative tumor suppressor in the cervix, and the c-Ab1/p73beta/IER3 axis is a novel and crucial signaling pathway that confers etoposide chemosensitivity. (PMID:25666857)
• High expression of IER3 is associated with hepatocarcinoma. (PMID:25684507)
• we determined the molecular mechanism responsible for IER3 degradation, involving a ternary complex of IER3, MDM2 and FHL2, which may contribute to cervical tumor growth. Furthermore, we demonstrated that FHL2 serves as a scaffold for E3 ligase and its substrate during the ubiquitination reaction, a function that has not been previously reported for this protein (PMID:26973248)
• Study characterized IEX-1’s expression and function in rheumatoid arthritis synovial fibroblasts and showed that IEX-1 is highly expressed in RA-SFs and negatively regulates RA-SF activation. (PMID:27736946)
• Analysis of consensus EGR-binding elements (EBEs) showed that the immediate early response 3 gene (IER3) is a novel transcriptional target gene of EGR2 as confirmed by the luciferase assay, electrophoretic mobility-shift assay (EMSA), chromatin immunoprecipitation (ChIP), and western blot analysis. (PMID:27890615)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:158343	ENSDARG00000099411
mus_musculus	Ier3	ENSMUSG00000003541
rattus_norvegicus	Ier3	ENSRNOG00000000827

Protein

Protein identifiers

Radiation-inducible immediate-early gene IEX-1 — P46695 (reviewed: P46695)

Alternative names: Differentiation-dependent gene 2 protein, Immediate early protein GLY96, Immediate early response 3 protein, PACAP-responsive gene 1 protein

All UniProt accessions (3): P46695, A0A1U9X7X2, Q5ST79

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in the ERK signaling pathway by inhibiting the dephosphorylation of ERK by phosphatase PP2A-PPP2R5C holoenzyme. Also acts as an ERK downstream effector mediating survival. As a member of the NUPR1/RELB/IER3 survival pathway, may provide pancreatic ductal adenocarcinoma with remarkable resistance to cell stress, such as starvation or gemcitabine treatment.

Subunit / interactions. Interacts with the PPP2R5C-PP2A holoenzyme and ERK kinases; regulates ERK dephosphorylation.

Subcellular location. Membrane.

Post-translational modifications. Phosphorylated at Thr-18, Thr-123 and Ser-126 by MAPK1/ERK2 and probably MAPK3/ERK1. Upon phosphorylation by MAPK1/ERK2 and MAPK3/ERK1, acquires the ability to inhibit cell death induced by various stimuli. Glycosylated.

Induction. By radiation, 12-O-tetradecanoyl phorbol-13 acetate (TPA), okadaic acid, TNF and NUPR1.

Similarity. Belongs to the IER3 family.

RefSeq proteins (1): NP_003888* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024829	IEX-1	Family

UniProt features (14 total): modified residue 4, topological domain 2, sequence conflict 2, chain 1, glycosylation site 1, sequence variant 1, transmembrane region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46695-F1	66.00	0.12

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 (4): 18, 31, 123, 126

Glycosylation sites (1): 133

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling

MSigDB gene sets: 641 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE45365_NK_CELL_VS_CD11B_DC_DN, CREL_01, LEE_SP4_THYMOCYTE, MODULE_52, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, MCLACHLAN_DENTAL_CARIES_UP, GOBP_REGULATION_OF_BLOOD_PRESSURE, MODULE_169, GOBP_CIRCULATORY_SYSTEM_PROCESS, BOYAULT_LIVER_CANCER_SUBCLASS_G56_DN, GOBP_INFLAMMATORY_RESPONSE

GO Biological Process (16): response to protozoan (GO:0001562), negative regulation of systemic arterial blood pressure (GO:0003085), glycolytic process (GO:0006096), regulation of DNA repair (GO:0006282), apoptotic process (GO:0006915), DNA damage response (GO:0006974), mitotic G2 DNA damage checkpoint signaling (GO:0007095), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), anatomical structure morphogenesis (GO:0009653), negative regulation of apoptotic process (GO:0043066), positive regulation of protein catabolic process (GO:0045732), negative regulation of glycolytic process (GO:0045820), regulation of nucleocytoplasmic transport (GO:0046822), negative regulation of inflammatory response (GO:0050728), negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway (GO:1901029), regulation of reactive oxygen species metabolic process (GO:2000377)

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

GO Cellular Component (4): nucleus (GO:0005634), mitochondrion (GO:0005739), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Negative regulation of the PI3K/AKT network	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
cytoplasm	2
cellular anatomical structure	2
response to other organism	1
regulation of systemic arterial blood pressure	1
negative regulation of blood pressure	1
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
pyruvate metabolic process	1
generation of precursor metabolites and energy	1
aerobic respiration	1
carbohydrate catabolic process	1
pyridine nucleotide catabolic process	1
glyceraldehyde-3-phosphate dehydrogenase [NAD(P)+] (phosphorylating) activity	1
ADP catabolic process	1
ATP metabolic process	1
nicotinamide nucleotide metabolic process	1
DNA repair	1
regulation of DNA metabolic process	1
regulation of cellular response to stress	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to stress	1
mitotic G2 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G2/M transition checkpoint	1
DNA damage response	1
intrinsic apoptotic signaling pathway	1
developmental process	1
anatomical structure development	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1

Protein interactions and networks

STRING

1012 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IER3	ADCYAP1	P18509	706
IER3	PHLDA1	Q8WV24	606
IER3	ATP5IF1	Q9UII2	591
IER3	MCL1	Q07820	555
IER3	DUSP5	Q16690	550
IER3	TNF	P01375	543
IER3	GGNBP2	Q9H3C7	542
IER3	DUSP6	Q16828	538
IER3	PLK3	Q9H4B4	536
IER3	CEBPA	P49715	531
IER3	RELA	Q04206	522
IER3	MAPK3	P27361	516
IER3	B3GLCT	Q6Y288	506
IER3	ZFP36	P26651	500
IER3	FOSL1	P15407	490

IntAct

50 interactions, top by confidence:

A	B	Type	Score
RELA	IER3	psi-mi:“MI:0915”(physical association)	0.590
IER3	RELA	psi-mi:“MI:0915”(physical association)	0.590
SGTA	IER3	psi-mi:“MI:0915”(physical association)	0.560
IER3	TMBIM6	psi-mi:“MI:0915”(physical association)	0.560
IER3	SLC13A4	psi-mi:“MI:0915”(physical association)	0.560
CD79A	IER3	psi-mi:“MI:0915”(physical association)	0.560
IER3	CISD2	psi-mi:“MI:0915”(physical association)	0.560
IER3	TMX2	psi-mi:“MI:0915”(physical association)	0.560
IER3	FKBP7	psi-mi:“MI:0915”(physical association)	0.560
PPP2R5B	IER3	psi-mi:“MI:0915”(physical association)	0.520
PPP2CA	IER3	psi-mi:“MI:0915”(physical association)	0.520
CAMLG	IER3	psi-mi:“MI:0915”(physical association)	0.510
IER3	MAPK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
IER3	PPP2R5C	psi-mi:“MI:0915”(physical association)	0.400
TNFSF10	IER3	psi-mi:“MI:0915”(physical association)	0.370
IER3	MCL1	psi-mi:“MI:0915”(physical association)	0.370
BAG6	IER3	psi-mi:“MI:0915”(physical association)	0.370
IER3	BCL2	psi-mi:“MI:0914”(association)	0.350
IER3		psi-mi:“MI:0914”(association)	0.350

BioGRID (34): IER3 (Reconstituted Complex), IER3 (Two-hybrid), FHL2 (Affinity Capture-Western), IER3 (Affinity Capture-Western), MDM2 (Affinity Capture-Western), MDM2 (Reconstituted Complex), IER3 (Affinity Capture-Western), IER3 (Biochemical Activity), FHL2 (Reconstituted Complex), IER3 (Two-hybrid), IER3 (PCA), IER3 (Affinity Capture-RNA), IER3 (Two-hybrid), IER3 (Two-hybrid), IER3 (Two-hybrid)

ESM2 similar proteins: A0A1B0GUA5, A0A1B0GVQ0, A0A286YF18, A0JNN8, A2VDX9, A5PK62, A6NGB7, A9CBA0, O09800, P04488, P06480, P06764, P07646, P0C171, P0DJK0, P0DJK1, P0DMQ5, P13291, P22389, P36342, P46695, P98162, Q08102, Q1RMT9, Q2HJ59, Q3TYP4, Q5BIR3, Q5EAA5, Q5JTB6, Q5NRQ0, Q6F5E0, Q6VUC0, Q6VUP9, Q703F0, Q765Z5, Q867A9, Q867D0, Q89448, Q8MJW9, Q8TEF2

Diamond homologs: P46694, P46695, Q0IHC5, Q3KQ18, Q5BKJ7, Q7YR42, Q568B8, Q8BH02, Q9NXH8, P0C7W2, P0C7W3, P0C7W1, Q8N2E6, Q8R1J9

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
IER3	down-regulates	PPP2R5C	binding
MDM2	“down-regulates quantity by destabilization”	IER3	ubiquitination
MAPK1	up-regulates	IER3	phosphorylation
HNRNPU	“up-regulates quantity by stabilization”	IER3	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 18 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
negative regulation of apoptotic process	6	12.3×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	19
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

57 predictions. Top by Δscore:

Variant	Effect	Δscore
6:30744192:CGGAC:C	acceptor_gain	1.0000
6:30744193:GGAC:G	acceptor_gain	1.0000
6:30744194:GAC:G	acceptor_gain	1.0000
6:30744195:AC:A	acceptor_gain	1.0000
6:30744196:CC:C	acceptor_gain	1.0000
6:30744196:CCTA:C	acceptor_loss	1.0000
6:30744197:C:CC	acceptor_gain	1.0000
6:30744198:T:G	acceptor_loss	1.0000
6:30744208:C:CT	acceptor_gain	1.0000
6:30744306:CA:C	donor_loss	1.0000
6:30744307:A:AC	donor_gain	1.0000
6:30744307:AC:A	donor_gain	1.0000
6:30744308:C:CG	donor_gain	1.0000
6:30744308:CC:C	donor_gain	1.0000
6:30744308:CCA:C	donor_gain	1.0000
6:30744308:CCACT:C	donor_gain	1.0000
6:30744197:C:T	acceptor_gain	0.9900
6:30744209:A:T	acceptor_gain	0.9900
6:30744193:GGACC:G	acceptor_gain	0.9800
6:30744194:GACCT:G	acceptor_gain	0.9800
6:30744195:ACC:A	acceptor_gain	0.9800
6:30744196:CCT:C	acceptor_gain	0.9800
6:30744197:C:A	acceptor_gain	0.9800
6:30744303:A:AC	donor_gain	0.9800
6:30744304:C:CC	donor_gain	0.9800
6:30744305:TCAC:T	donor_gain	0.9800
6:30744306:CACC:C	donor_gain	0.9800
6:30744307:ACCA:A	donor_gain	0.9800
6:30744308:CCAC:C	donor_gain	0.9800
6:30744198:T:A	acceptor_gain	0.9700

AlphaMissense

987 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:30744405:G:C	F38L	0.997
6:30744405:G:T	F38L	0.997
6:30744407:A:G	F38L	0.997
6:30744411:G:C	F36L	0.997
6:30744411:G:T	F36L	0.997
6:30744413:A:G	F36L	0.997
6:30744412:A:G	F36S	0.995
6:30744412:A:C	F36C	0.991
6:30744320:A:C	Y67D	0.988
6:30744406:A:G	F38S	0.987
6:30744121:A:G	C96R	0.985
6:30744406:A:C	F38C	0.985
6:30744413:A:C	F36V	0.984
6:30744413:A:T	F36I	0.984
6:30744325:A:T	V65D	0.981
6:30744126:A:T	V94D	0.975
6:30744407:A:T	F38I	0.972
6:30744319:T:C	Y67C	0.971
6:30744325:A:G	V65A	0.969
6:30744320:A:T	Y67N	0.967
6:30744317:G:T	P68T	0.965
6:30744317:G:A	P68S	0.964
6:30743939:G:C	F156L	0.963
6:30743939:G:T	F156L	0.963
6:30743941:A:G	F156L	0.963
6:30744138:A:C	L90R	0.963
6:30744316:G:A	P68L	0.963
6:30744407:A:C	F38V	0.963
6:30744409:G:A	T37I	0.961
6:30744316:G:T	P68H	0.959

dbSNP variants (sampled 300 via entrez): RS1000214172 (6:30743854 G>A,C), RS1000824290 (6:30745453 A>G), RS1001100498 (6:30743309 A>G), RS1001153712 (6:30745719 C>G), RS1001533409 (6:30743107 T>C,G), RS1003366995 (6:30745212 G>A,C), RS1003543330 (6:30746119 C>T), RS1003734617 (6:30743370 C>T), RS1004062714 (6:30743292 A>G), RS1006085486 (6:30742709 C>T), RS1006356571 (6:30744996 C>A), RS1007223277 (6:30746390 G>T), RS1009887169 (6:30742989 C>T), RS1010587120 (6:30743696 T>G), RS1012130828 (6:30745070 T>C)

Disease associations

OMIM: gene MIM:602996 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST000853_3	Ulcerative colitis	4.000000e-06
GCST001884_6	Age-related macular degeneration	2.000000e-11
GCST002711_2	Sleep duration	2.000000e-08
GCST002876_2	Type 1 diabetes and autoimmune thyroid diseases	3.000000e-14
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_121	Autism spectrum disorder or schizophrenia	3.000000e-13
GCST004521_132	Autism spectrum disorder or schizophrenia	2.000000e-09
GCST004521_171	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_2	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_210	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_263	Autism spectrum disorder or schizophrenia	7.000000e-17
GCST004521_265	Autism spectrum disorder or schizophrenia	7.000000e-14
GCST004521_27	Autism spectrum disorder or schizophrenia	1.000000e-09
GCST004521_295	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_3	Autism spectrum disorder or schizophrenia	2.000000e-15
GCST004521_48	Autism spectrum disorder or schizophrenia	1.000000e-09
GCST004521_56	Autism spectrum disorder or schizophrenia	1.000000e-22
GCST004521_70	Autism spectrum disorder or schizophrenia	8.000000e-20
GCST004521_79	Autism spectrum disorder or schizophrenia	1.000000e-16
GCST004746_5	Small cell lung carcinoma	4.000000e-06
GCST005541_13	Sarcoidosis (Lofgren’s syndrome vs non-Lofgren’s syndrome)	1.000000e-25
GCST005790_56	Rosacea symptom severity	1.000000e-07
GCST007692_120	Chronic obstructive pulmonary disease	2.000000e-21
GCST008533_1	Decreased fine motor function in Charcot-Marie-Tooth disease 1A (eating with utensils)	1.000000e-06
GCST90011900_182	Serum alkaline phosphatase levels	4.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009180	rosacea severity measurement
EFO:0010132	decreased fine motor function
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	11
Estradiol	affects expression, affects cotreatment, decreases expression, increases expression, decreases reaction	8
Particulate Matter	increases abundance, increases expression, decreases expression, affects cotreatment, affects expression (+1 more)	7
sodium arsenite	affects expression, decreases expression, increases expression	6
Aflatoxin B1	affects expression, increases expression	6
methylmercuric chloride	decreases expression, increases expression, affects cotreatment	5
Tetrachlorodibenzodioxin	decreases expression, increases expression	5
Air Pollutants	increases expression, affects cotreatment, decreases expression, increases abundance	4
Cisplatin	increases expression, decreases reaction	4
Tretinoin	decreases reaction, increases expression	4
Valproic Acid	affects expression, increases expression	4
Cyclosporine	increases expression, affects cotreatment, decreases expression	4
bisphenol A	affects expression, increases expression	3
trichostatin A	affects cotreatment, increases expression	3
nickel sulfate	increases expression	3
Vehicle Emissions	increases expression, affects expression, increases reaction, increases abundance	3
Hydrogen Peroxide	affects expression, decreases expression, increases expression	3
phenanthrene	decreases expression, increases expression	2
indeno(1,2,3-cd)pyrene	increases expression	2
perfluorooctane sulfonic acid	increases expression	2
Resveratrol	affects cotreatment, decreases expression	2
Decitabine	affects binding, affects cotreatment, increases reaction, increases expression	2
Vorinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Ethanol	decreases expression, affects cotreatment, increases abundance, increases expression	2
Arsenic	affects methylation, decreases expression	2
Dexamethasone	decreases expression, affects cotreatment	2
Doxorubicin	affects reaction, decreases expression, increases expression	2
Lipopolysaccharides	affects cotreatment, decreases expression, increases expression, affects response to substance	2
Methylcholanthrene	affects binding, increases reaction, increases expression	2

Clinical trials (associated diseases)

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