PENK

Summary

PENK (proenkephalin, HGNC:8831) is a protein-coding gene on chromosome 8q12.1, encoding Proenkephalin-A (P01210). Neuropeptide that competes with and mimic the effects of opiate drugs.

This gene encodes a preproprotein that is proteolytically processed to generate multiple protein products. These products include the pentapeptide opioids Met-enkephalin and Leu-enkephalin, which are stored in synaptic vesicles, then released into the synapse where they bind to mu- and delta-opioid receptors to modulate the perception of pain. Other non-opioid cleavage products may function in distinct biological activities.

Source: NCBI Gene 5179 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 59 total
• MANE Select transcript: NM_001135690

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8831
Approved symbol	PENK
Name	proenkephalin
Location	8q12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000181195
Ensembl biotype	protein_coding
OMIM	131330
Entrez	5179

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000314922, ENST00000451791, ENST00000517415, ENST00000518770, ENST00000518974, ENST00000520589, ENST00000521153, ENST00000523051, ENST00000523274, ENST00000961478, ENST00000961479, ENST00000961480, ENST00000961481

RefSeq mRNA: 1 — MANE Select: NM_001135690 NM_001135690

CCDS: CCDS6168

Canonical transcript exons

ENST00000451791 — 4 exons

Exon	Start	End
ENSE00001693758	56445816	56445956
ENSE00001767550	56446426	56446481
ENSE00002115822	56446569	56446641
ENSE00002130298	56440957	56441937

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 98.61.

FANTOM5 (CAGE): breadth broad, TPM avg 36.7854 / max 9398.7714, expressed in 489 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
93169	36.3649	485
93165	0.2181	59
93167	0.0983	35
93166	0.0772	34
93168	0.0269	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	98.61	gold quality
putamen	UBERON:0001874	97.84	gold quality
left testis	UBERON:0004533	97.83	gold quality
right testis	UBERON:0004534	97.83	gold quality
cartilage tissue	UBERON:0002418	97.77	gold quality
caudate nucleus	UBERON:0001873	96.97	gold quality
ganglionic eminence	UBERON:0004023	96.79	gold quality
middle frontal gyrus	UBERON:0002702	96.59	gold quality
lateral globus pallidus	UBERON:0002476	96.33	gold quality
testis	UBERON:0000473	95.95	gold quality
urethra	UBERON:0000057	95.31	gold quality
adult organism	UBERON:0007023	95.19	gold quality
sperm	CL:0000019	93.57	gold quality
male germ cell	CL:0000015	93.17	gold quality
cerebellar vermis	UBERON:0004720	91.86	gold quality
superior vestibular nucleus	UBERON:0007227	91.50	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.78	gold quality
hypothalamus	UBERON:0001898	87.83	gold quality
ventricular zone	UBERON:0003053	87.75	gold quality
penis	UBERON:0000989	87.47	gold quality
medulla oblongata	UBERON:0001896	87.32	gold quality
primary visual cortex	UBERON:0002436	87.10	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.78	gold quality
tibia	UBERON:0000979	84.22	gold quality
occipital lobe	UBERON:0002021	84.02	gold quality
gall bladder	UBERON:0002110	83.40	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.13	gold quality
cerebellar cortex	UBERON:0002129	82.83	gold quality
cerebellar hemisphere	UBERON:0002245	82.81	gold quality
left ovary	UBERON:0002119	82.52	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	1833.05
E-ENAD-27	yes	171.27
E-GEOD-124858	no	1452.39
E-ANND-3	no	2.50

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ATF3, ATF4, CREB1, DEAF1, EGR1, ESR1, ESR2, FOS, FOSB, IKZF1, IRF2BPL, IRF6, JUN, JUNB, JUND, NFKB, NR2F2, NR3C1, POU2F2, PTF1A, REST, TFAP2A, TFAP4, THRA, TTF1

miRNA regulators (miRDB)

41 targeting PENK, 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-4795-3P	100.00	74.62	4024
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-188-3P	100.00	68.76	1240
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-501-3P	99.33	66.12	651
HSA-MIR-502-3P	99.33	66.12	651
HSA-MIR-128-1-5P	99.33	60.46	332
HSA-MIR-128-2-5P	99.33	60.83	311
HSA-MIR-3614-5P	99.30	65.25	837
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-3675-3P	99.09	67.70	968
HSA-MIR-4464	98.95	67.73	820
HSA-MIR-4748	98.95	67.53	810
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-3145-5P	98.57	67.83	900

Literature-anchored findings (GeneRIF, showing 34)

• Results suggest that methylation-related inactivation of the ppENK gene is an intermediate or late event during pancreatic carcinogenesis. (PMID:12000709)
• Proenkephalin peptide F has varying immunoreactivity in different circulatory biocompartments after exercise (PMID:16406203)
• Proenkephalin A 119-159 is a stable proenkephalin A precursor fragment identified in human circulation (PMID:16621157)
• The discrete cell-phenotype localization and timing of the changes in the level of PEA and of piGABA-R mRNA. (PMID:17074347)
• Smoking was not associated with p16 or ppENK hypermethylation in pancreatic cancer patients (PMID:17198183)
• study provides evidence that the growth-responsive nuclear protein, proenkephalin (Penk), is required, in part, for apoptosis induction, in response to activation or overexpression of p53 and RelA(p65) (PMID:17599100)
• It found widespread expression of preproenkephalin (pPENK) mRNA and production of the enkephalin precursor protein proenkephalin (PENK) in rat and mouse tissues, as well as in tissues and cells from humans and pigs. (PMID:18082911)
• analysis of polymorphisms of proenkephalin (PENK) and prodynorphin (PDYN) genes in relation to heroin abuse and gene expression in the human striatum and the relevance of genetic dopaminergic tone (PMID:18184800)
• indicate alterations of the cerebral PENK A- and PTA-system in both, dementia and acute neuroinflammatory disorders (PMID:20207019)
• we demonstrated reduced ppE expression in patients with elevated psychological distress. (PMID:20628265)
• found higher levels for MOR mRNA (+27%) in schizophrenia but no differences in DOR or proenkephalin mRNAs (PMID:21810780)
• Differential tertiary conformations of PE subdomains undergo ordered proteolytic processing to generate active enkephalin peptides for cell-cell communication in the nervous and endocrine systems. (PMID:22102294)
• Expression of preproenkephalin is significantly decreased in brain from HIV-1 infected patients compared to HIV-1 negative subjects. (PMID:22391864)
• Findings indicate the unique function of cathepsin V for producing enkephalin and neuropeptide Y (NPY) neuropeptides required for neurotransmission in health and neurological diseases. (PMID:22393040)
• The findings suggest an important role for Neuroticism as an endophenotype linking PENK polymorphisms to cannabis-dependence vulnerability synergistically amplifying the apparent genetic risk. (PMID:22745721)
• Peptide F is bound to white blood cells in the blood. Exercise alters Peptide F in the plasma and white blood cell blood fractions. (PMID:23395721)
• Data from women undergoing hysterectomy for uterine fibroids suggest that uterine isthmian-cervical region exhibits nerve fibers expressing enkephalin (ENK); uterine fundus/corpus myoma pseudocapsules do not exhibit nerve fibers expressing ENK. (PMID:23937196)
• Promoter methylation of WIF1, PENK and NPY is associated with colorectal adenocarcinoma (CRC) diagnosis and can be used to CRC from other cancers. (PMID:24289328)
• EPS led to the discovery of two novel immunomodulatory proteins, MFAP5 and PENK that when administered to mice subjected to endotoxemic shock, reversed the cytokine storm and provided a significant survival benefit (PMID:24496384)
• increased plasma PENK-A levels are associated with disease severity and in-hospital mortality after acute intracerebral hemorrhage. (PMID:24937654)
• enhanced plasma proenkephalin A could be a useful, complementary tool to predict short- or long-term clinical outcome after severe traumatic brain injury. (PMID:24937655)
• BSP demonstrated that emodin, to a certain degree, affected the demethylation of tumor-suppressor genes P16, RASSF1A, and ppENK in the pancreatic cancer cell line PANC-1. (PMID:25891176)
• The PENK polymorphism-and potentially opioid neurotransmission more generally-modulates functioning and structural integrity of brain regions. (PMID:26164485)
• Serum PENK-A levels were not associated with all-cause mortality in patients with type 2 diabetes mellitus, and its association with cardiovascular mortality was strongly attenuated after accounting for all traditional risk factors. (PMID:26218633)
• Nav1.7 deletion has profound effects on gene expression, leading to an upregulation of enkephalin precursor Penk mRNA and met-enkephalin protein in sensory neurons. (PMID:26634308)
• These data indicate that in untrained women exercise training will not change resting of plasma Peptide F concentrations unless both forms of exercise are performed but will result in significant increases in the immediate post-exercise responses. (PMID:28263851)
• The concentration of PENK 143-183 was significantly greater in patients with Moyamoya disease (MMD) than control patients and decreased in an age-dependent manner in MMD. (PMID:29030229)
• High PENK is associated with increased risk of CKD defined by eGFR in men, but not in women. No association of PENK with CKD defined by urinary albumin excretion UAE was observed. (PMID:29466891)
• These results demonstrate that proinflammatory molecules and endogenous enkephalin have opposite gene regulation during Dry eye disease. (PMID:29673232)
• The opioid system, reflected by PENK (proenkephalin), is not only independently associated with glomerular dysfunction, but also with tubular damage in heart failure. (PMID:31091993)
• PENK-A was neither independently associated with functional outcome (OR: 1.29, 95% CI: 0.16-10.35) nor mortality (PMID:31973568)
• PENK inhibits osteosarcoma cell migration by activating the PI3K/Akt signaling pathway. (PMID:32334633)
• Proenkephalin as a biomarker correlates with acute kidney injury: a systematic review with meta-analysis and trial sequential analysis. (PMID:38057904)
• Plasma proenkephalin A and incident chronic kidney disease and albuminuria in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. (PMID:38200454)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	penka	ENSDARG00000004869
danio_rerio	penkb	ENSDARG00000036045
mus_musculus	Penk	ENSMUSG00000045573
rattus_norvegicus	Penk	ENSRNOG00000008943

Paralogs (2): PDYN (ENSG00000101327), PNOC (ENSG00000168081)

Protein

Protein identifiers

Proenkephalin-A — P01210 (reviewed: P01210)

All UniProt accessions (5): E5RFR1, E5RIP6, E5RJ72, P01210, H0YBT5

UniProt curated annotations — full annotation on UniProt →

Function. Neuropeptide that competes with and mimic the effects of opiate drugs. They play a role in a number of physiologic functions, including pain perception and responses to stress. Neuropeptide that competes with and mimic the effects of opiate drugs. They play a role in a number of physiologic functions, including pain perception and responses to stress. Met-enkephalin-Arg-Phe neuropeptide acts as a strong ligand of Mu-type opioid receptor OPRM1. Met-enkephalin-Arg-Phe-binding to OPRM1 in the nucleus accumbens of the brain increases activation of OPRM1, leading to long-term synaptic depression of glutamate release. Increases glutamate release in the striatum and decreases GABA concentration in the striatum. Neuropeptide that mediates stress-induced opioid analgesia. Also possesses non-opioid action by acting as a ligand for MRGPRX1 receptor to induce itch in a histamine-independent manner. Neuropeptide that induces itch in a histamine-independent manner as well as nociceptive sensations. Acts as a ligand for MRGPRX1 receptor in sensory neurons of dorsal root ganglion: MRGPRX1-binding in the peripheral nervous system elicits itch and scratching, while MRGPRX1-binding in the central nervous system dampens chronic pain. Increases glutamate release in the striatum.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Chromaffin granule lumen. Secreted.

Post-translational modifications. Proenkephalin-A is cleaved by CTSL to generate Met-enkephalin. Processed and degraded by ACE. Processed and degraded by ACE. Probably cleaved by ACE. Processed by ACE to generate Met-enkephalin in the nucleus accumbens of the brain. The N-terminal domain contains 6 conserved cysteines thought to be involved in disulfide bonding and/or processing.

Similarity. Belongs to the opioid neuropeptide precursor family.

RefSeq proteins (1): NP_001129162* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000703	Proenkphlin_A	Family
IPR006024	Opioid_neupept	Family

Pfam: PF01160

UniProt features (36 total): peptide 14, site 6, disulfide bond 3, sequence variant 2, mutagenesis site 2, sequence conflict 2, turn 2, signal peptide 1, region of interest 1, compositionally biased region 1, modified residue 1, propeptide 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
5E33	X-RAY DIFFRACTION	1.84
5E3A	X-RAY DIFFRACTION	2.05
8JGF	ELECTRON MICROSCOPY	2.7
8DWG	ELECTRON MICROSCOPY	2.71
8DWC	ELECTRON MICROSCOPY	2.87
8JGG	ELECTRON MICROSCOPY	3
1PLW	SOLUTION NMR
1PLX	SOLUTION NMR
2LWC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01210-F1	60.49	0.01

Antibody-complex structures (SAbDab): 4 — 8DWC, 8DWG, 8JGF, 8JGG

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 (6): 111–112 (cleavage; by ctsl); 112–113 (cleavage; by ctsl); 133–134 (cleavage; by ctsl); 214–215 (cleavage; by ctsl); 215–216 (cleavage; by ctsl); 218–219 (cleavage; by ctsl)

Post-translational modifications (1): 251

Disulfide bonds (3): 26–48, 30–52, 33–65

Mutagenesis-validated functional residues (2):

Position	Phenotype
229	abolished ability to activate mrgprx1.
230	abolished ability to activate mrgprx1.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-418594	G alpha (i) signalling events
R-HSA-8957275	Post-translational protein phosphorylation

MSigDB gene sets: 333 (showing top): MODULE_92, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, GOBP_CELLULAR_RESPONSE_TO_VIRUS, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, GOBP_RESPONSE_TO_ESTRADIOL, GOBP_RESPONSE_TO_IMMOBILIZATION_STRESS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOCC_SECRETORY_GRANULE, GOBP_ADULT_BEHAVIOR, MODULE_64, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_NEUROGENESIS

GO Biological Process (36): osteoblast differentiation (GO:0001649), behavioral fear response (GO:0001662), response to hypoxia (GO:0001666), startle response (GO:0001964), aggressive behavior (GO:0002118), signal transduction (GO:0007165), neuropeptide signaling pathway (GO:0007218), chemical synaptic transmission (GO:0007268), sensory perception (GO:0007600), response to toxic substance (GO:0009636), glial cell proliferation (GO:0014009), transmission of nerve impulse (GO:0019226), sensory perception of pain (GO:0019233), response to estradiol (GO:0032355), response to lipopolysaccharide (GO:0032496), cellular response to oxidative stress (GO:0034599), response to nicotine (GO:0035094), locomotory exploration behavior (GO:0035641), response to immobilization stress (GO:0035902), G protein-coupled opioid receptor signaling pathway (GO:0038003), drinking behavior (GO:0042756), behavioral response to ethanol (GO:0048149), response to calcium ion (GO:0051592), general adaptation syndrome, behavioral process (GO:0051867), cellular response to vitamin D (GO:0071305), cellular response to cAMP (GO:0071320), cellular response to transforming growth factor beta stimulus (GO:0071560), response to epinephrine (GO:0071871), cellular response to virus (GO:0098586), synaptic signaling via neuropeptide (GO:0099538), sensory perception of itch (GO:0160025), response to peptide (GO:1901652), positive regulation of behavioral fear response (GO:2000987), locomotory behavior (GO:0007626), response to bacterium (GO:0009617), response to ethanol (GO:0045471)

GO Molecular Function (4): opioid peptide activity (GO:0001515), neuropeptide hormone activity (GO:0005184), opioid receptor binding (GO:0031628), receptor ligand activity (GO:0048018)

GO Cellular Component (15): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), plasma membrane (GO:0005886), dendrite (GO:0030425), symmetric synapse (GO:0032280), chromaffin granule lumen (GO:0034466), synaptic vesicle lumen (GO:0034592), neuronal cell body (GO:0043025), perikaryon (GO:0043204), axon terminus (GO:0043679), cell body fiber (GO:0070852), neuronal dense core vesicle lumen (GO:0099013), axon (GO:0030424), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1
Metabolism of proteins	1
GPCR downstream signalling	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
neuron projection	3
response to stress	2
cell communication	2
G protein-coupled receptor signaling pathway	2
nervous system process	2
response to chemical	2
response to lipid	2
response to oxygen-containing compound	2
cellular anatomical structure	2
ossification	1
cell differentiation	1
behavioral defense response	1
fear response	1
response to decreased oxygen levels	1
response to external stimulus	1
neuromuscular process	1
behavior	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
anterograde trans-synaptic signaling	1
cell population proliferation	1
gliogenesis	1
action potential	1
chemical synaptic transmission	1
sensory perception	1
response to molecule of bacterial origin	1
response to oxidative stress	1
cellular response to chemical stress	1
locomotory behavior	1
exploration behavior	1
receptor ligand activity	1
hormone activity	1
neuropeptide activity	1
G protein-coupled receptor binding	1
signaling receptor binding	1
signal transduction	1
signaling receptor activator activity	1
endoplasmic reticulum	1

Protein interactions and networks

STRING

1802 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PENK	OGFR	Q9NZT2	987
PENK	OPRM1	P35372	894
PENK	POMC	P01189	886
PENK	TAC1	P20366	851
PENK	OPRD1	P41143	849
PENK	SST	P01166	799
PENK	ANKS6	Q68DC2	769
PENK	CHGB	P05060	725
PENK	NPY	P01303	722
PENK	CRH	P06850	698
PENK	PNMT	P11086	685
PENK	CPE	P16870	684
PENK	NTS	P30990	657
PENK	TH	P07101	605
PENK	FOS	P01100	586

IntAct

6 interactions, top by confidence:

A	B	Type	Score
PENK	CDC27	psi-mi:“MI:0914”(association)	0.530
PENK	FAM20C	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
PENK	nleA/espI	psi-mi:“MI:0915”(physical association)	0.370
PENK	PDYN	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): CDC27 (Affinity Capture-MS), CDC23 (Affinity Capture-MS), ANAPC5 (Affinity Capture-MS), ANAPC1 (Affinity Capture-MS), ANAPC4 (Affinity Capture-MS), ANAPC16 (Affinity Capture-MS), CDC26 (Affinity Capture-MS), PDYN (Affinity Capture-MS), ANAPC1 (Affinity Capture-MS), ANAPC4 (Affinity Capture-MS), CDC26 (Affinity Capture-MS), CDC23 (Affinity Capture-MS), ANAPC5 (Affinity Capture-MS), CDC27 (Affinity Capture-MS), ANAPC4 (Affinity Capture-MS)

ESM2 similar proteins: A0SIF1, A0SIX6, B2ZBA0, B2ZBA1, C0HKR2, C0HKS6, C0HKT6, C0HKW2, C0HL17, E2ADX8, E2AIS8, G3MU46, O18641, O44314, O61466, O76818, P01152, P01210, P01212, P04094, P07194, P11159, P12764, P19802, P21786, P22005, P41870, P42565, P47969, P50175, P85797, Q07981, Q10998, Q11088, Q18502, Q1MX22, Q21156, Q23212, Q295T3, Q29CA0

Diamond homologs: P01210, P01211, P01212, P04094, P07194, P0C2P6, P22005, P47969, P50175, Q28409, O35417, P06300, P0DP56

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
REST	“down-regulates quantity by repression”	PENK	“transcriptional regulation”
IRF2BPL	“down-regulates quantity by repression”	PENK	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	48
Likely benign	6
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

163 predictions. Top by Δscore:

Variant	Effect	Δscore
8:56441933:CAAGC:C	acceptor_gain	0.9900
8:56441935:AGCC:A	acceptor_loss	0.9900
8:56441936:GCC:G	acceptor_loss	0.9900
8:56441937:CCTG:C	acceptor_loss	0.9900
8:56445808:ACACT:A	donor_loss	0.9900
8:56445809:CACTC:C	donor_loss	0.9900
8:56445810:ACTCA:A	donor_loss	0.9900
8:56445811:CTCAC:C	donor_loss	0.9900
8:56445812:T:TA	donor_loss	0.9900
8:56445813:CACCA:C	donor_loss	0.9900
8:56445814:A:AC	donor_gain	0.9900
8:56445814:A:T	donor_loss	0.9900
8:56445815:C:CC	donor_gain	0.9900
8:56445815:C:G	donor_loss	0.9900
8:56441938:C:CC	acceptor_gain	0.9700
8:56445807:AACAC:A	donor_loss	0.9600
8:56441954:A:C	acceptor_gain	0.9500
8:56445429:G:C	donor_gain	0.9400
8:56441947:CAATT:C	acceptor_gain	0.9300
8:56441936:GC:G	acceptor_gain	0.9200
8:56441937:CC:C	acceptor_gain	0.9200
8:56442483:T:G	acceptor_gain	0.9200
8:56445465:T:TA	donor_gain	0.9200
8:56441934:AAGC:A	acceptor_gain	0.9100
8:56445814:AC:A	donor_gain	0.9000
8:56445815:CC:C	donor_gain	0.9000
8:56441935:AGC:A	acceptor_gain	0.8900
8:56441948:A:T	acceptor_gain	0.8700
8:56441951:T:C	acceptor_gain	0.8700
8:56445639:T:TA	donor_gain	0.8700

AlphaMissense

1761 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:56441432:C:G	R215T	0.999
8:56441437:G:C	F213L	0.999
8:56441437:G:T	F213L	0.999
8:56441438:A:C	F213C	0.999
8:56441438:A:G	F213S	0.999
8:56441439:A:G	F213L	0.999
8:56441444:C:T	G211E	0.999
8:56441431:T:A	R215S	0.998
8:56441431:T:G	R215S	0.998
8:56441428:T:A	R216S	0.997
8:56441428:T:G	R216S	0.997
8:56441432:C:A	R215I	0.997
8:56441452:C:A	K208N	0.997
8:56441452:C:G	K208N	0.997
8:56441761:T:A	K105N	0.997
8:56441761:T:G	K105N	0.997
8:56441284:A:C	F264L	0.996
8:56441284:A:T	F264L	0.996
8:56441286:A:G	F264L	0.996
8:56441410:C:A	W222C	0.996
8:56441410:C:G	W222C	0.996
8:56441454:T:C	K208E	0.996
8:56441509:G:C	F189L	0.996
8:56441509:G:T	F189L	0.996
8:56441511:A:G	F189L	0.996
8:56441746:G:C	F110L	0.996
8:56441746:G:T	F110L	0.996
8:56441748:A:G	F110L	0.996
8:56441762:T:A	K105I	0.996
8:56441441:C:T	G212D	0.995

dbSNP variants (sampled 300 via entrez): RS1000318875 (8:56442574 G>A), RS1000405758 (8:56441531 A>G), RS1000740966 (8:56444027 A>G), RS1001361768 (8:56443708 C>G,T), RS1001479172 (8:56447061 C>T), RS1001526639 (8:56446827 C>A), RS1002307941 (8:56444819 T>G), RS1002654228 (8:56444499 A>G), RS1002686073 (8:56443569 C>T), RS1003149248 (8:56446011 C>T), RS1003481515 (8:56447506 A>T), RS1003914033 (8:56446194 C>A,T), RS1004204729 (8:56447799 G>A), RS1004308282 (8:56441815 A>G), RS1004537297 (8:56446050 T>G)

Disease associations

OMIM: gene MIM:131330 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000175_46	Height	7.000000e-08
GCST002699_1	Suicide in bipolar disorder	5.000000e-06
GCST003809_3	Response to selective serotonin reuptake inhibitors and depression	1.000000e-06
GCST006585_1589	Blood protein levels	8.000000e-70
GCST010546_19	Problematic alcohol use	9.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006882	suicide behaviour measurement
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0009458	alcohol use disorder measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
Resveratrol	affects cotreatment, decreases expression	2
Ethanol	decreases expression, decreases reaction	2
methylmercuric chloride	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
arsenite	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Vorinostat	increases expression	1
Fomepizole	decreases expression, decreases reaction	1
Air Pollutants	decreases expression, increases abundance	1
Amphetamine	decreases expression	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Cadmium	increases expression	1
Carbamazepine	affects expression	1
Cocaine	decreases expression	1
Copper	affects cotreatment, decreases expression	1
Fonofos	increases methylation	1
Parathion	increases methylation	1
Plant Extracts	decreases expression, affects cotreatment	1
Rotenone	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Triclosan	increases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Medroxyprogesterone Acetate	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0U76	IAC/hPPE	Transformed cell line

Clinical trials (associated diseases)

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