GET3

Summary

GET3 (guided entry of tail-anchored proteins factor 3, ATPase, HGNC:752) is a protein-coding gene on chromosome 19p13.13, encoding ATPase GET3 (O43681). ATPase required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum. It is a selective cancer dependency (DepMap: 71.6% of cell lines).

This gene represents the human homolog of the bacterial arsA gene, encoding the arsenite-stimulated ATPase component of the arsenite transporter responsible for resistance to arsenicals. This protein is also a central component of a transmembrane domain (TMD) recognition complex (TRC) that is involved in the post-translational delivery of tail-anchored (TA) proteins from the cytosol to the endoplasmic reticulum (ER). It recognizes and selectively binds the TMD of TA proteins in the cytosol, and delivers them to the ER for insertion.

Source: NCBI Gene 439 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cardiomyopathy, dilated, 2H (Limited, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 42 total — 1 pathogenic
• Phenotypes (HPO): 22
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 71.6% of screened cell lines
• MANE Select transcript: NM_004317

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:752
Approved symbol	GET3
Name	guided entry of tail-anchored proteins factor 3, ATPase
Location	19p13.13
Locus type	gene with protein product
Status	Approved
Aliases	ARSA-I, TRC40
Ensembl gene	ENSG00000198356
Ensembl biotype	protein_coding
OMIM	601913
Entrez	439

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 14 protein_coding, 1 retained_intron

ENST00000357332, ENST00000590633, ENST00000591090, ENST00000904140, ENST00000904141, ENST00000904142, ENST00000935714, ENST00000935715, ENST00000935716, ENST00000935717, ENST00000935718, ENST00000935719, ENST00000935720, ENST00000935721, ENST00000935722

RefSeq mRNA: 3 — MANE Select: NM_004317 NM_001371488, NM_001371489, NM_004317

CCDS: CCDS32920

Canonical transcript exons

ENST00000357332 — 7 exons

Exon	Start	End
ENSE00000681706	12747395	12747592
ENSE00000681709	12747197	12747304
ENSE00000681719	12745377	12745525
ENSE00000836333	12747973	12748323
ENSE00001425509	12737497	12737666
ENSE00001505519	12745609	12745759
ENSE00003684440	12738511	12738658

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 96.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.4239 / max 172.4390, expressed in 1820 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174009	32.6554	1817
174008	1.7685	1303

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	96.23	gold quality
stromal cell of endometrium	CL:0002255	96.15	gold quality
prefrontal cortex	UBERON:0000451	96.11	gold quality
right adrenal gland	UBERON:0001233	96.07	gold quality
apex of heart	UBERON:0002098	96.04	gold quality
right adrenal gland cortex	UBERON:0035827	95.92	gold quality
mononuclear cell	CL:0000842	95.89	gold quality
leukocyte	CL:0000738	95.84	gold quality
right frontal lobe	UBERON:0002810	95.84	gold quality
left adrenal gland	UBERON:0001234	95.69	gold quality
right testis	UBERON:0004534	95.65	gold quality
islet of Langerhans	UBERON:0000006	95.60	gold quality
granulocyte	CL:0000094	95.56	gold quality
left adrenal gland cortex	UBERON:0035825	95.49	gold quality
left testis	UBERON:0004533	95.46	gold quality
endometrium epithelium	UBERON:0004811	95.22	gold quality
cingulate cortex	UBERON:0003027	95.08	gold quality
heart left ventricle	UBERON:0002084	95.05	gold quality
anterior cingulate cortex	UBERON:0009835	95.01	gold quality
metanephros cortex	UBERON:0010533	94.92	gold quality
skin of leg	UBERON:0001511	94.77	gold quality
cardiac ventricle	UBERON:0002082	94.76	gold quality
mucosa of transverse colon	UBERON:0004991	94.76	gold quality
body of stomach	UBERON:0001161	94.72	gold quality
cortical plate	UBERON:0005343	94.71	gold quality
nucleus accumbens	UBERON:0001882	94.67	gold quality
amygdala	UBERON:0001876	94.63	gold quality
adrenal cortex	UBERON:0001235	94.59	gold quality
caudate nucleus	UBERON:0001873	94.55	gold quality
skin of abdomen	UBERON:0001416	94.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.10

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting GET3, 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-574-5P	100.00	66.01	989
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-7109-5P	99.18	66.13	1057
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-6804-5P	98.39	65.77	1084
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-10398-5P	97.12	64.94	1051
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-5694	97.06	67.70	682
HSA-MIR-4652-5P	96.46	64.22	553
HSA-MIR-885-3P	95.14	63.08	448

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 71.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 18)

• Human ASNA1 is highly expressed in pancreatic beta cells, but not in other pancreatic endocrine cell types, and regulates insulin secretion in cultured cells. (PMID:17289575)
• TRC40/Asna-1 interacts posttranslationally with tail-anchored proteins in a transmembrane domain-dependent manner for delivery to a proteinaceous receptor at the endoplasmic reticulum membrane. (PMID:17382883)
• the hydrophobicity of the TA region dictates whether a precursor is delivered to the ER via the Hsp40/Hsc70 or Asna-1/TRC40-dependent route. (PMID:18667436)
• ASNA1 is a target to overcome platinum resistance in ovarian cancer (PMID:19724867)
• Asna1 can mediate membrane insertion of RAMP4 and Sec61beta without the participation of other cytosolic proteins by a mechanism that depends on the presence of ATP or ADP and a protease-sensitive receptor in the endoplasmic reticulum membrane. (PMID:20375064)
• Asna1 is required for efficient histocompatibility (HLA) class I downregulation mediated by viral protein BNLF2a. (PMID:21296983)
• The coiled-coil domain of WRB is the binding site for TRC40/Asna1. (PMID:21444755)
• Post-translational membrane insertion of tail-anchored transmembrane EF-hand Ca2+ sensor calneurons requires the TRC40/Asna1 protein chaperone. (PMID:21878631)
• Proteins bind to TRC40 and can utilise this component for their delivery to the ER membrane. (PMID:22505607)
• Results indicate calcium-modulating cyclophilin ligand (CAML) and WRB as components of the TRC40 receptor complex and a crucial mechanism for driving ER membrane insertion of TA proteins in mammalian cells. (PMID:23041287)
• PEX19 formed a complex with the peroxisomal tail anchored protein PEX26 in the cytosol and translocated it directly to peroxisomes by a TRC40-independent class I pathway. (PMID:23460677)
• The repertoire of VAPB interactors is more diverse than previously anticipated and link VAPB to the function of ATPase complexes such as p97/FAF1 and ASNA1/transmembrane-domain recognition complex. (PMID:24885147)
• Emerin interacts with TRC40 in situ. (PMID:26675233)
• reveal unanticipated complexity in the mutual regulation of the TRC40 receptor subunits and raise the question as to the role of the excess CAML in the endoplasmic reticulum (PMID:27226539)
• The authors conclude that the TRC40 pathway is critical for hearing and propose that otoferlin is an essential substrate of this pathway in hair cells. (PMID:27458190)
• Asna1/TRC40 is required at a late step of herpes simplex virus type 1 infection for efficient release of mature virions to the extracellular milieu. (PMID:27765046)
• Golgi-resident tail-anchored proteins such as the golgins golgin-84, CASP and giantin as well as the vesicle-associated membrane-protein-associated proteins VAPA and VAPB interact with TRC40. (PMID:31182645)
• Mutation in ASNA1 cause severe pediatric cardiomyopathy and early death. (PMID:31461301)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	get3	ENSDARG00000018190
mus_musculus	Get3	ENSMUSG00000052456
rattus_norvegicus	Get3	ENSRNOG00000003747
drosophila_melanogaster	CG1598	FBGN0033191
caenorhabditis_elegans		WBGENE00014025

Protein

Protein identifiers

ATPase GET3 — O43681 (reviewed: O43681)

Alternative names: Arsenical pump-driving ATPase, Arsenite-stimulated ATPase, Guided entry of tail-anchored proteins factor 3, ATPase, Transmembrane domain recognition complex 40 kDa ATPase subunit, hARSA-I, hASNA-I

All UniProt accessions (1): O43681

UniProt curated annotations — full annotation on UniProt →

Function. ATPase required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum. Recognizes and selectively binds the transmembrane domain of TA proteins in the cytosol. This complex then targets to the endoplasmic reticulum by membrane-bound receptors GET1/WRB and CAMLG/GET2, where the tail-anchored protein is released for insertion. This process is regulated by ATP binding and hydrolysis. ATP binding drives the homodimer towards the closed dimer state, facilitating recognition of newly synthesized TA membrane proteins. ATP hydrolysis is required for insertion. Subsequently, the homodimer reverts towards the open dimer state, lowering its affinity for the GET1-CAMLG receptor, and returning it to the cytosol to initiate a new round of targeting. May be involved in insulin signaling.

Subunit / interactions. Homodimer. Component of the Golgi to ER traffic (GET) complex, which is composed of GET1/WRB, CAMLG/GET2 and GET3/TRC40. Within the complex, CAMLG and GET1 form a heterotetramer which is stabilized by phosphatidylinositol binding and which binds to the GET3 homodimer. Interacts with CAMLG (via N-terminus). GET3 shows a higher affinity for CAMLG than for GET1. Interacts with SERP1 and SEC61B. Interacts with GET4.

Subcellular location. Cytoplasm. Endoplasmic reticulum. Nucleus. Nucleolus.

Tissue specificity. Expressed in the epithelial cells of the liver, kidney, and stomach wall, in the adrenal medulla, in the islet cells of the pancreas, in the red pulp of the spleen, and in cardiac and skeletal muscle.

Disease relevance. Cardiomyopathy, dilated, 2H (CMD2H) [MIM:620203] A form of dilated cardiomyopathy, a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD2H is an autosomal recessive form characterized by rapid progression and death in early infancy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the arsA ATPase family.

RefSeq proteins (3): NP_001358417, NP_001358418, NP_004308* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016300	ATPase_ArsA/GET3	Family
IPR025723	ArsA/GET3_ATPase-like	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR027542	ATPase_ArsA/GET3_euk	Family

Pfam: PF02374

Enzyme classification (BRENDA):

• EC 7.3.2.7 — arsenite-transporting ATPase (BRENDA: 14 organisms, 34 substrates, 5 inhibitors, 15 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.021–2	11
ARSENITE	0.1	1
SB3+	—	1

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (48 total): helix 15, binding site 12, strand 8, sequence variant 4, sequence conflict 3, mutagenesis site 2, initiator methionine 1, chain 1, modified residue 1, active site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8CQZ	X-RAY DIFFRACTION	2.8
8CR1	ELECTRON MICROSCOPY	3.2
6SO5	ELECTRON MICROSCOPY	4.2
8CR2	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43681-F1	79.69	0.50

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 (1): 74

Ligand- & substrate-binding residues (12): 278; 289; 292; 319; 321; 45; 46; 49; 50; 51; 52; 251

Post-translational modifications (1): 2

Mutagenesis-validated functional residues (2):

Position	Phenotype
46	abolishes atpase activity, dominantly inhibits the ta protein insertion pathway.
86	reduces ta protein insertion pathway.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9609523	Insertion of tail-anchored proteins into the endoplasmic reticulum membrane

MSigDB gene sets: 179 (showing top): STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, SHIPP_DLBCL_CURED_VS_FATAL_DN, MODULE_70, MARTINEZ_RB1_TARGETS_UP, RICKMAN_METASTASIS_DN, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, CYTAGCAAY_UNKNOWN, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, USF_02, GOBP_MEMBRANE_ORGANIZATION, GRUETZMANN_PANCREATIC_CANCER_UP, GOBP_ENDOPLASMIC_RETICULUM_ORGANIZATION

GO Biological Process (3): protein insertion into ER membrane (GO:0045048), tail-anchored membrane protein insertion into ER membrane (GO:0071816), antigen processing and presentation of endogenous peptide antigen via MHC class I (GO:0019885)

GO Molecular Function (8): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), metal ion binding (GO:0046872), protein carrier activity (GO:0140597), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787), membrane insertase activity (GO:0032977)

GO Cellular Component (8): nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), GET complex (GO:0043529), extracellular exosome (GO:0070062), nucleus (GO:0005634), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear lumen	2
cellular anatomical structure	2
intracellular membrane-bounded organelle	2
endoplasmic reticulum organization	1
protein localization to organelle	1
protein insertion into membrane	1
protein insertion into ER membrane	1
antigen processing and presentation of peptide antigen via MHC class I	1
antigen processing and presentation of endogenous peptide antigen	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
cation binding	1
molecular carrier activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
establishment of protein localization to membrane	1
protein carrier activity	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endoplasmic reticulum protein-containing complex	1
extracellular vesicle	1
cytoplasm	1
endomembrane system	1

Protein interactions and networks

STRING

2186 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GET3	GET4	Q7L5D6	997
GET3	UBL4A	P11441	996
GET3	GET1	O00258	984
GET3	SGTA	O43765	912
GET3	CAMLG	P49069	831
GET3	BAG6	P46379	808
GET3	STX5	Q13190	807
GET3	SEC61A1	P38378	764
GET3	SRP54	P13624	732
GET3	PEX19	P40855	697
GET3	PEX3	P56589	676
GET3	ARSD	P51689	669
GET3	PEX26	Q7Z412	656
GET3	RNF126	Q9BV68	619
GET3	EMC3	Q9P0I2	606
GET3	EMC6	Q9BV81	606

IntAct

172 interactions, top by confidence:

A	B	Type	Score
CAMLG	GET3	psi-mi:“MI:0914”(association)	0.820
GET3	CAMLG	psi-mi:“MI:0915”(physical association)	0.820
GET3	GET4	psi-mi:“MI:0915”(physical association)	0.800
GET4	GET3	psi-mi:“MI:0914”(association)	0.800
GPX7	GET3	psi-mi:“MI:0915”(physical association)	0.720
GET3	GPX7	psi-mi:“MI:0915”(physical association)	0.720
STX5	GOSR2	psi-mi:“MI:0914”(association)	0.670
GET3	GET1	psi-mi:“MI:0914”(association)	0.640
GET3	ASPH	psi-mi:“MI:0915”(physical association)	0.560
HILPDA	GET3	psi-mi:“MI:0915”(physical association)	0.560
ASPH	GET3	psi-mi:“MI:0915”(physical association)	0.560
GET3	CPR5	psi-mi:“MI:0915”(physical association)	0.560
CPR5	GET3	psi-mi:“MI:0915”(physical association)	0.560
GET3	AGR2	psi-mi:“MI:0915”(physical association)	0.560
GET3	CSPG5	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (172): ASNA1 (Affinity Capture-MS), ASPH (Two-hybrid), GPX7 (Two-hybrid), HILPDA (Two-hybrid), ASNA1 (Affinity Capture-MS), ASNA1 (Affinity Capture-MS), ASNA1 (Affinity Capture-MS), ASNA1 (Affinity Capture-MS), ASNA1 (Co-fractionation), ASNA1 (Co-fractionation), ASNA1 (Co-fractionation), ASNA1 (Co-fractionation), ASNA1 (Co-fractionation), ASNA1 (Co-fractionation), PSMA2 (Co-fractionation)

ESM2 similar proteins: A0A0U1WZ18, A0A1S4A695, A4FV08, A4IHW6, A5PJI5, F6V515, G3V9T7, O43681, O54984, O88958, P46926, P50395, P50397, P50399, P62495, P62496, P62497, Q0IIZ2, Q0VCX5, Q16HW7, Q17QL1, Q1W374, Q1W375, Q1W376, Q1W377, Q259G4, Q29NT9, Q2KJ61, Q503E1, Q5HZM6, Q5R8T8, Q5RIC0, Q5U2Q7, Q5ZHS1, Q5ZIH0, Q61598, Q64422, Q6GNQ1, Q6IQE5, Q6NVL5

Diamond homologs: A0BZ55, A0E7A5, A1CKN5, A1D6T7, A3LX15, A4QUI2, A5AAA1, A5DGM1, A5DVY5, A5K5W9, A5PJI5, A6QRP2, A6S7T2, A6ZXM9, A7EHP6, A7RQM5, A7TH32, A8B3G9, A8IXB8, A8N0V8, A8Q0M1, A8Q3T2, A8WNH9, B0CPJ0, B0EHY7, B0WEV5, B0XXL5, B2B7D9, B2DFU2, B2VVF0, B3L1G8, B3LGZ3, B3MHB7, B3N9X2, B4H8J5, B4HR35, B4J4F6, B4KTG7, B4LN33, B4N645

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GET3	“form complex”	“GET complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	8	69.2×	3e-11

GO biological processes:

GO term	Partners	Fold	FDR
tail-anchored membrane protein insertion into ER membrane	6	80.2×	4e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	29
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2443825	NM_004317.4(GET3):c.488T>C (p.Val163Ala)	Pathogenic

SpliceAI

1033 predictions. Top by Δscore:

Variant	Effect	Δscore
19:12738658:GGT:G	donor_loss	1.0000
19:12738660:T:A	donor_loss	1.0000
19:12738661:G:GG	donor_loss	1.0000
19:12745367:T:TA	acceptor_gain	1.0000
19:12745368:G:A	acceptor_gain	1.0000
19:12745372:CCCAG:C	acceptor_loss	1.0000
19:12745373:CCAG:C	acceptor_loss	1.0000
19:12745375:A:AG	acceptor_gain	1.0000
19:12745375:A:AT	acceptor_loss	1.0000
19:12745375:AG:A	acceptor_gain	1.0000
19:12745376:G:GT	acceptor_gain	1.0000
19:12745376:GG:G	acceptor_gain	1.0000
19:12745376:GGA:G	acceptor_gain	1.0000
19:12745376:GGAGA:G	acceptor_gain	1.0000
19:12745500:GCCA:G	donor_gain	1.0000
19:12745508:C:G	donor_gain	1.0000
19:12745522:TGAG:T	donor_loss	1.0000
19:12745607:AGGCT:A	acceptor_gain	1.0000
19:12745608:GGCTG:G	acceptor_gain	1.0000
19:12745739:A:G	donor_gain	1.0000
19:12747299:GACCC:G	donor_gain	1.0000
19:12747300:ACCCT:A	donor_gain	1.0000
19:12747301:CCCT:C	donor_gain	1.0000
19:12747303:CTGT:C	donor_loss	1.0000
19:12747304:TG:T	donor_loss	1.0000
19:12747305:G:GG	donor_gain	1.0000
19:12747306:T:A	donor_loss	1.0000
19:12747314:G:GA	donor_gain	1.0000
19:12747391:GTA:G	acceptor_loss	1.0000
19:12747392:TA:T	acceptor_loss	1.0000

AlphaMissense

2327 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:12737620:T:A	W39R	1.000
19:12737620:T:C	W39R	1.000
19:12737630:T:A	V42D	1.000
19:12737632:G:A	G43R	1.000
19:12737632:G:C	G43R	1.000
19:12737632:G:T	G43W	1.000
19:12737633:G:A	G43E	1.000
19:12737635:G:C	G44R	1.000
19:12737635:G:T	G44C	1.000
19:12737636:G:A	G44D	1.000
19:12737636:G:T	G44V	1.000
19:12737638:A:C	K45Q	1.000
19:12737639:A:T	K45M	1.000
19:12737640:G:C	K45N	1.000
19:12737640:G:T	K45N	1.000
19:12737641:G:C	G46R	1.000
19:12737641:G:T	G46C	1.000
19:12737642:G:A	G46D	1.000
19:12737644:G:C	G47R	1.000
19:12737645:G:A	G47D	1.000
19:12737650:G:C	G49R	1.000
19:12737650:G:T	G49C	1.000
19:12737651:G:A	G49D	1.000
19:12737651:G:T	G49V	1.000
19:12737653:A:C	K50Q	1.000
19:12737654:A:T	K50M	1.000
19:12737655:G:C	K50N	1.000
19:12737655:G:T	K50N	1.000
19:12737657:C:T	T51I	1.000
19:12738513:G:A	C55Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000031173 (19:12746080 T>C), RS1000033355 (19:12739750 A>G,T), RS1000654736 (19:12743113 C>T), RS1001068184 (19:12744600 A>G), RS1001216930 (19:12737889 A>G,T), RS1001442076 (19:12744054 A>G), RS1001505056 (19:12741060 A>G), RS1001663408 (19:12735402 C>T), RS1001701734 (19:12740834 G>A), RS1002101261 (19:12747188 C>A,T), RS1002201453 (19:12736370 C>T), RS1002211285 (19:12736756 T>C), RS1002449628 (19:12735627 G>A,T), RS1003120551 (19:12738287 C>G), RS1003369354 (19:12748347 A>G)

Disease associations

OMIM: gene MIM:601913 | disease phenotypes: MIM:620203

GenCC curated gene-disease

Disease	Classification	Inheritance
cardiomyopathy, dilated, 2H	Limited	Autosomal recessive
acute proliferative glomerulonephritis	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
cardiomyopathy, dilated, 2H	Limited	AR

Mondo (3): prostate cancer (MONDO:0008315), cardiomyopathy, dilated, 2H (MONDO:0859358), acute proliferative glomerulonephritis (MONDO:0001644)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000969	Edema
HP:0001635	Congestive heart failure
HP:0001644	Dilated cardiomyopathy
HP:0001684	Secundum atrial septal defect
HP:0001727	Thromboembolic stroke
HP:0002789	Tachypnea
HP:0002875	Exertional dyspnea
HP:0003198	Myopathy
HP:0003457	EMG abnormality
HP:0003623	Neonatal onset
HP:0003811	Neonatal death
HP:0006543	Cardiorespiratory arrest
HP:0011623	Muscular ventricular septal defect
HP:0011675	Arrhythmia
HP:0011968	Feeding difficulties
HP:0012378	Fatigue
HP:0012664	Reduced left ventricular ejection fraction
HP:0012764	Orthopnea
HP:0025169	Left ventricular systolic dysfunction
HP:0100578	Lipoatrophy

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066311 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.78	Kd	16.48	nM	CHEMBL5653589
7.78	ED50	16.48	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147897: Binding affinity to human ASNA1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0165	uM

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, increases activity	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	increases expression	1
perfluorooctanoic acid	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases secretion	1
Arsenic Trioxide	increases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arbutin	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects response to substance	1
Dactinomycin	affects cotreatment, increases secretion	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Ozone	increases abundance, affects cotreatment, increases oxidation	1
Smoke	decreases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases expression	1
Aflatoxin B1	increases expression	1
Volatile Organic Compounds	affects cotreatment, increases oxidation	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
CHEMBL5650939	Binding	Binding affinity to human ASNA1 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)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer