MAGED2

Summary

MAGED2 (MAGE family member D2, HGNC:16353) is a protein-coding gene on chromosome Xp11.21, encoding Melanoma-associated antigen D2 (Q9UNF1). Regulates the expression, localization to the plasma membrane and function of the sodium chloride cotransporters SLC12A1 and SLC12A3, two key components of salt reabsorption in the distal renal tubule.

This gene is a member of the MAGED gene family. The MAGED genes are clustered on chromosome Xp11. This gene is located in Xp11.2, a hot spot for X-linked intellectual disability (XLID). Mutations in this gene cause a form of transient antenatal Bartter’s syndrome. This gene may also be involved in several types of cancer, including breast cancer and melanoma. The protein encoded by this gene is progressively recruited from the cytoplasm to the nucleoplasm during the interphase and after nucleolar stress and is thus thought to play a role in cell cycle regulation. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10916 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Bartter disease type 5 (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 256 total — 10 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 11
• MANE Select transcript: NM_177433

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16353
Approved symbol	MAGED2
Name	MAGE family member D2
Location	Xp11.21
Locus type	gene with protein product
Status	Approved
Aliases	JCL-1, BCG1, 11B6, MAGE-D2, HCA10, MAGED, MGC8386
Ensembl gene	ENSG00000102316
Ensembl biotype	protein_coding
OMIM	300470
Entrez	10916

Gene structure

Transcript identifiers

Ensembl transcripts: 62 — 57 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000218439, ENST00000347546, ENST00000375053, ENST00000375058, ENST00000375060, ENST00000375068, ENST00000396224, ENST00000463787, ENST00000485483, ENST00000487463, ENST00000487482, ENST00000497484, ENST00000627068, ENST00000872297, ENST00000872298, ENST00000872299, ENST00000872300, ENST00000872301, ENST00000872302, ENST00000872303, ENST00000872304, ENST00000872305, ENST00000872306, ENST00000872307, ENST00000872308, ENST00000872309, ENST00000872310, ENST00000872311, ENST00000872312, ENST00000872313, ENST00000872314, ENST00000872315, ENST00000872316, ENST00000872317, ENST00000872318, ENST00000872319, ENST00000872320, ENST00000919654, ENST00000919655, ENST00000919656, ENST00000919657, ENST00000919658, ENST00000919659, ENST00000919660, ENST00000919661, ENST00000919662, ENST00000919663, ENST00000919664, ENST00000919665, ENST00000919666, ENST00000919667, ENST00000919668, ENST00000919669, ENST00000944662, ENST00000944663, ENST00000944664, ENST00000944665, ENST00000944666, ENST00000944667, ENST00000944668, ENST00000944669, ENST00000944670

RefSeq mRNA: 3 — MANE Select: NM_177433 NM_014599, NM_177433, NM_201222

CCDS: CCDS14362

Canonical transcript exons

ENST00000375068 — 13 exons

Exon	Start	End
ENSE00001465666	54815248	54815690
ENSE00001609312	54813118	54813160
ENSE00001714222	54814661	54814775
ENSE00001751094	54811574	54811653
ENSE00001760112	54813488	54813550
ENSE00003467086	54809722	54810213
ENSE00003474095	54812945	54813024
ENSE00003607560	54810821	54811129
ENSE00003610740	54811250	54811313
ENSE00003674962	54812157	54812251
ENSE00003709406	54809303	54809376
ENSE00003849539	54807745	54807802
ENSE00003851184	54815881	54816015

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 72.4152 / max 637.6356, expressed in 1817 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196443	33.9714	1726
196446	20.8232	1745
196445	10.1948	1756
196444	4.0515	1607
196442	3.2096	1269
196441	0.1648	74

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	99.23	gold quality
adenohypophysis	UBERON:0002196	99.23	gold quality
right ovary	UBERON:0002118	99.19	gold quality
ganglionic eminence	UBERON:0004023	99.16	gold quality
right uterine tube	UBERON:0001302	99.14	gold quality
stromal cell of endometrium	CL:0002255	99.11	gold quality
adrenal tissue	UBERON:0018303	99.10	gold quality
endocervix	UBERON:0000458	99.03	gold quality
descending thoracic aorta	UBERON:0002345	99.03	gold quality
cortical plate	UBERON:0005343	99.03	gold quality
popliteal artery	UBERON:0002250	99.02	gold quality
tibial artery	UBERON:0007610	99.02	gold quality
ventricular zone	UBERON:0003053	99.00	gold quality
aorta	UBERON:0000947	98.89	gold quality
metanephros cortex	UBERON:0010533	98.86	gold quality
ascending aorta	UBERON:0001496	98.85	gold quality
thoracic aorta	UBERON:0001515	98.85	gold quality
right coronary artery	UBERON:0001625	98.84	gold quality
right lobe of thyroid gland	UBERON:0001119	98.81	gold quality
body of uterus	UBERON:0009853	98.81	gold quality
left lobe of thyroid gland	UBERON:0001120	98.77	gold quality
nerve	UBERON:0001021	98.69	gold quality
tibial nerve	UBERON:0001323	98.69	gold quality
left coronary artery	UBERON:0001626	98.53	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.53	gold quality
gall bladder	UBERON:0002110	98.46	gold quality
left uterine tube	UBERON:0001303	98.45	gold quality
ectocervix	UBERON:0012249	98.21	gold quality
mucosa of stomach	UBERON:0001199	98.20	gold quality
smooth muscle tissue	UBERON:0001135	98.19	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-10662	yes	1616.77
E-MTAB-7407	yes	1197.68
E-MTAB-8205	yes	802.75
E-HCAD-10	yes	67.02
E-MTAB-6701	yes	62.28
E-CURD-112	yes	33.78
E-GEOD-134144	yes	31.07
E-MTAB-9067	yes	27.33
E-MTAB-10042	yes	10.36
E-HCAD-13	no	495.61
E-MTAB-6524	no	248.72
E-GEOD-99795	no	227.81
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting MAGED2, 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-12119	99.87	68.35	1653
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-4463	98.56	66.05	1071
HSA-MIR-3620-3P	97.78	64.88	772
HSA-MIR-6869-5P	97.17	67.06	634
HSA-MIR-5586-3P	95.51	67.00	805

Literature-anchored findings (GeneRIF, showing 15)

• Expression pattern and further characterization of human MAGED2 and identification of rodent orthologues (PMID:11856887)
• Maged2 is mainly expressed in tissues of mesodermal origin (PMID:15162511)
• Results identified a cDNA clone, corresponding to MAGE D2 mRNA, from primary human bronchial epithelial cells which exhibits increased expression in vitro after treatment with all-trans retinoic acid. (PMID:15465002)
• MAGED2, a novel protein, is a p53-dissociator. (PMID:17912449)
• these results identify the expression of MAGE-D2 suppresses TRAIL receptor 2 and protects againstas TRAIL-induced apoptosis (PMID:22791814)
• Increased expression of MAGE-D2 mRNA was associated with distant metastasis in Gastric Cancer. (PMID:25743330)
• MAGE-D2 is a dynamic protein whose shuttling properties could suggest a role in cell cycle regulation. (PMID:26705694)
• We found that MAGED2 mutations caused X-linked polyhydramnios with prematurity and a severe but transient form of antenatal Bartter’s syndrome. (PMID:27120771)
• MAGED2 mutations explained 9% of cases of antenatal Bartter syndrome in a French cohort, and accounted for 38% of patients without other characterized mutations and for 44% of male probands of negative cases. (PMID:29146702)
• MAGED2 loss of function is the cause of an X-linked transient form of antenatal Bartter’s syndrome. Moreover, our findings showed that MAGE-D2 promotes the biogenesis of kidney membrane transporters. (PMID:29677005)
• MAGED2 controls vasopressin-induced aquaporin-2 expression in collecting duct cells. (PMID:34775100)
• Reciprocal Regulation of MAGED2 and HIF-1alpha Augments Their Expression under Hypoxia: Role of cAMP and PKA Type II. (PMID:36359819)
• MAGED2 Depletion Promotes Stress-Induced Autophagy by Impairing the cAMP/PKA Pathway. (PMID:37686237)
• Proteomic Analysis Revealed the Potential Role of MAGE-D2 in the Therapeutic Targeting of Triple-Negative Breast Cancer. (PMID:38128647)
• Identification of a novel intronic mutation of MAGED2 gene in a Chinese family with antenatal Bartter syndrome. (PMID:38238844)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ndnl2	ENSDARG00000058212
mus_musculus	Maged2	ENSMUSG00000025268
rattus_norvegicus	Maged2	ENSRNOG00000002449
drosophila_melanogaster	MAGE	FBGN0037481

Paralogs (37): MAGEC2 (ENSG00000046774), TRO (ENSG00000067445), MAGEB2 (ENSG00000099399), MAGEB4 (ENSG00000120289), MAGEA9 (ENSG00000123584), MAGEA10 (ENSG00000124260), MAGEA4 (ENSG00000147381), MAGED4 (ENSG00000154545), MAGEC1 (ENSG00000155495), MAGEA8 (ENSG00000156009), MAGEC3 (ENSG00000165509), MAGEB6 (ENSG00000176746), MAGEB18 (ENSG00000176774), MAGEF1 (ENSG00000177383), MAGEB10 (ENSG00000177689), MAGED1 (ENSG00000179222), NDN (ENSG00000182636), MAGEB17 (ENSG00000182798), MAGEA2B (ENSG00000183305), NSMCE3 (ENSG00000185115), MAGEA11 (ENSG00000185247), MAGEE2 (ENSG00000186675), MAGED4B (ENSG00000187243), MAGEH1 (ENSG00000187601), MAGEB5 (ENSG00000188408), MAGEB16 (ENSG00000189023), MAGEA6 (ENSG00000197172), MAGEA1 (ENSG00000198681), MAGEB3 (ENSG00000198798), MAGEE1 (ENSG00000198934), MAGEA12 (ENSG00000213401), MAGEB1 (ENSG00000214107), MAGEA3 (ENSG00000221867), MAGEB6B (ENSG00000232030), MAGEL2 (ENSG00000254585), MAGEA9B (ENSG00000267978), MAGEA2 (ENSG00000268606)

Protein

Protein identifiers

Melanoma-associated antigen D2 — Q9UNF1 (reviewed: Q9UNF1)

Alternative names: 11B6, Breast cancer-associated gene 1 protein, Hepatocellular carcinoma-associated protein JCL-1, MAGE-D2 antigen

All UniProt accessions (3): Q9UNF1, Q5H907, Q5H909

UniProt curated annotations — full annotation on UniProt →

Function. Regulates the expression, localization to the plasma membrane and function of the sodium chloride cotransporters SLC12A1 and SLC12A3, two key components of salt reabsorption in the distal renal tubule.

Subunit / interactions. Interacts with GNAS. May interact with DNAJB1.

Tissue specificity. Widely expressed. In the developing and adult kidney, expressed in the thick ascending limb of the loop of Henle and the distal convoluted tubules outside the loop.

Disease relevance. Bartter syndrome 5, antenatal, transient (BARTS5) [MIM:300971] An X-linked recessive form of Bartter syndrome, a disorder characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and varying degrees of hypercalciuria. BARTS5 is an antenatal form beginning in utero with marked fetal polyuria that leads to polyhydramnios and premature delivery. It is characterized by severe but transient symptoms that can resolve with age. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UNF1-1	1	yes
Q9UNF1-2	2

RefSeq proteins (3): NP_055414, NP_803182, NP_957516 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002190	MHD_dom	Domain
IPR037445	MAGE	Family
IPR041898	MAGE_WH1	Homologous_superfamily
IPR041899	MAGE_WH2	Homologous_superfamily

Pfam: PF01454

UniProt features (32 total): modified residue 12, compositionally biased region 6, sequence variant 5, region of interest 3, sequence conflict 2, initiator methionine 1, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UNF1-F1	59.89	0.16

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 (12): 2, 5, 72, 157, 190, 191, 194, 197, 244, 247, 264, 265

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-109582	Hemostasis
R-HSA-76002	Platelet activation, signaling and aggregation
R-HSA-76005	Response to elevated platelet cytosolic Ca2+

MSigDB gene sets: 246 (showing top): AHRARNT_01, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, FAELT_B_CLL_WITH_VH_REARRANGEMENTS_DN, TGCGCANK_UNKNOWN, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, SP3_Q3, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GGGTGGRR_PAX4_03, CHANDRAN_METASTASIS_DN, CEBPB_01, GOBP_MONOATOMIC_CATION_TRANSPORT, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_SUSTAINDED_IN_ERYTHROCYTE_UP, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_ERYTHROCYTE_UP

GO Biological Process (3): negative regulation of transcription by RNA polymerase II (GO:0000122), female pregnancy (GO:0007565), renal sodium ion absorption (GO:0070294)

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

GO Cellular Component (7): extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytosol (GO:0005829), membrane (GO:0016020), platelet alpha granule lumen (GO:0031093)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Hemostasis	1
Platelet activation, signaling and aggregation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
nuclear lumen	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
multi-organism reproductive process	1
multi-multicellular organism process	1
renal sodium ion transport	1
renal absorption	1
binding	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
cytoplasm	1
platelet alpha granule	1
secretory granule lumen	1

Protein interactions and networks

STRING

896 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAGED2	CSAG1	Q6PB30	748
MAGED2	NPAS4	Q8IUM7	650
MAGED2	NAP1L1	P55209	597
MAGED2	BRCA1	P38398	571
MAGED2	CLCNKB	P51801	570
MAGED2	BSND	Q8WZ55	570
MAGED2	TP53	P04637	557
MAGED2	SLC12A1	Q13621	507
MAGED2	TUBB	P05218	501
MAGED2	NAP1L4	Q99733	499
MAGED2	TUBB2A	Q13885	495
MAGED2	DTNA	Q9Y4J8	494
MAGED2	ZNF350	Q9GZX5	493
MAGED2	NAP1L5	Q96NT1	482
MAGED2	ANGPTL8	Q6UXH0	479

IntAct

144 interactions, top by confidence:

A	B	Type	Score
MAGED2	JAK3	psi-mi:“MI:0915”(physical association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
IRS4	PIK3R2	psi-mi:“MI:0914”(association)	0.640
CBFA2T2	CBFA2T3	psi-mi:“MI:0914”(association)	0.530
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
GNAS	CPT2	psi-mi:“MI:0914”(association)	0.530
MAGED2	GNAL	psi-mi:“MI:0914”(association)	0.530
ARRDC4	WWP2	psi-mi:“MI:0914”(association)	0.530
NAP1L1	FNTB	psi-mi:“MI:0914”(association)	0.530
POP4	RPP40	psi-mi:“MI:0914”(association)	0.530
CDK18	UBL4A	psi-mi:“MI:0914”(association)	0.530
HSPA8	ARHGEF10	psi-mi:“MI:2364”(proximity)	0.480
	AP3D1	psi-mi:“MI:0914”(association)	0.460
MAGED2	FKBP5	psi-mi:“MI:0915”(physical association)	0.400
MAGED2	CHRM3	psi-mi:“MI:0915”(physical association)	0.370
JAK3	BAG2	psi-mi:“MI:0914”(association)	0.350
OTUB1		psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
Tipin	NEMF	psi-mi:“MI:0914”(association)	0.350
Papss1	TCOF1	psi-mi:“MI:0914”(association)	0.350
Cep55	UMAD1	psi-mi:“MI:0914”(association)	0.350
PRKCI	TRAPPC13	psi-mi:“MI:0914”(association)	0.350
Ppp4c	NAP1L1	psi-mi:“MI:0914”(association)	0.350
Slc6a8	SSR3	psi-mi:“MI:0914”(association)	0.350
NCSTN	ESYT2	psi-mi:“MI:0914”(association)	0.350
TIGD6	ZRANB2	psi-mi:“MI:0914”(association)	0.350

BioGRID (311): MAGED2 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS), MAGED2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0J9YX94, A0A0J9YXQ4, A0A0J9YY54, A0A494C1R9, A5D7L8, A6NDY0, A6NKD2, A7E321, E9PGG2, F6SZT2, O14771, O19110, O75807, O88852, P0CV98, P0CV99, P0CW00, P0CW01, P0CW24, P17564, P78358, Q01534, Q0P5N2, Q15735, Q2KI51, Q2M329, Q587J8, Q5DTT8, Q5R5G8, Q5R6R8, Q5SV97, Q60465, Q62881, Q69ZB3, Q6P752, Q86V59, Q8BSI6, Q8IWY8, Q8N3D4, Q8VD63

Diamond homologs: A0A0J9YX57, A1A5P9, A2A368, A2A9R3, A6NCF6, A6QLI5, A8MXT2, O15479, O15480, O15481, O60732, P25233, P43355, P43356, P43357, P43358, P43360, P43361, P43362, P43363, P43364, P43365, P43366, Q12816, Q4R998, Q5PPP4, Q5RFC2, Q6AY37, Q6ITT4, Q6PCZ4, Q8BQR7, Q8N7X4, Q8TD90, Q8TD91, Q96JG8, Q96LZ2, Q96M61, Q96MG7, Q99608, Q9BE18

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	7
Uncertain significance	79
Likely benign	29
Benign	41

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1695306	NM_177433.3(MAGED2):c.1085_1085+12del	Pathogenic
226031	NM_177433.3(MAGED2):c.1038C>G (p.Tyr346Ter)	Pathogenic
226032	NM_177433.3(MAGED2):c.991-2A>G	Pathogenic
226033	NM_177433.3(MAGED2):c.386_387del (p.Val129fs)	Pathogenic
226035	NM_177433.3(MAGED2):c.397A>T (p.Lys133Ter)	Pathogenic
2575215	NM_177433.3(MAGED2):c.262C>T (p.Gln88Ter)	Pathogenic
2687474	NM_177433.3(MAGED2):c.1271+4_1271+7del	Pathogenic
3893182	NM_177433.3(MAGED2):c.1329G>A (p.Trp443Ter)	Pathogenic
3910024	NM_177433.3(MAGED2):c.481C>T (p.Gln161Ter)	Pathogenic
4759358	NM_177433.3(MAGED2):c.532C>T (p.Arg178Ter)	Pathogenic
1805201	NM_177433.3(MAGED2):c.1386+1G>A	Likely pathogenic
226034	NM_177433.3(MAGED2):c.1336C>T (p.Arg446Cys)	Likely pathogenic
242888	NM_177433.3(MAGED2):c.1003del (p.Gln335fs)	Likely pathogenic
2700715	NM_177433.3(MAGED2):c.990+1G>A	Likely pathogenic
4056395	NM_177433.3(MAGED2):c.1452GGCTGCAGCTGA[1] (p.486AAEA[1])	Likely pathogenic
4531339	NM_177433.3(MAGED2):c.1347T>G (p.Tyr449Ter)	Likely pathogenic
4710851	NM_177433.3(MAGED2):c.1271+1G>A	Likely pathogenic

SpliceAI

1465 predictions. Top by Δscore:

Variant	Effect	Δscore
X:54809716:TTGCA:T	acceptor_loss	1.0000
X:54809719:CAGG:C	acceptor_loss	1.0000
X:54809721:G:A	acceptor_loss	1.0000
X:54810212:AGGT:A	donor_loss	1.0000
X:54810213:GGTAA:G	donor_loss	1.0000
X:54810214:G:GA	donor_loss	1.0000
X:54810214:G:GG	donor_gain	1.0000
X:54810215:T:G	donor_loss	1.0000
X:54811240:A:AG	acceptor_gain	1.0000
X:54811569:TGCA:T	acceptor_loss	1.0000
X:54811572:A:AG	acceptor_gain	1.0000
X:54811572:A:AT	acceptor_loss	1.0000
X:54811573:G:A	acceptor_loss	1.0000
X:54811573:G:GT	acceptor_gain	1.0000
X:54811573:GAC:G	acceptor_gain	1.0000
X:54811573:GACA:G	acceptor_gain	1.0000
X:54811573:GACAT:G	acceptor_gain	1.0000
X:54811649:AGAAG:A	donor_loss	1.0000
X:54811650:GAAGG:G	donor_loss	1.0000
X:54811651:AAG:A	donor_loss	1.0000
X:54811652:AGG:A	donor_loss	1.0000
X:54811653:GG:G	donor_loss	1.0000
X:54811654:G:T	donor_loss	1.0000
X:54811655:T:G	donor_loss	1.0000
X:54812247:GGAAC:G	donor_gain	1.0000
X:54812248:GAAC:G	donor_gain	1.0000
X:54812248:GAACG:G	donor_gain	1.0000
X:54812249:A:T	donor_gain	1.0000
X:54812252:G:GG	donor_gain	1.0000
X:54812931:T:TA	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000050377 (X:54811746 C>G), RS1000478111 (X:54806685 T>C), RS1000654621 (X:54813774 G>A,C), RS1001026062 (X:54807341 G>A,C), RS1001138484 (X:54807796 G>A), RS1001344689 (X:54808497 C>T), RS1001479948 (X:54808834 C>A), RS1002669895 (X:54812068 A>G), RS1003828385 (X:54811098 C>T), RS1004364983 (X:54815007 A>G), RS1004698302 (X:54812665 C>T), RS1004729273 (X:54812345 G>A,T), RS1004893812 (X:54812796 C>T), RS1005292605 (X:54813414 C>T), RS1006025796 (X:54806189 T>G)

Disease associations

OMIM: gene MIM:300470 | disease phenotypes: MIM:300971, MIM:220200

GenCC curated gene-disease

Disease	Classification	Inheritance
Bartter disease type 5	Definitive	X-linked
antenatal Bartter syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Bartter disease type 5	Definitive	XL

Mondo (4): Bartter disease type 5 (MONDO:0010503), attention deficit-hyperactivity disorder (MONDO:0007743), Dandy-Walker syndrome (MONDO:0009072), (MONDO:0100343)

Orphanet (3): Bartter syndrome (Orphanet:112), Bartter syndrome type 5 (Orphanet:570371), Isolated Dandy-Walker malformation (Orphanet:217)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000103	Polyuria
HP:0000848	Increased circulating renin concentration
HP:0001419	X-linked recessive inheritance
HP:0001561	Polyhydramnios
HP:0001563	Fetal polyuria
HP:0001622	Premature birth
HP:0002150	Hypercalciuria
HP:0002900	Hypokalemia
HP:0002902	Hyponatremia
HP:0003113	Hypochloremia
HP:0012408	Medullary nephrocalcinosis

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003616	Dandy-Walker Syndrome	C10.228.140.252.300; C10.228.140.602.500; C10.500.205; C16.131.666.205

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
bisphenol F	decreases expression, increases expression, affects cotreatment	2
bisphenol A	decreases expression, increases expression	2
cobaltous chloride	decreases expression	2
Cadmium	increases abundance, increases expression	2
Cisplatin	affects cotreatment, increases expression, affects response to substance	2
aristolochic acid I	decreases expression	1
2,4,6-tribromophenol	increases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	increases expression	1
avobenzone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases secretion	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Vehicle Emissions	affects expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Benztropine	affects cotreatment, decreases expression	1
Caffeine	affects phosphorylation	1
Coumestrol	decreases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00181571	PHASE4	COMPLETED	A Double-Blind Comparison of Concerta and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181675	PHASE4	COMPLETED	A Double-Blind Comparison of Galantamine HBr and Placebo in Adults With Attention Deficit Hyperactivity Disorder
NCT00181714	PHASE4	COMPLETED	Prevention of Cigarette Smoking in Attention Deficit Hyperactivity Disorder (ADHD) Youth With Concerta
NCT00181948	PHASE4	COMPLETED	Strattera Treatment in Children With ADHD Who Have Poor Response to Stimulant Therapy
NCT00181987	PHASE4	COMPLETED	Concerta in the Treatment of ADHD in Youth and Adults With Bipolar Disorder
NCT00190736	PHASE4	COMPLETED	Efficacy and Safety of Once-Daily Atomoxetine Hydrochloride in Adults With ADHD Over an Extended Period of Time (6 Months)
NCT00190775	PHASE4	COMPLETED	A Randomized, Double-Blind Comparison of Placebo and Atomoxetine Hydrochloride Given Once a Day in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)
NCT00190879	PHASE4	COMPLETED	Placebo-Controlled Study of Atomoxetine Hydrochloride in the Treatment of Adults With ADHD and Comorbid Social Anxiety Disorder
NCT00190957	PHASE4	COMPLETED	Atomoxetine Treatment of Adults With ADHD and Comorbid Alcohol Abuse
NCT00191035	PHASE4	COMPLETED	Maintenance of Benefit With Atomoxetine Hydrochloride in Adolescents With ADHD
NCT00191048	PHASE4	COMPLETED	Treatment With Atomoxetine Hydrochloride in Children and Adolescents With ADHD
NCT00191633	PHASE4	COMPLETED	Study of Atomoxetine in Children With ADHD to Assess Symptomatic and Functional Outcomes
NCT00191906	PHASE4	COMPLETED	Comparison of Atomoxetine and Placebo in Children With Attention-Deficit/Hyperactivity Disorder (ADHD) and/or Reading Disorder (RD)
NCT00216918	PHASE4	COMPLETED	Neuropsychological Functioning in Children With Attention-Deficit/Hyperactivity Disorder.
NCT00221962	PHASE4	COMPLETED	Study of Aripiprazole (Abilify) in Children With ADHD (Attention Deficit Hyperactivity Disorder)
NCT00223561	PHASE4	COMPLETED	Methylphenidate and Driving Ability in Adult Patients With Attention-Deficit Hyperactivity Disorder
NCT00299234	PHASE4	TERMINATED	Atomoxetine for Children With Acquired Attentional Disorders Following Completion of Chemotherapy for ALL
NCT00302406	PHASE4	COMPLETED	Naturalistic Substitution of Concerta in Adult Subject With ADHD Receiving Immediate Release Methylphenidate
NCT00305370	PHASE4	COMPLETED	Aripiprazole Associated With Methylphenidate in Children and Adolescents With Bipolar Disorder and ADHD
NCT00381758	PHASE4	COMPLETED	The COMACS Study: A Comparison of Methylphenidates in an Analog Classroom Setting
NCT00406354	PHASE4	COMPLETED	Comparison of Atomoxetine Versus Placebo in Children and Adolescents With ADHD and Comorbid ODD in Germany
NCT00434213	PHASE4	COMPLETED	Characterization of Dermal Reactions in Pediatric Patients With ADHD Using DAYTRANA
NCT00468143	PHASE4	COMPLETED	A Within-Subject Cross-Over Comparison Between Immediate Release and Extended Release Adderall
NCT00471354	PHASE4	COMPLETED	A Study for Patients With Attention-Deficit/Hyperactivity Disorder Treated With Atomoxetine
NCT00483106	PHASE4	COMPLETED	Clinical and Pharmacogenetic Study of Attention Deficit With Hyperactivity Disorder (ADHD)
NCT00485849	PHASE4	COMPLETED	A Study of Atomoxetine for Attention Deficit and Hyperactive/Impulsive Behaviour Problems in Children With ASD
NCT00485875	PHASE4	COMPLETED	Safety and Efficacy of Switching From a Stimulant Medication to Atomoxetine in Children and Adolescents With ADHD
NCT00486122	PHASE4	COMPLETED	Evaluation of Continuous Symptom Treatment of ADHD
NCT00500071	PHASE4	COMPLETED	Dose-Optimization Study Evaluating the Efficacy, Safety and Tolerability of Vyvanse (Lisdexamfetamine Dimesylate) in Children Aged 6-12 Diagnosed With ADHD
NCT00506727	PHASE4	COMPLETED	Analog Classroom Study Comparison of ADDERALL XR With STRATTERA in Children Aged 6-12 With ADHD
NCT00510276	PHASE4	COMPLETED	Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) With Atomoxetine in Young Adults and Its Effects on Functional Outcomes
NCT00517504	PHASE4	COMPLETED	Methylphenidate Study in Young Children With Developmental Disorders
NCT00517647	PHASE4	COMPLETED	Atomoxetine Pilot Study in Preschool Children With ADHD
NCT00518232	PHASE4	COMPLETED	A Study to Determine Effective and Tolerable Titration Scheme for OROS-Methylphenidate in Children With Attention-deficit Hyperactivity Disorder
NCT00530257	PHASE4	COMPLETED	Study of the Effects of Osmotic-Release Oral System (OROS) Methylphenidate (Concerta) on Attention and Memory
NCT00536419	PHASE4	UNKNOWN	Impact of Attention Deficit/Hyperactivity Disorder and Substance Use Disorder on Motorcycle Traffic Accidents
NCT00546910	PHASE4	COMPLETED	Comparison of Atomoxetine Versus Placebo in Children With Attention-Deficit/Hyperactivity Disorder (ADHD)
NCT00552266	PHASE4	UNKNOWN	Methylphenidate in ADHD With Trichotillomania
NCT00564954	PHASE4	COMPLETED	A Study of Dex-methylphenidate Extended Release in Children (6-12 Years) With Attention-Deficit/Hyperactivity Disorder (ADHD)