TBX18

Summary

TBX18 (T-box transcription factor 18, HGNC:11595) is a protein-coding gene on chromosome 6q14.3, encoding T-box transcription factor TBX18 (O95935). Acts as a transcriptional repressor involved in developmental processes of a variety of tissues and organs, including the heart and coronary vessels, the ureter and the vertebral column.

This genes codes for a member of an evolutionarily conserved family of transcription factors that plays a crucial role in embryonic development. The family is characterized by the presence of the DNA-binding T-box domain and is divided into five sub-families based on sequence conservation in this domain. The encoded protein belongs to the vertebrate specific Tbx1 sub-family. The protein acts as a transcriptional repressor by antagonizing transcriptional activators in the T-box family. The protein forms homo- or heterodimers with other transcription factors of the T-box family or other transcription factors.

Source: NCBI Gene 9096 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital anomalies of kidney and urinary tract 2 (Strong, GenCC)
• GWAS associations: 15
• Clinical variants (ClinVar): 261 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 16
• Transcription factor: yes — 13 downstream targets (CollecTRI)
• MANE Select transcript: NM_001080508

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11595
Approved symbol	TBX18
Name	T-box transcription factor 18
Location	6q14.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000112837
Ensembl biotype	protein_coding
OMIM	604613
Entrez	9096

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000330469, ENST00000369663, ENST00000606325, ENST00000606521, ENST00000606621, ENST00000606784, ENST00000607343

RefSeq mRNA: 1 — MANE Select: NM_001080508 NM_001080508

CCDS: CCDS34495

Canonical transcript exons

ENST00000369663 — 8 exons

Exon	Start	End
ENSE00000760213	84747920	84748087
ENSE00000760214	84756698	84756869
ENSE00000760215	84760255	84760356
ENSE00001153965	84762544	84762748
ENSE00001450575	84763890	84764598
ENSE00001910253	84732496	84737409
ENSE00002141393	84738497	84738591
ENSE00003790440	84744261	84744325

Expression profiles

Bgee: expression breadth ubiquitous, 162 present calls, max score 95.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.7104 / max 229.4747, expressed in 975 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74586	3.9784	818
74582	1.7717	615
74584	0.3098	165
74581	0.2979	176
74583	0.2407	133
74585	0.1120	48

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right coronary artery	UBERON:0001625	95.98	gold quality
popliteal artery	UBERON:0002250	95.57	gold quality
tibial artery	UBERON:0007610	95.56	gold quality
left coronary artery	UBERON:0001626	94.26	gold quality
aorta	UBERON:0000947	93.60	gold quality
descending thoracic aorta	UBERON:0002345	93.52	gold quality
calcaneal tendon	UBERON:0003701	92.74	gold quality
coronary artery	UBERON:0001621	92.10	gold quality
thoracic aorta	UBERON:0001515	91.42	gold quality
ascending aorta	UBERON:0001496	91.22	gold quality
tibial nerve	UBERON:0001323	87.00	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.49	gold quality
right atrium auricular region	UBERON:0006631	82.17	gold quality
cardiac atrium	UBERON:0002081	80.57	gold quality
subcutaneous adipose tissue	UBERON:0002190	79.67	gold quality
tendon	UBERON:0000043	79.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.36	gold quality
lower esophagus muscularis layer	UBERON:0035833	77.77	gold quality
lower esophagus	UBERON:0013473	77.74	gold quality
skin of leg	UBERON:0001511	77.40	gold quality
heart	UBERON:0000948	77.04	gold quality
sural nerve	UBERON:0015488	76.67	gold quality
skin of abdomen	UBERON:0001416	75.72	gold quality
right ovary	UBERON:0002118	74.11	gold quality
heart left ventricle	UBERON:0002084	74.06	gold quality
zone of skin	UBERON:0000014	73.60	gold quality
apex of heart	UBERON:0002098	73.57	gold quality
mucosa of stomach	UBERON:0001199	73.50	gold quality
cardiac ventricle	UBERON:0002082	73.43	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	73.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.33

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

13 targets.

Target	Regulation
CDKN2A
DISC1
DKK1
DLL1	Repression
DPPA4
GJA1
GNA11
LEFTY2
NPPA
SLIT1
SNAI2	Unknown
TBX6
THY1

JASPAR motifs

Motif	Name	Family
MA1565.1	TBX18	TBX1-related factors
MA1565.2	TBX18	TBX1-related factors

JASPAR matrix evidence (PMIDs): PMID:17584735

Upstream regulators (CollecTRI, top): POU5F1, WT1

miRNA regulators (miRDB)

213 targeting TBX18, 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-5011-5P	100.00	83.46	5820
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-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593

Literature-anchored findings (GeneRIF, showing 14)

• Tbx18 interacts with Gata4 and Nkx2-5 and competes Tbx5-mediated activation of the cardiac Natriuretic peptide precursor type a-promoter. Tbx18 down-regulates Tbx6-activated Delta-like 1 expression in the somitic mesoderm in vivo (PMID:17584735)
• connexin43 transcriptional suppression by TBX18 undermines cardiomyocyte cell-cell electrical coupling (PMID:21205823)
• The DNA sequence variants within the TBX18 gene promoter identified in ventricular septal defects (VSD) patients may be involved in the VSD etiology. (PMID:23749171)
• Mutations in TBX18 cause dominant urinary tract malformations via transcriptional dysregulation of ureter development. (PMID:26235987)
• Gene product expressions of SHH, TBX18 and TSHZ3 are statistically higher in patients with UPJ obstruction, when compared with control group. The explanation may be the reactivation of the processes, which had shown their effects in the embryological period, due to the chronic inflammation and long-term micro-trauma created by the disease (PMID:27381532)
• Data indicate that human T-box 18 (TBX18) gene induces rat adipose-derived stem cells (ADSCs) to differentiate into pacemaker-like cells in the cardiac microenvironment. (PMID:27632938)
• Tbx18-positive cells represent a part of PE cells in the initial phase of differentiation and subsequently include SMCs as well as fibroblasts. These results indicate that Tbx18-positive cells serve as a PE progenitor to supply a variety of cells that contribute to the formation of coronary arteries. (PMID:28794400)
• Study identified and characterized new TBX18 binding partners that may influence the transcriptional activity of TBX18 in vivo. Proteomic screen strongly supports an exclusive nuclear function of TBX18 as a repressor of chromatin accessibility. (PMID:30071041)
• TBX18 gene over expression induces human-induced pluripotent stem cells to differentiate into pacemaker-like cells. (PMID:30078203)
• Although TBX3 and TBX18 do not play a significant role in promoting the enrichment and differentiation of HiPS into sinoatrial node-like cells, TBX3 shows a certain promoting trend, which can be further explored in the future. (PMID:30983202)
• Tbx18 promoted the conversion of human-induced pluripotent stem cell-derived cardiomyocytes into sinoatrial node-like pacemaker cells. (PMID:34882885)
• The role of TBX18 in congenital heart defects in humans not confirmed. (PMID:36418409)
• MicroRNA-dependent suppression of biological pacemaker activity induced by TBX18. (PMID:36543116)
• TBX18 knockdown sensitizes esophageal squamous cell carcinoma to radiotherapy by blocking the CHN1/RhoA axis. (PMID:37399907)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbx18	ENSDARG00000036930
mus_musculus	Tbx18	ENSMUSG00000032419
rattus_norvegicus	Tbx18	ENSRNOG00000010685
drosophila_melanogaster	org-1	FBGN0021767
caenorhabditis_elegans		WBGENE00003376

Paralogs (16): TBX21 (ENSG00000073861), TBX5 (ENSG00000089225), TBX15 (ENSG00000092607), TBX2 (ENSG00000121068), TBX4 (ENSG00000121075), TBX22 (ENSG00000122145), TBX3 (ENSG00000135111), TBR1 (ENSG00000136535), TBX19 (ENSG00000143178), TBX6 (ENSG00000149922), EOMES (ENSG00000163508), TBXT (ENSG00000164458), TBX20 (ENSG00000164532), TBX10 (ENSG00000167800), MGA (ENSG00000174197), TBX1 (ENSG00000184058)

Protein

Protein identifiers

T-box transcription factor TBX18 — O95935 (reviewed: O95935)

All UniProt accessions (4): O95935, U3KQ31, U3KQH2, U3KQQ9

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional repressor involved in developmental processes of a variety of tissues and organs, including the heart and coronary vessels, the ureter and the vertebral column. Required for embryonic development of the sino atrial node (SAN) head area.

Subunit / interactions. Homodimer. Can form a heterodimer with TBX15. Interacts with GATA4 and NKX2-5. Interacts with PAX3. Interacts (via engrailed homology 1 repressor motif) with TLE3; this interaction represses TBX18 transcriptional activity. Interacts with SIX1.

Subcellular location. Nucleus.

Disease relevance. Congenital anomalies of kidney and urinary tract 2 (CAKUT2) [MIM:143400] A disorder encompassing a broad spectrum of renal and urinary tract malformations that include renal agenesis, kidney hypodysplasia, multicystic kidney dysplasia, duplex collecting system, posterior urethral valves and ureter abnormalities. Congenital anomalies of kidney and urinary tract are the commonest cause of chronic kidney disease in children. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_001073977* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001699	TF_T-box	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR018186	TF_T-box_CS	Conserved_site
IPR036960	T-box_sf	Homologous_superfamily
IPR046360	T-box_DNA-bd	Domain

Pfam: PF00907

UniProt features (11 total): sequence variant 5, short sequence motif 2, chain 1, DNA-binding 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-O95935-F1	61.09	0.32

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 210 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_URETER_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, GOBP_CELL_CELL_SIGNALING, GOBP_CARDIAC_CONDUCTION_SYSTEM_DEVELOPMENT, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, DAWSON_METHYLATED_IN_LYMPHOMA_TCL1, GOBP_EAR_DEVELOPMENT

GO Biological Process (16): negative regulation of transcription by RNA polymerase II (GO:0000122), cell fate specification (GO:0001708), somitogenesis (GO:0001756), sinoatrial node development (GO:0003163), regulation of transcription by RNA polymerase II (GO:0006357), morphogenesis of embryonic epithelium (GO:0016331), neural plate anterior/posterior regionalization (GO:0021999), positive regulation of DNA-templated transcription (GO:0045893), smooth muscle cell differentiation (GO:0051145), sinoatrial node cell fate commitment (GO:0060930), sinoatrial node cell development (GO:0060931), ureter development (GO:0072189), negative regulation of canonical Wnt signaling pathway (GO:0090090), cochlea morphogenesis (GO:0090103), regulation of SA node cell action potential (GO:0098907), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), protein homodimerization activity (GO:0042803), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), RNA polymerase II transcription repressor complex (GO:0090571)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
anterior/posterior pattern specification	2
embryonic morphogenesis	2
DNA-templated transcription	2
sinoatrial node cell differentiation	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
cell fate commitment	1
cellular developmental process	1
segmentation	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
somite development	1
cardiac conduction system development	1
atrial cardiac muscle tissue development	1
morphogenesis of an epithelium	1
neural plate regionalization	1
positive regulation of RNA biosynthetic process	1
muscle cell differentiation	1
cardiac pacemaker cell fate commitment	1
cardiac pacemaker cell development	1
tube development	1
animal organ development	1
renal system development	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
inner ear morphogenesis	1
cochlea development	1
regulation of cell communication	1
SA node cell action potential	1
regulation of cardiac muscle cell action potential	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1

Protein interactions and networks

STRING

1218 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBX18	TCF21	O43680	769
TBX18	NKX2-5	P52952	752
TBX18	SHOX2	O60902	748
TBX18	HCN4	Q9Y3Q4	738
TBX18	WT1	P19544	731
TBX18	MESP2	Q0VG99	695
TBX18	ISL1	P20663	679
TBX18	ALDH1A2	O94788	665
TBX18	SEMA3D	O95025	605
TBX18	GATA4	P43694	598
TBX18	GJA5	P36382	589
TBX18	TNNT2	P45379	571
TBX18	SOX2	P48431	537
TBX18	POU5F1	P31359	532
TBX18	PAX9	P55771	528

IntAct

18 interactions, top by confidence:

A	B	Type	Score
TBX18	ARC	psi-mi:“MI:0915”(physical association)	0.560
TBX18	PLEKHG4	psi-mi:“MI:0915”(physical association)	0.560
TBX18	KRTAP8-1	psi-mi:“MI:0915”(physical association)	0.560
TBX18	TRAF1	psi-mi:“MI:0915”(physical association)	0.560
AIP	TBX18	psi-mi:“MI:0915”(physical association)	0.400
	TBX18	psi-mi:“MI:0915”(physical association)	0.370
TBX18	PAPSS2	psi-mi:“MI:0914”(association)	0.350
TBX20	TBX18	psi-mi:“MI:0914”(association)	0.350
SLC26A5	ASMTL	psi-mi:“MI:0914”(association)	0.350
TBX18	TRAF1	psi-mi:“MI:0915”(physical association)	0.000
TBX18	PLEKHG4	psi-mi:“MI:0915”(physical association)	0.000
TBX18	ARC	psi-mi:“MI:0915”(physical association)	0.000
TBX18	KRTAP8-1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (10): TBX18 (Two-hybrid), KRTAP8-1 (Two-hybrid), PLEKHG4 (Two-hybrid), ARC (Two-hybrid), TBX20 (Affinity Capture-MS), PAPSS2 (Affinity Capture-MS), TBX18 (Affinity Capture-MS), TBX18 (Affinity Capture-MS), TBX18 (Affinity Capture-MS), TBX18 (Proximity Label-MS)

ESM2 similar proteins: A1YF56, A2AEV7, A6NCS4, A7Y7W2, D3ZJK7, E1BEA8, F1MUS9, O15534, O35973, O43435, O43638, O60248, O75333, O77728, O94983, O95935, O95947, P22736, P46099, P51666, P56261, P57082, P70325, P70327, Q03484, Q0V8F0, Q15744, Q497V6, Q5DTT2, Q61660, Q61663, Q63HR2, Q64731, Q66JL1, Q6PZD9, Q6ZQN5, Q80Y50, Q810F8, Q861Q9, Q8AV66

Diamond homologs: A1YF56, A2AWL7, D3ZJK7, E1BEA8, O01409, O13161, O15119, O15178, O17212, O43435, O54839, O60806, O70306, O73718, O75333, O95935, O95936, O95947, P20293, P24781, P55965, P56158, P57082, P70323, P70324, P70325, P70326, P70327, P79742, P79777, P79778, P79779, P79944, P80492, P87377, P90971, Q07998, Q13207, Q16650, Q17134

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
POU5F1	“down-regulates quantity by repression”	TBX18	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	154
Likely benign	66
Benign	21

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1177415	NM_001080508.3(TBX18):c.692_693insT (p.Glu233fs)	Pathogenic
208529	NM_001080508.3(TBX18):c.487A>G (p.Lys163Glu)	Pathogenic
2441800	NM_001080508.3(TBX18):c.1045C>T (p.Arg349Ter)	Pathogenic
1344613	NM_001080508.3(TBX18):c.1802A>G (p.Gln601Arg)	Likely pathogenic
3899978	NM_001080508.3(TBX18):c.1654G>T (p.Gly552Ter)	Likely pathogenic

SpliceAI

1595 predictions. Top by Δscore:

Variant	Effect	Δscore
6:84747984:C:CA	donor_gain	1.0000
6:84748065:T:C	acceptor_gain	1.0000
6:84748083:ATAAT:A	acceptor_gain	1.0000
6:84748084:TAAT:T	acceptor_gain	1.0000
6:84748088:C:CC	acceptor_gain	1.0000
6:84756690:CTACT:C	donor_loss	1.0000
6:84756691:TAC:T	donor_loss	1.0000
6:84756692:ACT:A	donor_loss	1.0000
6:84756693:C:CA	donor_loss	1.0000
6:84756694:TCAC:T	donor_loss	1.0000
6:84756695:CA:C	donor_loss	1.0000
6:84756696:A:AC	donor_gain	1.0000
6:84756697:C:CT	donor_gain	1.0000
6:84756697:CATG:C	donor_gain	1.0000
6:84756697:CATGG:C	donor_gain	1.0000
6:84756865:CATAC:C	acceptor_gain	1.0000
6:84756867:TAC:T	acceptor_gain	1.0000
6:84756867:TACC:T	acceptor_loss	1.0000
6:84738607:CAGGA:C	acceptor_gain	0.9900
6:84742836:T:TA	donor_gain	0.9900
6:84744229:T:C	donor_gain	0.9900
6:84747914:CAATA:C	donor_loss	0.9900
6:84747916:ATACC:A	donor_loss	0.9900
6:84747917:TACCT:T	donor_loss	0.9900
6:84747918:A:AG	donor_loss	0.9900
6:84747919:CCTG:C	donor_gain	0.9900
6:84748065:T:TC	acceptor_gain	0.9900
6:84748067:G:C	acceptor_gain	0.9900
6:84748070:C:CT	acceptor_gain	0.9900
6:84748071:A:AC	acceptor_gain	0.9900

AlphaMissense

3932 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:84744279:C:G	R329P	1.000
6:84744280:G:C	R329G	1.000
6:84744281:G:C	F328L	1.000
6:84744281:G:T	F328L	1.000
6:84744282:A:C	F328C	1.000
6:84744282:A:G	F328S	1.000
6:84744283:A:C	F328V	1.000
6:84744283:A:G	F328L	1.000
6:84744283:A:T	F328I	1.000
6:84744285:C:A	G327V	1.000
6:84744285:C:T	G327D	1.000
6:84744286:C:A	G327C	1.000
6:84744286:C:G	G327R	1.000
6:84744286:C:T	G327S	1.000
6:84744287:T:A	K326N	1.000
6:84744287:T:G	K326N	1.000
6:84744288:T:A	K326I	1.000
6:84744288:T:G	K326T	1.000
6:84744289:T:C	K326E	1.000
6:84744289:T:G	K326Q	1.000
6:84744291:G:A	A325V	1.000
6:84744291:G:T	A325D	1.000
6:84744292:C:G	A325P	1.000
6:84744292:C:T	A325T	1.000
6:84744293:A:C	F324L	1.000
6:84744293:A:T	F324L	1.000
6:84744294:A:C	F324C	1.000
6:84744294:A:G	F324S	1.000
6:84744295:A:C	F324V	1.000
6:84744295:A:G	F324L	1.000

dbSNP variants (sampled 300 via entrez): RS1000001327 (6:84760594 T>C), RS1000013134 (6:84762408 G>A), RS1000031398 (6:84748676 G>C), RS1000094469 (6:84747341 C>T), RS1000185147 (6:84742286 A>G), RS1000286895 (6:84742875 C>T), RS1000314814 (6:84755632 CT>C,CTT), RS1000413304 (6:84735856 C>T), RS1000442537 (6:84749384 T>C,G), RS1000490931 (6:84762208 CTAAA>C), RS1000512183 (6:84736247 C>T), RS1000520664 (6:84743941 G>A), RS1000550997 (6:84748486 T>C), RS1000568681 (6:84743259 A>G), RS1000594266 (6:84743729 C>T)

Disease associations

OMIM: gene MIM:604613 | disease phenotypes: MIM:143400, MIM:610805, MIM:191830

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital anomalies of kidney and urinary tract 2	Strong	Autosomal dominant

Mondo (5): congenital anomalies of kidney and urinary tract 2 (MONDO:0027676), congenital anomaly of kidney and urinary tract (MONDO:0019719), proteinuria (MONDO:0003634), renal agenesis (MONDO:0018470), chronic kidney disease (MONDO:0005300)

Orphanet (3): OBSOLETE: Congenital hydronephrosis (Orphanet:2190), Renal or urinary tract malformation (Orphanet:93545), Renal agenesis (Orphanet:411709)

HPO phenotypes

16 total (18 of 16 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000072	Hydroureter
HP:0000074	Ureteropelvic junction obstruction
HP:0000083	Renal insufficiency
HP:0000089	Renal hypoplasia
HP:0000110	Renal dysplasia
HP:0000126	Hydronephrosis
HP:0003418	Back pain
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0004719	Hyperechogenic kidneys
HP:0008676	Congenital megaureter
HP:0011461	Fetal onset
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0030157	Flank pain
HP:0000104	Renal agenesis
HP:0008678	Renal hypoplasia/aplasia

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST002684_1	Diabetic retinopathy in type 2 diabetes	1.000000e-06
GCST003996_36	Monobrow	2.000000e-19
GCST006626_2	Pulse pressure	5.000000e-14
GCST010057_4	Lung function	2.000000e-06
GCST011946_13	White matter hyperintensity volume	2.000000e-06
GCST011947_15	White matter hyperintensity volume	1.000000e-06
GCST011950_5	White matter hyperintensity volume (adjusted for hypertension)	6.000000e-06
GCST011952_11	White matter hyperintensity volume x hypertension interaction (2df)	1.000000e-05
GCST011953_13	White matter hyperintensity volume x hypertension interaction (2df)	1.000000e-05
GCST012226_677	Waist circumference adjusted for body mass index	2.000000e-09
GCST012226_678	Waist circumference adjusted for body mass index	2.000000e-08
GCST012228_276	Waist-hip index	2.000000e-08
GCST012228_277	Waist-hip index	2.000000e-09
GCST012230_465	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST90020029_1411	Waist circumference adjusted for body mass index	6.000000e-11

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007906	synophrys measurement
EFO:0005763	pulse pressure measurement
EFO:0004312	vital capacity
EFO:0005665	white matter hyperintensity measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D007676	Kidney Failure, Chronic	C12.050.351.968.419.780.750.500; C12.200.777.419.780.750.500; C12.950.419.780.750.500; C23.550.291.500.906.500
D011507	Proteinuria	C12.050.351.968.934.734; C12.200.777.934.734; C12.950.934.734; C23.888.942.750
C566906	Cakut (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects methylation, affects cotreatment, increases expression	2
methylparaben	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
Temozolomide	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Manganese	increases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1
Valproic Acid	affects cotreatment, increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B5QJ	WAe009-A-78	Embryonic stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00067990	PHASE4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00234871	PHASE4	COMPLETED	Tarka® vs. Lotrel® in Hypertensive, Diabetic Subjects With Renal Disease (TANDEM)
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus
NCT00369538	PHASE4	SUSPENDED	Specific Blockage of Angiotensine 2 and Podocyturia in Glomerular Nephropathies With Hypertension and Proteinuria
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00550095	PHASE4	COMPLETED	To Assess the Effects of Valsartan on Albuminuria/Proteinuria in Hypertensive Patients With Type 2 Diabetes Mellitus
NCT00674596	PHASE4	COMPLETED	The Effect of Renin Angiotensin System Blockage (RAS) Blockade On PTX3 Levels In Diabetic Patients With Proteinuria
NCT00858299	PHASE4	UNKNOWN	The Change of Urinary Angiotensinogen Excretion After Valsartan Treatment in Patients With Persistent Proteinuria
NCT00893425	PHASE4	COMPLETED	Effect of Renin Angiotensin System Blockade on the Fas Antigen (CD95) and Asymmetric Dimethylarginine (ADMA) Levels in Type-2 Diabetic Patients With Proteinuria
NCT00921570	PHASE4	COMPLETED	The Effects of Renin Angiotensin System Blockage (RAS), Calcium Channel Blocker and Combined Drugs on TWEAK, PTX3 and FMD Levels in Diabetic Proteinuric Patients With Hypertension
NCT00961207	PHASE4	TERMINATED	Triple Blockade of the Renin Angiotensin Aldosterone System in Diabetic (Type 1&2) Proteinuric Patients
NCT01169857	PHASE4	WITHDRAWN	Velcade for Proliferative Lupus Nephritis
NCT01219413	PHASE4	COMPLETED	Influence of Aliskiren on Proteinuria
NCT01386554	PHASE4	COMPLETED	Acthar for Treatment of Proteinuria in Membranous Nephropathy Patients
NCT01512862	PHASE4	UNKNOWN	Anti-proteinuric Effect of Calcitriol in Non-diabetic Kidney Disease Patients
NCT01541267	PHASE4	COMPLETED	The Effect of Various Types of the Renin-angiotensin-aldosterone System Blockade on Proteinuria
NCT01637259	PHASE4	COMPLETED	MARCH Renal Substudy
NCT01703234	PHASE4	COMPLETED	FGF-23 and Endothelial Dysfunction in Diabetic Proteinuric Patients
NCT01820832	PHASE4	UNKNOWN	Oral Calcitriol for Reduction of Mild Proteinuria in Patients With CKD
NCT01827202	PHASE4	COMPLETED	RAS Quantification in Patients With Aliskiren or Candesartan
NCT02057523	PHASE4	TERMINATED	Acthar as Rescue Therapy for Transplant Glomerulopathy in Kidney Transplant Recipients
NCT02063100	PHASE4	UNKNOWN	Efficacy and Safety of Shenyankangfu Tablets for Primary Glomerulonephritis
NCT02382523	PHASE4	WITHDRAWN	Acthar on Proteinuria in IgA Nephropathy Patients
NCT02522650	PHASE4	UNKNOWN	A Crossover Pilot Study of the Effect of Amiloride on Proteinuria
NCT03195023	PHASE4	UNKNOWN	Effect of RAS Blockers on CKD Progression in Elderly Patients With Non Proteinuric Nephropathies (PROERCAN01)
NCT03550859	PHASE4	UNKNOWN	HMG-CoA Reductase add-on in Chronic Kidney Disease Patients With Proteinuria
NCT03983551	PHASE4	COMPLETED	Comparing the Renal Effect of Dipeptidyl-peptidase 4 Inhibitors and Sulfonylureas
NCT04531397	PHASE4	WITHDRAWN	Efficacy and Safety of Dapagliflozin in Children With Proteinuric Chronic Kidney Disease
NCT04534270	PHASE4	COMPLETED	Efficacy and Safety of Dapagliflozin in Children With Proteinuria
NCT06374043	PHASE4	COMPLETED	Decentralized N=1 Study: A Feasible Approach to Evaluate Individual Therapy Response to Dapagliflozin.
NCT07030894	PHASE4	RECRUITING	Nefecon and Ambrisentan in IgA Nephropathy
NCT07219121	PHASE4	RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT07358520	PHASE4	NOT_YET_RECRUITING	Clinical Study on the Use of Huaier Granules for the Treatment of Proteinuria Related to Bevacizumab and Anlotinib in Lung Cancer Patients
NCT00073710	PHASE4	COMPLETED	Study to Evaluate the Effects of Zemplar Injection and Calcijex on Intestinal Absorption of Calcium
NCT00125593	PHASE4	COMPLETED	Study of Heart and Renal Protection
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00155246	PHASE4	COMPLETED	Efficacy of Pentoxifylline on Chronic Kidney Disease
NCT00175149	PHASE4	TERMINATED	Active Vitamin D Effect on Left Ventricular Hypertrophy
NCT00184769	PHASE4	COMPLETED	Growth Hormone Treatment in Infants Aged 1 to 2 Years With Chronic Renal Insufficiency (CRI) and Growth Retardation.
NCT00190580	PHASE4	COMPLETED	Kanagawa Valsartan Trial (KVT): Effects of Valsartan on Renal and Cardiovascular Disease