SIX2

Summary

SIX2 (SIX homeobox 2, HGNC:10888) is a protein-coding gene on chromosome 2p21, encoding Homeobox protein SIX2 (Q9NPC8). Transcription factor that plays an important role in the development of several organs, including kidney, skull and stomach.

This gene is a member of the vertebrate gene family which encode proteins homologous to the Drosophila ‘sine oculis’ homeobox protein. The encoded protein is a transcription factor which, like other members of this gene family, may be involved in limb or eye development.

Source: NCBI Gene 10736 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital anomaly of kidney and urinary tract (Limited, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 119 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 22
• MANE Select transcript: NM_016932

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10888
Approved symbol	SIX2
Name	SIX homeobox 2
Location	2p21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170577
Ensembl biotype	protein_coding
OMIM	604994
Entrez	10736

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000303077, ENST00000933251

RefSeq mRNA: 1 — MANE Select: NM_016932 NM_016932

CCDS: CCDS1822

Canonical transcript exons

ENST00000303077 — 2 exons

Exon	Start	End
ENSE00001158942	45008551	45009452
ENSE00001165147	45005182	45006485

Expression profiles

Bgee: expression breadth ubiquitous, 156 present calls, max score 92.44.

FANTOM5 (CAGE): breadth broad, TPM avg 2.1341 / max 100.2125, expressed in 511 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28163	1.6094	444
28164	0.4573	229
28165	0.0674	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory segment of nasal mucosa	UBERON:0005386	92.44	gold quality
gastrocnemius	UBERON:0001388	87.41	gold quality
parotid gland	UBERON:0001831	86.72	gold quality
muscle of leg	UBERON:0001383	86.51	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.67	gold quality
nasal cavity mucosa	UBERON:0001826	85.55	gold quality
nasal cavity epithelium	UBERON:0005384	85.00	gold quality
tendon of biceps brachii	UBERON:0008188	83.30	gold quality
muscle organ	UBERON:0001630	83.26	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.38	gold quality
tibialis anterior	UBERON:0001385	78.85	silver quality
palpebral conjunctiva	UBERON:0001812	77.72	gold quality
pituitary gland	UBERON:0000007	77.70	gold quality
tendon	UBERON:0000043	77.08	gold quality
mucosa of paranasal sinus	UBERON:0005030	76.81	silver quality
omental fat pad	UBERON:0010414	76.45	gold quality
saliva-secreting gland	UBERON:0001044	76.37	gold quality
peritoneum	UBERON:0002358	76.36	gold quality
periodontal ligament	UBERON:0008266	76.15	gold quality
epithelium of bronchus	UBERON:0002031	76.01	gold quality
adipose tissue of abdominal region	UBERON:0007808	75.78	gold quality
bronchus	UBERON:0002185	75.72	gold quality
islet of Langerhans	UBERON:0000006	75.61	gold quality
calcaneal tendon	UBERON:0003701	75.23	gold quality
adenohypophysis	UBERON:0002196	75.07	gold quality
deltoid	UBERON:0001476	74.45	silver quality
skeletal muscle tissue	UBERON:0001134	74.19	gold quality
minor salivary gland	UBERON:0001830	73.84	gold quality
thoracic aorta	UBERON:0001515	73.64	gold quality
descending thoracic aorta	UBERON:0002345	73.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.73

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
GDNF	Activation
SIX2	Activation

JASPAR motifs

Motif	Name	Family
MA1119.1	SIX2	HD-SINE
MA1119.2	SIX2	HD-SINE

JASPAR matrix evidence (PMIDs): PMID:15327782

Upstream regulators (CollecTRI, top): HOXA2, SIX2

miRNA regulators (miRDB)

66 targeting SIX2, 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-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-4428	99.73	66.41	1733

Literature-anchored findings (GeneRIF, showing 25)

• Defects in these proteins could affect kidney development at multiple stages, leading to the congenital anomalies observed in patients with renal hypodysplasia (PMID:18305125)
• Lack of mutations in the coding regions of SIX2 among the sporadic microtia patients (PMID:20542577)
• Nuclear protein & mRNA expression of SIX2 were similar across all stages of disease, in favorable or unfavorable histology & in treatment failure or success. It is not found in normal kidney. (PMID:22703800)
• in tumors with DGCR8 E518K and DROSHA exon 29 (miRNAPG-HS) mutations … greater prevalence of tumors with blastemal predominant histology in patients with miRNAPG-HS and/or SIX1/2 Q177R mutations (PMID:25670082)
• Recurrent mutations included a hotspot mutation (Q177R) in the homeo-domain of SIX1 and SIX2 in tumors with high proliferative potential (18.1% of blastemal cases); mutations in the DROSHA/DGCR8 microprocessor genes (PMID:25670083)
• SIX2 overexpression and concomitantly decreased promoter methylation. (PMID:25921281)
• SIX2 deletion is associated with frontonasal dysplasia syndrome. (PMID:26581443)
• These data suggest differential SIX-factor regulation might have contributed to species differences in nephron progenitor programs such as the duration of nephrogenesis and the final nephron count (PMID:26884396)
• We suggest SIX2 haploinsufficiency as a potential congenital factor could be attributed to developmental malformation of the middle ear ossicles and upper eyelid. (PMID:27383657)
• elevated expressions of SIX2, SIX4, and SIX6 predicted poor overall survival (OS) in NSCLC and poor relapse-free survival (RFS) in lung adenocarcinoma (PMID:27821176)
• these findings delineate the important function of the TGFbeta signaling pathway in the early development of kidney and TbetaRII was shown to be able to promote the expression of Six2 through Smad3 mediating transcriptional regulation and in turn activate the proliferation of MM cells. (PMID:28420207)
• DDX3-mediated colorectal cancer aggressiveness and cetuximab resistance were regulated by the YAP1/SIX2 axis in KRAS-wild type cells and further confirmed in animal models. (PMID:28435452)
• the phenotypic spectrum of SIX2 haploinsufficiency is widened. Moreover, 2p21 microdeletions with SIX2 haploinsufficiency appear to lead to a recognizable phenotype with facial features resembling blepharophimosis-ptosis-epicanthus inversus syndrome. (PMID:29315086)
• Six2 is negatively correlated with good prognosis and decreases 5-FU sensitivity via suppressing E-cadherin expression in HCC cells. (PMID:29772441)
• High Six2 expression is associated with Late-Stage Metastasis in triple-negative breast cancer. (PMID:30606720)
• findings identify a NIK-SIX signalling axis that fine-tunes inflammatory gene expression programs under both physiological and pathological conditions (PMID:30894749)
• Six2 expression negatively correlated with the overall survival of clear cell renal cell carcinoma patients. (PMID:31090452)
• Glomerular Six-2 deposits in renal biopsy should be validated in prospective series as a predictor of renal outcome in renal amyloidosis (PMID:31343337)
• The six2 knockdown attenuated the stemness of Renal cell carcinoma (RCC) cells, which was evident by decreased spheroid formation ability and stemness marker (sox2 and nanog) expression. (PMID:31420918)
• Elevated Six2 expression in hepatocellular carcinoma patients was associated with negative prognosis. Upregulated Six2 promoted tumor growth and facilitated HCC metastasis via TGF-beta/Smad signal pathway. (PMID:31564506)
• SIX2 Regulates Human beta Cell Differentiation from Stem Cells and Functional Maturation In Vitro. (PMID:32460030)
• Maternal SLE and brachytelephalangic chondrodysplasia punctata in a patient with unrelated de novo RAF1 and SIX2 variants. (PMID:32506814)
• Analysis of the mutational status of SIX1/2 and microRNA processing genes in paired primary and relapsed Wilms tumors and association with relapse. (PMID:33281191)
• Overexpression of Sine Oculis Homeobox Homolog 2 Predicts Poor Survival and Clinical Parameters of Patients with Colon Adenocarcinoma. (PMID:33334785)
• De novo SIX2 activation in human kidneys treated with neonatal kidney stem/progenitor cells. (PMID:35913414)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	six2a	ENSDARG00000058004
mus_musculus	Six2	ENSMUSG00000024134
rattus_norvegicus	Six2	ENSRNOG00000085124
drosophila_melanogaster	Optix	FBGN0025360
caenorhabditis_elegans		WBGENE00000453

Paralogs (6): SIX4 (ENSG00000100625), SIX1 (ENSG00000126778), SIX3 (ENSG00000138083), SIX5 (ENSG00000177045), SIX6 (ENSG00000184302), ANHX (ENSG00000227059)

Protein

Protein identifiers

Homeobox protein SIX2 — Q9NPC8 (reviewed: Q9NPC8)

Alternative names: Sine oculis homeobox homolog 2

All UniProt accessions (1): Q9NPC8

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that plays an important role in the development of several organs, including kidney, skull and stomach. During kidney development, maintains cap mesenchyme multipotent nephron progenitor cells in an undifferentiated state by opposing the inductive signals emanating from the ureteric bud and cooperates with WNT9B to promote renewing progenitor cells proliferation. Acts through its interaction with TCF7L2 and OSR1 in a canonical Wnt signaling independent manner preventing transcription of differentiation genes in cap mesenchyme such as WNT4. Also acts independently of OSR1 to activate expression of many cap mesenchyme genes, including itself, GDNF and OSR1. During craniofacial development plays a role in growth and elongation of the cranial base through regulation of chondrocyte differentiation. During stomach organogenesis, controls pyloric sphincter formation and mucosal growth through regulation of a gene network including NKX2-5, BMPR1B, BMP4, SOX9 and GREM1. During branchial arch development, acts to mediate HOXA2 control over the insulin-like growth factor pathway. May also be involved in limb tendon and ligament development. Plays a role in cell proliferation and migration.

Subunit / interactions. Interacts with TCF7L2; in a canonical Wnt signaling independent manner; prevents transcription of differentiation genes in cap mesenchyme. Interacts with OSR1; form a strong repressor complex with TCF7L2, TLE2 and TLE3 to prevent the activation of Wnt/beta-catenin target genes in the cap mesenchyme. Interacts with HOXA11, EYA1 and EYA3.

Subcellular location. Nucleus.

Tissue specificity. Strongly expressed in skeletal muscle. Expressed in Wilms’ tumor and in the cap mesenchyme of fetal kidney (at protein level).

Similarity. Belongs to the SIX/Sine oculis homeobox family.

RefSeq proteins (1): NP_058628* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR031701	SIX1_SD	Domain

Pfam: PF00046, PF16878

UniProt features (9 total): compositionally biased region 3, sequence variant 3, chain 1, DNA-binding region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NPC8-F1	75.99	0.49

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9830674	Formation of the ureteric bud
R-HSA-1266738	Developmental Biology
R-HSA-9830369	Kidney development

MSigDB gene sets: 257 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_METANEPHRIC_NEPHRON_MORPHOGENESIS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, WANG_CLIM2_TARGETS_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_AXIS_SPECIFICATION, GOBP_REGULATION_OF_MORPHOGENESIS_OF_A_BRANCHING_STRUCTURE, GOBP_METANEPHROS_DEVELOPMENT, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER

GO Biological Process (29): kidney development (GO:0001822), chondrocyte differentiation (GO:0002062), mesenchymal to epithelial transition involved in metanephros morphogenesis (GO:0003337), regulation of transcription by RNA polymerase II (GO:0006357), protein import into nucleus (GO:0006606), mesodermal cell fate specification (GO:0007501), cell population proliferation (GO:0008283), anatomical structure morphogenesis (GO:0009653), anterior/posterior axis specification (GO:0009948), cell migration (GO:0016477), regulation of ossification (GO:0030278), negative regulation of epithelial cell differentiation (GO:0030857), regulation of chondrocyte differentiation (GO:0032330), middle ear morphogenesis (GO:0042474), embryonic digestive tract morphogenesis (GO:0048557), embryonic cranial skeleton morphogenesis (GO:0048701), nephron development (GO:0072006), nephron morphogenesis (GO:0072028), mesenchymal stem cell maintenance involved in nephron morphogenesis (GO:0072038), condensed mesenchymal cell proliferation (GO:0072137), mesenchymal cell differentiation involved in kidney development (GO:0072161), regulation of branching involved in ureteric bud morphogenesis (GO:0090189), mesenchymal stem cell proliferation (GO:0097168), positive regulation of chondrocyte proliferation (GO:1902732), metanephros development (GO:0001656), regulation of DNA-templated transcription (GO:0006355), epithelial cell differentiation (GO:0030855), positive regulation of transcription by RNA polymerase II (GO:0045944), embryonic skeletal system morphogenesis (GO:0048704)

GO Molecular Function (9): 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 activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), protein-containing complex binding (GO:0044877), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Kidney development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
anatomical structure development	2
binding	2
animal organ development	1
renal system development	1
cell differentiation	1
cartilage development	1
metanephros morphogenesis	1
epithelial cell differentiation involved in kidney development	1
mesenchymal to epithelial transition	1
metanephric renal vesicle morphogenesis	1
transcription by RNA polymerase II	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
cell fate specification	1
mesodermal cell fate commitment	1
cellular process	1
developmental process	1
axis specification	1
anterior/posterior pattern specification	1
cell motility	1
ossification	1
regulation of multicellular organismal process	1
epithelial cell differentiation	1
regulation of epithelial cell differentiation	1
negative regulation of cell differentiation	1
chondrocyte differentiation	1
regulation of cell differentiation	1
regulation of cartilage development	1
ear morphogenesis	1
embryonic morphogenesis	1
digestive tract morphogenesis	1
embryonic organ morphogenesis	1
embryonic digestive tract development	1
embryonic skeletal system morphogenesis	1
cranial skeletal system development	1
kidney development	1

Protein interactions and networks

STRING

1286 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIX2	EYA1	Q99502	915
SIX2	SALL1	Q9NSC2	859
SIX2	EYA2	O00167	844
SIX2	PAX2	Q02962	784
SIX2	CITED1	Q99966	784
SIX2	FOXD1	Q16676	739
SIX2	WT1	P19544	726
SIX2	EYA3	Q99504	726
SIX2	WNT9B	O14905	712
SIX2	LHX1	P48742	683
SIX2	DACH1	Q9UI36	676
SIX2	LBX1	P52954	646
SIX2	HOXB7	P09629	643
SIX2	WNT4	P56705	638
SIX2	PAX3	P23760	625

IntAct

22 interactions, top by confidence:

A	B	Type	Score
CLIP4	SIX2	psi-mi:“MI:0915”(physical association)	0.560
TLE5	SIX2	psi-mi:“MI:0915”(physical association)	0.560
TLE3	SIX2	psi-mi:“MI:0915”(physical association)	0.560
SIX2	EYA2	psi-mi:“MI:0914”(association)	0.530
SIX2	KPNB1	psi-mi:“MI:0914”(association)	0.530
SIX2	RELA	psi-mi:“MI:0915”(physical association)	0.510
RELA	SIX2	psi-mi:“MI:0915”(physical association)	0.510
SIX2	RELB	psi-mi:“MI:0915”(physical association)	0.400
SIX2		psi-mi:“MI:0915”(physical association)	0.400
SIX2		psi-mi:“MI:0915”(physical association)	0.370
	SIX2	psi-mi:“MI:0915”(physical association)	0.370
CDKN2A	SIX2	psi-mi:“MI:0915”(physical association)	0.370
SIX2	EYA4	psi-mi:“MI:0914”(association)	0.350
EYA1	SPAG9	psi-mi:“MI:0914”(association)	0.350
EYA4	SUPT5H	psi-mi:“MI:0914”(association)	0.350
TLE3	SIX2	psi-mi:“MI:0915”(physical association)	0.000
SIX2	TLE5	psi-mi:“MI:0915”(physical association)	0.000
TLE5	SIX2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (47): SIX2 (Affinity Capture-MS), SIX2 (Affinity Capture-MS), EYA1 (Affinity Capture-MS), EYA4 (Affinity Capture-MS), EYA3 (Affinity Capture-MS), ERCC6L (Affinity Capture-MS), PRKD1 (Affinity Capture-MS), BCDIN3D (Affinity Capture-MS), EYA2 (Affinity Capture-MS), CHMP3 (Affinity Capture-MS), CHMP1A (Affinity Capture-MS), ANKHD1 (Affinity Capture-MS), PSMG3 (Affinity Capture-MS), THNSL1 (Affinity Capture-MS), MARK2 (Affinity Capture-MS)

ESM2 similar proteins: A0A8M9QN10, A1YER0, A2ARM1, A2D5H2, E9Q0S6, O35260, O42406, O43147, O54943, O73916, O93307, O95343, O95475, P12813, P20263, P49335, P59729, Q13009, Q15475, Q1LVK9, Q5PQS0, Q5PRF9, Q5SXA9, Q5U464, Q62231, Q62232, Q62233, Q64249, Q6DHF9, Q6NXJ0, Q6NZ04, Q6TNU3, Q6ZUJ8, Q7TSI1, Q7TSZ8, Q80TC6, Q80XS6, Q8K3T2, Q8WYP3, Q91474

Diamond homologs: A1YER0, A2D5H2, A6NDR6, A8K0S8, A8WL06, B3DM47, B4F6V6, O00470, O04134, O04135, O14770, O17894, O22299, O35317, O35984, O42406, O46339, O65034, O73916, O80416, O93307, O95343, O95475, P10842, P24345, P40424, P40425, P40426, P40427, P41778, P41779, P41817, P46608, P46609, P46639, P46640, P48731, P53147, P56661, P56662

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	70
Likely benign	37
Benign	9

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2684486	GRCh37/hg19 2p21(chr2:45037498-45298668)x1	Pathogenic
393288	NM_016932.5(SIX2):c.760G>A (p.Ala254Thr)	Likely pathogenic

SpliceAI

270 predictions. Top by Δscore:

Variant	Effect	Δscore
2:45008543:A:AC	donor_gain	1.0000
2:45008544:C:CT	donor_gain	1.0000
2:45008544:CTCGT:C	donor_gain	1.0000
2:45006486:C:CC	acceptor_gain	0.9900
2:45006492:G:GC	acceptor_gain	0.9900
2:45008544:CT:C	donor_gain	0.9900
2:45008554:T:A	donor_gain	0.9900
2:45006481:TCTCC:T	acceptor_gain	0.9800
2:45006482:CTCC:C	acceptor_gain	0.9800
2:45006482:CTCCC:C	acceptor_gain	0.9800
2:45006483:TCC:T	acceptor_gain	0.9800
2:45006483:TCCCT:T	acceptor_gain	0.9800
2:45006484:CC:C	acceptor_gain	0.9800
2:45006484:CCC:C	acceptor_gain	0.9800
2:45006484:CCCTG:C	acceptor_loss	0.9800
2:45006485:CC:C	acceptor_gain	0.9800
2:45006487:T:G	acceptor_loss	0.9800
2:45006495:C:CT	acceptor_gain	0.9800
2:45008536:TCTAC:T	donor_loss	0.9800
2:45008537:CTACT:C	donor_loss	0.9800
2:45008538:TACTT:T	donor_loss	0.9800
2:45008539:AC:A	donor_loss	0.9800
2:45008540:CT:C	donor_loss	0.9800
2:45008541:TTAC:T	donor_loss	0.9800
2:45008542:TAC:T	donor_loss	0.9800
2:45008543:A:AG	donor_loss	0.9800
2:45008544:CTCG:C	donor_gain	0.9800
2:45008545:TCGTA:T	donor_loss	0.9800
2:45008546:CGTA:C	donor_loss	0.9800
2:45008547:GTAC:G	donor_loss	0.9800

AlphaMissense

1887 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:45008572:C:G	R180P	1.000
2:45008572:C:T	R180Q	1.000
2:45008573:G:A	R180W	1.000
2:45008573:G:C	R180G	1.000
2:45008575:T:A	D179V	1.000
2:45008576:C:G	D179H	1.000
2:45008578:C:A	R178L	1.000
2:45008578:C:G	R178P	1.000
2:45008578:C:T	R178H	1.000
2:45008579:G:A	R178C	1.000
2:45008579:G:C	R178G	1.000
2:45008579:G:T	R178S	1.000
2:45008580:C:A	Q177H	1.000
2:45008580:C:G	Q177H	1.000
2:45008581:T:C	Q177R	1.000
2:45008581:T:G	Q177P	1.000
2:45008582:G:T	Q177K	1.000
2:45008584:C:A	R176L	1.000
2:45008584:C:G	R176P	1.000
2:45008584:C:T	R176Q	1.000
2:45008585:G:A	R176W	1.000
2:45008585:G:C	R176G	1.000
2:45008587:C:G	R175P	1.000
2:45008588:G:C	R175G	1.000
2:45008589:G:C	N174K	1.000
2:45008589:G:T	N174K	1.000
2:45008590:T:A	N174I	1.000
2:45008590:T:C	N174S	1.000
2:45008590:T:G	N174T	1.000
2:45008591:T:A	N174Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000075535 (2:45006659 G>A), RS1000529074 (2:45010727 G>C,T), RS1000897434 (2:45011209 C>G,T), RS1001124272 (2:45005741 A>G), RS1001237437 (2:45007015 G>A), RS1002113655 (2:45005177 G>A), RS1002594544 (2:45007680 G>A), RS1002658879 (2:45006058 G>A,T), RS1002912470 (2:45008247 G>A), RS1002922576 (2:45008081 G>A), RS1003138261 (2:45008008 T>A), RS1003727325 (2:45009363 C>A), RS1003996649 (2:45009150 C>G), RS1004051576 (2:45007346 C>T), RS1004244007 (2:45008988 C>T)

Disease associations

OMIM: gene MIM:604994 | disease phenotypes: MIM:610805, MIM:157170

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital anomaly of kidney and urinary tract	Limited	Autosomal dominant

Mondo (2): congenital anomaly of kidney and urinary tract (MONDO:0019719), holoprosencephaly 2 (MONDO:0007999)

Orphanet (2): Renal or urinary tract malformation (Orphanet:93545), Holoprosencephaly (Orphanet:2162)

HPO phenotypes

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

HPO	Term
HP:0000077	Abnormality of the kidney
HP:0000256	Macrocephaly
HP:0000260	Wide anterior fontanel
HP:0000316	Hypertelorism
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000455	Broad nasal tip
HP:0000508	Ptosis
HP:0000537	Epicanthus inversus
HP:0000820	Abnormality of the thyroid gland
HP:0001263	Global developmental delay
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0002007	Frontal bossing
HP:0002693	Abnormal skull base morphology
HP:0004322	Short stature
HP:0005280	Depressed nasal bridge
HP:0005453	Absent/hypoplastic paranasal sinuses
HP:0005494	Premature posterior fontanelle closure
HP:0009119	Aplasia/Hypoplasia of the frontal sinuses
HP:0010291	Prominent palatine ridges
HP:0011330	Metopic synostosis

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001233_18	Metabolite levels	1.000000e-12
GCST002586_5	Fasting plasma glucose	3.000000e-13
GCST004748_80	Lung cancer	6.000000e-07
GCST005145_2	Glycated hemoglobin levels	9.000000e-09
GCST005913_1	Fasting blood glucose	2.000000e-08
GCST006001_19	Hemoglobin A1c levels	4.000000e-17
GCST006002_3	Blood sugar levels	7.000000e-46
GCST009426_1	Retinal arteriole-to-venule ratio	7.000000e-07
GCST009817_1	Clozapine-induced myocarditis in schizophrenia	4.000000e-07
GCST010002_389	Refractive error	3.000000e-26
GCST011587_2	Fasting blood glucose	7.000000e-25

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004541	HbA1c measurement
EFO:0004468	glucose measurement
EFO:0010554	retinal vasculature measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C566906	Cakut (supp.)
C563579	Holoprosencephaly 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, increases expression	3
propionaldehyde	increases expression	1
sodium arsenite	decreases expression	1
vanadyl sulfate	decreases expression	1
pentanal	increases expression	1
NSC 689534	decreases expression, affects binding	1
Arsenic Trioxide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Azacitidine	affects reaction, decreases expression	1
Cisplatin	affects reaction, decreases expression	1
Copper	affects binding, decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Estradiol	decreases expression	1
Formaldehyde	decreases expression	1
Lead	affects expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Antirheumatic Agents	increases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A6E8	SEES3-1V human SIX2, clone1	Embryonic stem cell	Male
CVCL_A6E9	SEES3-1V human SIX2, clone2	Embryonic stem cell	Male
CVCL_A6F0	SEES3-1V human SIX2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04115345	PHASE1	COMPLETED	A Study of a Renal Autologous Cell Therapy (REACT) in Patients With Chronic Kidney Disease (CKD) From Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
NCT05694169	PHASE1	TERMINATED	A Study of Participants With Chronic Kidney Disease Previously Treated With REACT
NCT04537364	Not specified	COMPLETED	Prediction of Renal Parenchymal Damage of CAKUT
NCT06921733	Not specified	RECRUITING	Ultrasound Localization Microscopy in Patient With Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)