PAX4

Summary

PAX4 (paired box 4, HGNC:8618) is a protein-coding gene on chromosome 7q32.1, encoding Paired box protein Pax-4 (O43316). Plays an important role in the differentiation and development of pancreatic islet beta cells.

This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically contain a paired box domain, an octapeptide, and a paired-type homeodomain. These genes play critical roles during fetal development and cancer growth. The paired box 4 gene is involved in pancreatic islet development and mouse studies have demonstrated a role for this gene in differentiation of insulin-producing beta cells.

Source: NCBI Gene 5078 — RefSeq curated summary.

At a glance

• Gene–disease (curated): maturity-onset diabetes of the young (Supportive, GenCC) — +3 more curated relationships
• GWAS associations: 15
• Clinical variants (ClinVar): 204 total
• Phenotypes (HPO): 45
• MANE Select transcript: NM_001366110

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8618
Approved symbol	PAX4
Name	paired box 4
Location	7q32.1
Locus type	gene with protein product
Status	Approved
Aliases	MODY9
Ensembl gene	ENSG00000106331
Ensembl biotype	protein_coding
OMIM	167413
Entrez	5078

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 3 retained_intron

ENST00000341640, ENST00000378740, ENST00000463946, ENST00000477423, ENST00000483494, ENST00000639438, ENST00000868896

RefSeq mRNA: 2 — MANE Select: NM_001366110 NM_001366110, NM_001366111

CCDS: CCDS94190, CCDS94191

Canonical transcript exons

ENST00000639438 — 12 exons

Exon	Start	End
ENSE00000720721	127614880	127615095
ENSE00003502662	127613450	127613532
ENSE00003524498	127615916	127616027
ENSE00003530967	127614482	127614557
ENSE00003535917	127613756	127613881
ENSE00003535919	127615401	127615531
ENSE00003668001	127613022	127613091
ENSE00003675759	127611945	127612000
ENSE00003682741	127610292	127611206
ENSE00003745527	127611535	127611676
ENSE00003806665	127617962	127618142
ENSE00003811408	127617275	127617400

Expression profiles

Bgee: expression breadth broad, 32 present calls, max score 79.97.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1098 / max 172.3115, expressed in 8 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86036	0.0732	7
86035	0.0191	2
86037	0.0175	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.97	gold quality
cerebellar vermis	UBERON:0004720	69.21	gold quality
Brodmann (1909) area 10	UBERON:0013541	68.85	gold quality
endometrium epithelium	UBERON:0004811	68.64	gold quality
rectum	UBERON:0001052	61.78	gold quality
mucosa of transverse colon	UBERON:0004991	61.37	gold quality
nasal cavity epithelium	UBERON:0005384	60.21	gold quality
decidua	UBERON:0002450	58.71	gold quality
vena cava	UBERON:0004087	57.53	gold quality
parotid gland	UBERON:0001831	57.22	gold quality
sperm	CL:0000019	55.22	gold quality
male germ cell	CL:0000015	55.06	gold quality
quadriceps femoris	UBERON:0001377	53.44	gold quality
paraflocculus	UBERON:0005351	53.34	gold quality
cartilage tissue	UBERON:0002418	52.75	gold quality
metanephric glomerulus	UBERON:0004736	52.64	gold quality
hair follicle	UBERON:0002073	52.43	gold quality
vastus lateralis	UBERON:0001379	52.32	gold quality
trachea	UBERON:0003126	52.26	gold quality
duodenum	UBERON:0002114	51.94	gold quality
heart right ventricle	UBERON:0002080	51.92	gold quality
pons	UBERON:0000988	51.87	gold quality
tibialis anterior	UBERON:0001385	51.59	silver quality
thymus	UBERON:0002370	51.22	gold quality
deltoid	UBERON:0001476	51.13	silver quality
islet of Langerhans	UBERON:0000006	50.64	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
pancreatic ductal cell	CL:0002079	49.62	silver quality
oviduct epithelium	UBERON:0004804	49.62	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.12

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
ARAP1
ARX	Repression
BCL2L1	Activation
FZD8	Activation
GCG	Repression
INS	Repression
ISL1	Unknown
NXNL1	Repression
REG3A	Activation

JASPAR motifs

Motif	Name	Family
MA0068.2	PAX4	Paired plus homeo domain

JASPAR matrix evidence (PMIDs): PMID:10567552

Upstream regulators (CollecTRI, top): ARX, HNF1A, MITF, NEUROG3, REST

Literature-anchored findings (GeneRIF, showing 40)

• Beta-cell dysfunction in late-onset diabetic subjects carrying homozygous mutation in transcription factor Pax4. (PMID:12200761)
• The R121W mutation in PAX4 is a predisposing factor for the development of type 2 diabetes in Okinawans. (PMID:12604352)
• The expression of this gene is regulated by REST protein. (PMID:12829700)
• Located at 7q32 and participates downstream of ISL1 in the transcription factor cascade critical to beta-cell development. Association with type 1 diabetes was also observed using the transmission disequilibrium test for two haplotypes at the PAX4 locus. (PMID:15161765)
• The mechanism by which the beta-cell transcription factor Pax4 influences cell function/mass was studied in human islets of Langerhans. (PMID:15596543)
• Pax4 is an essential regulator of pancreatic beta-cell development [review] (PMID:15650323)
• C/C genotype of the A1168C polymorphism in PAX4 can be viewed as a predisposition marker that can help to detect individuals prone to develop type 1 diabetes. (PMID:15834548)
• A predisposition marker for susceptibility for type 1 diabetes. (PMID:15838687)
• The data indicate that the +1,168 C/A variant of PAX4 gene does not play any essential role in genetic type 1 diabetes susceptibility. (PMID:16123375)
• The Arg121Trp variant in the PAX4 gene is associated with beta cell dysfunction in Japanese subjects with type 2 diabetes. mellitus. (PMID:16423628)
• activin A enhances PAX4 expression by enhanced transactivation of E47/E12 proteins and might result in a cumulative transactivation of the promoter (PMID:16546275)
• Forced expression of the PAX4 gene in the HEK293 and SHSY/610 cell lines conferred positive effects on cell growth. This profile of PAX4 thus corresponds to that of a candidate oncogene in hematologic malignancies. (PMID:16701883)
• two possible pathogenic mutations of PAX4, R164W, and IVS7-1G>A; for one, we have shown evidence of segregation with diabetes and a functional impact on PAX4 activity and polymorphism R192H might influence the age at onset of diabetes (PMID:17426099)
• The A1168C single nucleotide polymorphism in PAX4 gene may not play an essential role in genetic T1DM susceptibility in Chinese Han population (PMID:17633464)
• Pax4 protein transduction could be a safe and valuable strategy for protecting islet cell growth in culture from apoptosis and promoting islet cell differentiation. (PMID:17717051)
• pax4 gene expression is epigenetically regulated and induced by physiological stimuli through the concerted action of multiple signalling pathways. (PMID:17989064)
• Constitutive expression of Pax4 in HESC substantially enhances their propensity to form putative beta-cells. Our findings provide a novel foundation to study the mechanism of pancreatic beta-cells differentiation during early human development (PMID:18335054)
• PAX4 has the potential to function as a tumor suppressor in human melanoma. (PMID:18949370)
• Four genes, PCSK1, (P=0.008), EGFR,(P=0.003), PAX4,(P=0.008), and LYN,(P=0.002) consistently yielded statistical evidence for association with longevity. (PMID:19641380)
• Sixteen single-nucleotide polymorphisms(SNPs) were evaluated for IRS1 and 10 for PAX4. Transmission disequilibrium testing neither show type I diabetes association of SNPs in the two genes, nor did haplotype analysis. (PMID:19956100)
• A1168C polymorphism in PAX4 gene may not play an essential role in the genetic susceptibility of the islet autoantibody-negative ketosis-prone diabetes in Chinese Han population. (PMID:20360641)
• PAX4 R192H mutation (rs2233580) was significantly associated with impaired glucose tolerance in childhood acute lymphoblastic leukemia. (PMID:20485196)
• study did not detect causal mutations in the PAX4 gene in a large group of Czech MODYX probands, which may suggest-together with data from other European populations- MODY in Caucasians could only very rarely, if ever, be attributed to PAX4 mutations (PMID:21059099)
• A novel mutation of PAX4 is likely to be associated with diabetes in this Japanese family. (PMID:21263211)
• PAX4 R192H polymorphism generated a protein with defect in transcriptional repressor activities on its target genes, which may lead to beta-cell dysfunction associated with maturity onset diabetes of the young and early onset-age of type 2 diabetes. (PMID:22521316)
• MAFA nuclear expression in pancreatic alpha and beta cells, and the percentage of alpha cells expressing PAX4 are altered in patients with type 2 diabetes. (PMID:24013263)
• Tph1 and increased EC cell number occurred before the onset of obesity and hyperleptinemi. In addition, leptin deficiency was associated with reduced Pax4 mRNA, oral leptin treatment enhanced both Tph1 and Pax4 mRNA. (PMID:24468700)
• The PAX4 variant rs6467136 was associated with the therapeutic effect of rosiglitazone in Chinese T2DM patients. (PMID:24752311)
• PAX4-miR-144/451-ADAMs axis regulates human epithelial cancer metastasis (PMID:25151965)
• These data suggest that acute PAX4 overexpression can reduce expression of aristaless related homeobox and glucagon during embryonic stem cell differentiation resulting in improved numbers of unihormonal insulin-positive cells. (PMID:25483960)
• PAX4 IVS7-1G>A contributes to the pathogenesis of diabetes in this maturity-onset diabetes of the young, type 9 family through beta-cell dysfunction (PMID:25951767)
• Viability of beta-cell was reduced under glucotoxic stress condition for the cells overexpressing either PAX4 R192H or PAX4 P321H or both. Thus these PAX4 polymorphisms may increase T2D risk by defective transcription regulation of target genes and/or decreased beta-cell survival in high glucose condition. (PMID:27334367)
• Study identified the association of a PAX4 Asian-specific missense variant rs2233580 with type 2 diabetes in an exome-chip association analysis, supporting the involvement of PAX4 in the pathogenesis of type 2 diabetes. (PMID:27744525)
• The rs10229583 polymorphism near PAX4 is associated with gestational diabetes mellitus in Chinese women. (PMID:28730907)
• genetic association studies in population in Republic of Korea: Data suggest that SNPs in PAX4 and GLP1R are associated with type 2 diabetes (T2D) in the population studied. In genome-wide associations, PAX4 Arg192His increased risk of T2D; GLP1R Arg131Gln decreased risk of T2D. (PAX4 = paired box 4 protein; GLP1R = glucagon-like peptide 1 receptor) (PMID:29941447)
• [Alternative Variants of Pax4 Human Transcription Factor: Comparative Transcriptional Activity]. (PMID:33009794)
• Transcription factor PAX4 facilitates gastric cancer progression through interacting with miR-27b-3p/Grb2 axis. (PMID:34162761)
• Evaluation of Evidence for Pathogenicity Demonstrates That BLK, KLF11, and PAX4 Should Not Be Included in Diagnostic Testing for MODY. (PMID:35108381)
• Ethnic-Specific Type 2 Diabetes Risk Factor PAX4 R192H Is Associated with Attention-Specific Cognitive Impairment in Chinese with Type 2 Diabetes. (PMID:35570489)
• Pax4 in Health and Diabetes. (PMID:37175989)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pax4	ENSMUSG00000029706
rattus_norvegicus	Pax4	ENSRNOG00000008020

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Paired box protein Pax-4 — O43316 (reviewed: O43316)

All UniProt accessions (3): O43316, A0A1W2PPX4, J3KPG0

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in the differentiation and development of pancreatic islet beta cells. Transcriptional repressor that binds to a common element in the glucagon, insulin and somatostatin promoters. Competes with PAX6 for this same promoter binding site. Isoform 2 appears to be a dominant negative form antagonizing PAX4 transcriptional activity.

Subcellular location. Nucleus.

Disease relevance. Type 2 diabetes mellitus (T2D) [MIM:125853] A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Diabetes mellitus, ketosis-prone (KPD) [MIM:612227] An atypical form of diabetes mellitus characterized by an acute initial presentation with severe hyperglycemia and ketosis, as seen in classic type 1 diabetes, but after initiation of insulin therapy, prolonged remission is often possible with cessation of insulin therapy and maintenance of appropriate metabolic control. Metabolic studies show a markedly blunted insulin secretory response to glucose, partially reversible with the improvement of blood glucose control. Variable levels of insulin resistance are observed, especially in obese patients. Pancreatic beta-cell autoimmunity is a rare finding. Disease susceptibility is associated with variants affecting the gene represented in this entry. Maturity-onset diabetes of the young 9 (MODY9) [MIM:612225] A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the paired homeobox family.

Isoforms (3)

UniProt ID	Names	Canonical?
O43316-1	1, Pax4	yes
O43316-2	2, Pax4V
O43316-4	3

RefSeq proteins (2): NP_001353039, NP_001353040 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR001523	Paired_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR043182	PAIRED_DNA-bd_site	Conserved_site
IPR043565	PAX_fam	Family

Pfam: PF00046, PF00292

UniProt features (20 total): sequence variant 9, splice variant 4, region of interest 4, DNA-binding region 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43316-F1	70.35	0.44

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-210746	Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells

MSigDB gene sets: 170 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, XU_GH1_AUTOCRINE_TARGETS_UP, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_PANCREAS_DEVELOPMENT, MODULE_66, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_ENDOCRINE_PANCREAS_DEVELOPMENT, chr7q32, GOBP_HEAD_DEVELOPMENT, GOBP_ENTEROENDOCRINE_CELL_DIFFERENTIATION, MODULE_88, RYTTCCTG_ETS2_B, GOBP_ENDOCRINE_SYSTEM_DEVELOPMENT, GOBP_SENSORY_ORGAN_DEVELOPMENT

GO Biological Process (18): type B pancreatic cell differentiation (GO:0003309), regulation of transcription by RNA polymerase II (GO:0006357), brain development (GO:0007420), sensory organ development (GO:0007423), animal organ morphogenesis (GO:0009887), forebrain development (GO:0030900), retina development in camera-type eye (GO:0060041), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), circadian rhythm (GO:0007623), response to xenobiotic stimulus (GO:0009410), cell differentiation (GO:0030154), positive regulation of epithelial cell differentiation (GO:0030858), negative regulation of apoptotic process (GO:0043066), regulation of cell differentiation (GO:0045595), negative regulation of DNA-templated transcription (GO:0045892), animal organ development (GO:0048513), response to cAMP (GO:0051591)

GO Molecular Function (6): 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 (GO:0003677), sequence-specific double-stranded DNA binding (GO:1990837), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), double-stranded DNA binding (GO:0003690)

GO Cellular Component (3): chromatin (GO:0000785), nucleoplasm (GO:0005654), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Regulation of beta-cell development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
animal organ development	3
anatomical structure development	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
DNA-templated transcription	2
cellular anatomical structure	2
endocrine pancreas development	1
enteroendocrine cell differentiation	1
central nervous system development	1
head development	1
anatomical structure morphogenesis	1
brain development	1
camera-type eye development	1
negative regulation of DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
rhythmic process	1
response to chemical	1
cellular developmental process	1
epithelial cell differentiation	1
regulation of epithelial cell differentiation	1
positive regulation of cell differentiation	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cell differentiation	1
regulation of developmental process	1
regulation of cellular process	1
negative regulation of RNA biosynthetic process	1
response to purine-containing compound	1
response to organophosphorus	1
response to oxygen-containing compound	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
nucleic acid binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1

Protein interactions and networks

STRING

1738 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAX4	NEUROD1	Q13562	940
PAX4	NEUROG3	Q9Y4Z2	921
PAX4	INS	P01308	911
PAX4	HNF1A	P20823	888
PAX4	NKX2-2	O95096	885
PAX4	ISL1	P20663	821
PAX4	GCG	P01275	811
PAX4	KLF11	O14901	803
PAX4	SLC2A2	P11168	803
PAX4	ABCC8	Q09428	765
PAX4	NXNL1	Q96CM4	753
PAX4	SST	P01166	750
PAX4	BLK	P51451	741
PAX4	RFX6	Q8HWS3	720
PAX4	PPY	P01298	720

IntAct

3 interactions, top by confidence:

A	B	Type	Score
PAX4	HNRNPU	psi-mi:“MI:0915”(physical association)	0.400
PAX4	PITRM1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (19): GMCL1 (Two-hybrid), PAX4 (Reconstituted Complex), GMCL1 (Two-hybrid), FLNC (Affinity Capture-MS), PAX4 (Two-hybrid), PAX4 (Two-hybrid), PAX4 (Two-hybrid), PAX4 (Two-hybrid), PAX4 (Two-hybrid), PAX4 (Two-hybrid), FBXO2 (Two-hybrid), NECAB1 (Two-hybrid), EIF4A3 (Two-hybrid), NME7 (Two-hybrid), NAIF1 (Two-hybrid)

ESM2 similar proteins: A0JN76, A1YGK1, A2T7E6, A8K8V0, B1WBS3, B2RXF5, O43316, O43918, O88282, O95201, O95863, P10074, P10754, P57059, Q1H9T6, Q1L8W0, Q2QGD7, Q3KNW1, Q3URR7, Q58DK7, Q5R633, Q5RJR4, Q5T619, Q6NV66, Q7ZWZ4, Q811H0, Q8BI69, Q8BXX2, Q8C8V1, Q8JZL0, Q8N143, Q8NCA9, Q8WUU4, Q91X45, Q96C55, Q96SZ4, Q99592, Q9D0B1, Q9GZV8, Q9H5J0

Diamond homologs: A0A1W2PPF3, A1YEY5, A1YFI3, A1YG57, A2T733, A2T7P4, A6NLW8, A6NNA5, F1NEA7, G5EBU4, G5EDS1, O18381, O35137, O35160, O42250, O43186, O43316, O43812, O54751, O70137, O73917, O75360, O75364, O95076, P09088, P0CJ85, P0CJ86, P0CJ87, P0CJ88, P0CJ89, P0CJ90, P21711, P22810, P26367, P26630, P29454, P32242, P32243, P34764, P34765

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	116
Likely benign	51
Benign	17

Top pathogenic / likely-pathogenic (0)

SpliceAI

1180 predictions. Top by Δscore:

Variant	Effect	Δscore
7:127615395:CATTA:C	donor_loss	1.0000
7:127615396:ATTAC:A	donor_loss	1.0000
7:127615397:TTA:T	donor_loss	1.0000
7:127615398:TACC:T	donor_loss	1.0000
7:127615400:C:A	donor_loss	1.0000
7:127613566:C:CT	acceptor_gain	0.9900
7:127613567:G:T	acceptor_gain	0.9900
7:127615603:AGGCC:A	donor_gain	0.9900
7:127611674:CTG:C	acceptor_gain	0.9800
7:127613767:G:A	donor_gain	0.9800
7:127615627:C:CT	donor_gain	0.9800
7:127615603:AGG:A	donor_gain	0.9700
7:127615603:AGGC:A	donor_gain	0.9700
7:127615644:T:A	donor_gain	0.9700
7:127614568:CAGGG:C	acceptor_gain	0.9600
7:127615093:TACCT:T	acceptor_loss	0.9500
7:127615096:CTG:C	acceptor_loss	0.9500
7:127615097:T:G	acceptor_loss	0.9500
7:127615622:TCCC:T	donor_gain	0.9500
7:127615628:C:CT	donor_gain	0.9500
7:127615639:T:TA	donor_gain	0.9500
7:127611574:TCAGA:T	donor_gain	0.9400
7:127611575:CAGAC:C	donor_gain	0.9400
7:127611576:AGACA:A	donor_gain	0.9400
7:127613879:CAG:C	acceptor_gain	0.9400
7:127615623:C:A	donor_gain	0.9400
7:127611403:CA:C	acceptor_gain	0.9300
7:127613531:CT:C	acceptor_gain	0.9300
7:127615622:T:TA	donor_gain	0.9300
7:127613725:CTCTG:C	donor_gain	0.9200

AlphaMissense

2221 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000082823 (7:127614195 T>C), RS1000151792 (7:127612928 G>A), RS1000264787 (7:127619291 C>T), RS1000331794 (7:127618663 CAG>C), RS1000830527 (7:127619605 C>T), RS1001655292 (7:127614961 A>C), RS1001724095 (7:127615229 C>A,T), RS1002007716 (7:127610021 G>A), RS1002018081 (7:127616201 G>A), RS1002047773 (7:127616476 C>T), RS1002607589 (7:127611405 T>C), RS1002896964 (7:127617209 A>T), RS1003694272 (7:127617677 G>A), RS1003726837 (7:127617913 G>A), RS1003810499 (7:127618493 A>G)

Disease associations

OMIM: gene MIM:167413 | disease phenotypes: MIM:125853, MIM:612225, MIM:612227, MIM:125850, MIM:606391

GenCC curated gene-disease

Disease	Classification	Inheritance
maturity-onset diabetes of the young	Supportive	Autosomal dominant
diabetes mellitus, noninsulin-dependent	Limited	Unknown
maturity-onset diabetes of the young type 9	Limited	Unknown
monogenic diabetes	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
monogenic diabetes	Refuted	AD

Mondo (7): type 2 diabetes mellitus (MONDO:0005148), maturity-onset diabetes of the young type 9 (MONDO:0012818), diabetes mellitus, ketosis-prone (MONDO:0100180), monogenic diabetes (MONDO:0015967), maturity-onset diabetes of the young (MONDO:0018911), hyperglycemia (MONDO:0002909), (MONDO:0007455)

Orphanet (2): MODY (Orphanet:552), Rare genetic diabetes mellitus (Orphanet:183625)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000077	Abnormality of the kidney
HP:0000103	Polyuria
HP:0000107	Renal cyst
HP:0000112	Nephropathy
HP:0000119	Abnormality of the genitourinary system
HP:0000488	Retinopathy
HP:0000819	Diabetes mellitus
HP:0000825	Hyperinsulinemic hypoglycemia
HP:0000831	Insulin-resistant diabetes mellitus
HP:0000855	Insulin resistance
HP:0000956	Acanthosis nigricans
HP:0001426	Non-Mendelian inheritance
HP:0001511	Intrauterine growth retardation
HP:0001513	Obesity
HP:0001520	Large for gestational age
HP:0001738	Exocrine pancreatic insufficiency
HP:0001952	Glucose intolerance
HP:0001953	Diabetic ketoacidosis
HP:0001959	Polydipsia
HP:0001993	Ketoacidosis
HP:0001998	Neonatal hypoglycemia
HP:0002594	Pancreatic hypoplasia
HP:0002919	Ketonuria
HP:0002960	Autoimmunity
HP:0003074	Hyperglycemia
HP:0003076	Glycosuria
HP:0003584	Late onset
HP:0004904	Maturity-onset diabetes of the young

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST001351_2	Type 2 diabetes	5.000000e-11
GCST001919_1	Type 2 diabetes	2.000000e-10
GCST003400_39	Type 2 diabetes	8.000000e-10
GCST007515_30	Type 2 diabetes	2.000000e-12
GCST007516_24	Type 2 diabetes (adjusted for BMI)	4.000000e-13
GCST007847_114	Type 2 diabetes	1.000000e-08
GCST007847_31	Type 2 diabetes	4.000000e-74
GCST009356_10	Nonsyndromic cleft palate	6.000000e-09
GCST009391_580	Metabolite levels	1.000000e-06
GCST010118_154	Type 2 diabetes	3.000000e-31
GCST010118_155	Type 2 diabetes	3.000000e-132
GCST010118_156	Type 2 diabetes	5.000000e-105
GCST010136_49	Fruit consumption	9.000000e-10
GCST010436_1	Type 2 diabetes	2.000000e-10
GCST90013421_16	Left-handedness	6.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0010501	indole-3-propionate measurement
EFO:0008111	diet measurement
EFO:0009902	handedness

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
D006943	Hyperglycemia	C18.452.394.952
C562772	Mason-Type Diabetes (supp.)
C567393	Maturity-Onset Diabetes Of The Young, Type 9 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs114202595	Efficacy	3	repaglinide	Diabetes Mellitus
rs6467136	Efficacy	3	rosiglitazone	Diabetes Mellitus;Type 2

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6467136	PAX4	3	5.25	1	rosiglitazone
rs10229583	PAX4		0.00	0
rs114202595	PAX4	3	1.50	1	repaglinide

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Azacitidine	increases expression	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Vitamin E	decreases expression	1
Aflatoxin B1	decreases methylation	1
Magnetite Nanoparticles	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A5D5	SEES3-1V human PAX4, clone1	Embryonic stem cell	Male
CVCL_A5D6	SEES3-1V human PAX4, clone2	Embryonic stem cell	Male
CVCL_A5D7	SEES3-1V human PAX4, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus