PAX4

paired box 4, the group of Paired boxes|PRD class homeoboxes and pseudogenes

Basic information

Region (hg38): 7:127610291-127618142

Links

ENSG00000106331 ∙ NCBI:5078 ∙ OMIM:167413 ∙ HGNC:8618 ∙ Uniprot:O43316 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• diabetes mellitus, noninsulin-dependent (Limited), mode of inheritance: Unknown
• maturity-onset diabetes of the young (Supportive), mode of inheritance: AD
• maturity-onset diabetes of the young type 9 (Limited), mode of inheritance: Unknown
• monogenic diabetes (Refuted Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Diabetes mellitus	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Endocrine	14602731; 15509590; 17130187; 16520476; 17426099; 18292467; 21263211

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PAX4 gene.

• not provided (97 variants)
• Maturity onset diabetes mellitus in young (49 variants)
• not specified (24 variants)
• Monogenic diabetes (7 variants)
• Inborn genetic diseases (7 variants)
• Type 2 diabetes mellitus;Diabetes mellitus, ketosis-prone;Maturity-onset diabetes of the young type 9 (7 variants)
• Maturity-onset diabetes of the young type 9;Type 2 diabetes mellitus (5 variants)
• Maturity-onset diabetes of the young type 9;Type 2 diabetes mellitus;Diabetes mellitus, ketosis-prone (5 variants)
• Diabetes mellitus, ketosis-prone;Maturity-onset diabetes of the young type 9;Type 2 diabetes mellitus (5 variants)
• Type 2 diabetes mellitus (3 variants)
• PAX4-related condition (3 variants)
• Maturity-onset diabetes of the young type 9 (2 variants)
• Diabetes mellitus, ketosis-prone, susceptibility to (2 variants)
• Type 2 diabetes mellitus;Maturity-onset diabetes of the young type 9;Diabetes mellitus, ketosis-prone (1 variants)
• Hyperglycemia (1 variants)
• Type 2 diabetes mellitus;Maturity-onset diabetes of the young type 9 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PAX4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				11		11
missense			43	9		52
nonsense			2			2
start loss						0
frameshift			3			3
inframe indel			1			1
splice donor/acceptor (+/-2bp)			1			1
splice region			2	2		4
non coding			14	26	15	55
Total	0	0	64	46	15

Variants in PAX4

This is a list of pathogenic ClinVar variants found in the PAX4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
7-127610342-A-G		Maturity onset diabetes mellitus in young	Uncertain significance (Jun 14, 2016)
7-127610393-CAT-C		Maturity onset diabetes mellitus in young	Likely benign (Jun 14, 2016)
7-127610543-G-A		Maturity onset diabetes mellitus in young	Benign (Jun 14, 2016)
7-127610543-GTCAGTGT-ATCA		Maturity onset diabetes mellitus in young	Uncertain significance (Jun 14, 2016)
7-127610543-GTCA-ATCAGTGT		Maturity onset diabetes mellitus in young	Uncertain significance (Jun 14, 2016)
7-127610546-AGT-A		Maturity onset diabetes mellitus in young	Uncertain significance (Jun 14, 2016)
7-127610546-A-AGT		Maturity onset diabetes mellitus in young	Uncertain significance (Jun 14, 2016)
7-127610546-A-AGTGT		Maturity onset diabetes mellitus in young	Uncertain significance (Jun 14, 2016)
7-127610566-TGTGTGC-T		Maturity onset diabetes mellitus in young	Uncertain significance (Jun 14, 2016)
7-127610570-T-TGC		Maturity onset diabetes mellitus in young	Likely benign (Jun 14, 2016)
7-127610570-T-TGTGC		Maturity onset diabetes mellitus in young	Likely benign (Jun 14, 2016)
7-127610572-C-T		Maturity onset diabetes mellitus in young	Likely benign (Jun 14, 2016)
7-127610587-G-A		Maturity onset diabetes mellitus in young	Benign (Jun 14, 2016)
7-127610586-C-CACAT		Maturity onset diabetes mellitus in young	Benign (Jun 14, 2016)
7-127610586-C-CGCAT		Maturity onset diabetes mellitus in young	Uncertain significance (Jun 14, 2016)
7-127610587-G-GCATA		Maturity onset diabetes mellitus in young	Benign (Jun 14, 2016)
7-127610662-A-G		Maturity onset diabetes mellitus in young	Likely benign (Jun 14, 2016)
7-127610777-G-A		Maturity onset diabetes mellitus in young	Likely benign (Jun 14, 2016)
7-127610853-T-C		Maturity onset diabetes mellitus in young • Type 2 diabetes mellitus • PAX4-related disorder	Benign (Sep 05, 2021)
7-127610868-G-A		not specified	Uncertain significance (Jul 12, 2023)
7-127610872-G-A		PAX4-related disorder	Likely benign (Aug 26, 2022)
7-127610874-G-A		Maturity onset diabetes mellitus in young • not specified • PAX4-related disorder	Benign/Likely benign (Jun 26, 2019)
7-127610899-G-A		PAX4-related disorder	Likely benign (Mar 09, 2021)
7-127610998-G-A		Maturity onset diabetes mellitus in young	Uncertain significance (Jun 14, 2016)
7-127611031-T-G		Maturity onset diabetes mellitus in young	Likely benign (Aug 09, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PAX4	protein_coding	protein_coding	ENST00000341640	9	5637

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000423	0.965	125735	0	13	125748	0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.560	211	189	1.11	0.0000120	2128
Missense in Polyphen		94	81.251	1.1569		858
Synonymous	-0.651	80	72.9	1.10	0.00000362	764
Loss of Function	1.88	8	16.1	0.495	8.44e-7	173

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.000109	0.000105
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: 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.
• Disease: DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own 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. {ECO:0000269|PubMed:11723072}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, insulin-dependent (IDDM) [MIM:222100]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:15834548}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:15509590}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:17426099}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Maturity onset diabetes of the young - Homo sapiens (human) (Consensus)

Recessive Scores

• pRec: 0.215

Intolerance Scores

• loftool: 0.174
• rvis_EVS: 0.49
• rvis_percentile_EVS: 79.46

Haploinsufficiency Scores

• pHI: 0.0673
• hipred: N
• hipred_score: 0.212

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.421

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Pax4
• Phenotype: homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); growth/size/body region phenotype

Zebrafish Information Network

• Gene name: pax4
• Affected structure: pancreatic A cell
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;circadian rhythm;animal organ morphogenesis;cell differentiation;endocrine pancreas development;response to drug;negative regulation of apoptotic process;positive regulation of cell differentiation;response to cAMP;retina development in camera-type eye
• Cellular component: nucleoplasm
• Molecular function: RNA polymerase II distal enhancer sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription repressor activity, RNA polymerase II-specific;DNA binding