PAX5

Summary

PAX5 (paired box 5, HGNC:8619) is a protein-coding gene on chromosome 9p13.2, encoding Paired box protein Pax-5 (Q02548). Transcription factor that plays an essential role in commitment of lymphoid progenitors to the B-lymphocyte lineage.

This gene encodes a member of the paired box (PAX) family of transcription factors. The central feature of this gene family is a novel, highly conserved DNA-binding motif, known as the paired box. Paired box transcription factors are important regulators in early development, and alterations in the expression of their genes are thought to contribute to neoplastic transformation. This gene encodes the B-cell lineage specific activator protein that is expressed at early, but not late stages of B-cell differentiation. Its expression has also been detected in developing CNS and testis and so the encoded protein may also play a role in neural development and spermatogenesis. This gene is located at 9p13, which is involved in t(9;14)(p13;q32) translocations recurring in small lymphocytic lymphomas of the plasmacytoid subtype, and in derived large-cell lymphomas. This translocation brings the potent E-mu enhancer of the IgH gene into close proximity of the PAX5 promoter, suggesting that the deregulation of transcription of this gene contributes to the pathogenesis of these lymphomas. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 5079 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukemia, acute lymphoblastic, susceptibility to, 3 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 500 total — 2 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 1
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• Transcription factor: yes — 73 downstream targets (CollecTRI)
• MANE Select transcript: NM_016734

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8619
Approved symbol	PAX5
Name	paired box 5
Location	9p13.2
Locus type	gene with protein product
Status	Approved
Aliases	BSAP, PAX-5
Ensembl gene	ENSG00000196092
Ensembl biotype	protein_coding
OMIM	167414
Entrez	5079

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 14 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000358127, ENST00000377840, ENST00000377847, ENST00000377852, ENST00000377853, ENST00000414447, ENST00000446742, ENST00000520083, ENST00000520154, ENST00000520281, ENST00000522003, ENST00000522932, ENST00000523145, ENST00000523241, ENST00000523493, ENST00000524340, ENST00000651199, ENST00000651550

RefSeq mRNA: 11 — MANE Select: NM_016734 NM_001280547, NM_001280548, NM_001280549, NM_001280550, NM_001280551, NM_001280552, NM_001280553, NM_001280554, NM_001280555, NM_001280556, NM_016734

CCDS: CCDS65039, CCDS65040, CCDS65041, CCDS65042, CCDS65043, CCDS65044, CCDS65045, CCDS65046, CCDS65047, CCDS65048, CCDS6607

Canonical transcript exons

ENST00000358127 — 10 exons

Exon	Start	End
ENSE00000928305	36923355	36923484
ENSE00001148771	36966549	36966724
ENSE00001148776	37002648	37002776
ENSE00001662228	37006473	37006537
ENSE00001700848	37020636	37020801
ENSE00001860138	36833269	36840636
ENSE00003486280	37014997	37015194
ENSE00003636861	36882004	36882105
ENSE00003660361	36846843	36846929
ENSE00003843207	37033986	37034268

Expression profiles

Bgee: expression breadth ubiquitous, 131 present calls, max score 97.60.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.7407 / max 317.2535, expressed in 155 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100715	0.4617	55
100718	0.3949	67
100716	0.2042	45
100709	0.1846	54
100707	0.1364	53
100704	0.0969	33
100708	0.0879	41
100714	0.0757	24
100717	0.0582	26
100706	0.0401	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.60	gold quality
epithelium of nasopharynx	UBERON:0001951	90.78	gold quality
lymph node	UBERON:0000029	89.73	gold quality
vermiform appendix	UBERON:0001154	86.56	gold quality
type B pancreatic cell	CL:0000169	86.02	gold quality
caecum	UBERON:0001153	83.43	gold quality
olfactory bulb	UBERON:0002264	83.00	gold quality
bone marrow cell	CL:0002092	81.78	gold quality
spleen	UBERON:0002106	81.69	gold quality
ileal mucosa	UBERON:0000331	80.77	gold quality
bone marrow	UBERON:0002371	79.80	gold quality
granulocyte	CL:0000094	77.66	gold quality
blood	UBERON:0000178	76.96	gold quality
tonsil	UBERON:0002372	76.88	gold quality
trabecular bone tissue	UBERON:0002483	75.90	gold quality
diaphragm	UBERON:0001103	75.76	gold quality
cervix squamous epithelium	UBERON:0006922	75.74	gold quality
superficial temporal artery	UBERON:0001614	75.18	gold quality
vastus lateralis	UBERON:0001379	74.82	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	74.31	gold quality
quadriceps femoris	UBERON:0001377	73.77	gold quality
tongue squamous epithelium	UBERON:0006919	72.88	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	72.72	gold quality
cervix epithelium	UBERON:0004801	72.19	gold quality
superior surface of tongue	UBERON:0007371	71.86	gold quality
periodontal ligament	UBERON:0008266	71.59	silver quality
triceps brachii	UBERON:0001509	71.41	gold quality
substantia nigra pars compacta	UBERON:0001965	71.34	silver quality
gluteal muscle	UBERON:0002000	71.23	gold quality
nipple	UBERON:0002030	70.56	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	429.74
E-MTAB-6911	yes	301.47
E-CURD-112	yes	41.26
E-ANND-3	yes	23.19
E-MTAB-9067	yes	20.28
E-CURD-122	yes	18.75
E-MTAB-9221	yes	17.49

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

73 targets.

Target	Regulation
ABL1
AICDA	Activation
ATP11C
BACH2	Unknown
BAX	Activation
BCL2	Repression
BCR
BGLAP	Repression
BLK	Repression
BLNK	Unknown
CCND1	Repression
CD19	Activation
CD72	Activation
CD79A	Activation
CDKN1A	Activation
CEL
CR1	Unknown
CR2	Unknown
CSF1R	Repression
CTNNB1	Activation
DLEU2
EBF1	Activation
EXOSC1
FCER2	Unknown
FDPS	Unknown
FGF8
FHL2	Activation
FLT3
GADD45A
GSTM1

JASPAR motifs

Motif	Name	Family
MA0014.2	PAX5	Paired domain only
MA0014.3	PAX5	Paired domain only
MA0014.4	PAX5	Paired domain only

JASPAR matrix evidence (PMIDs): PMID:8406007

Upstream regulators (CollecTRI, top): AHR, CEBPA, EBF1, IL21, LEF1, MTA1, PAX2, PAX5, PRDM1, SOX11, SPI1, STAT5A, STAT5B, TCF3, TP53

miRNA regulators (miRDB)

396 targeting PAX5, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4510	100.00	66.60	2050
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-9-5P	100.00	72.28	2361
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-432-3P	100.00	67.86	705
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-186-5P	99.99	70.83	3707
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6870-5P	99.99	68.55	2115

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• interaction with Daxx resulting in transcriptional activation in B cells (PMID:11799127)
• were expressed by human PCs following a gradient of increasing maturity in the direction: tonsil–>blood–>BM (PMID:11877292)
• Multiple isoforms of Pax5 & low levels of the full-length Pax5 were seen in B cells from MM patients. Premature Blimp-1 expression & altered, deficient Pax5 expression causes some proliferating B cells to prematurely differentiate to plasma cells. (PMID:12453881)
• The frequent expression of B-cell-specific activator protein (BSAP)in Reed-Sternberg (H/RS) cells of classical Hodgkin’s disease provides further evidence for its B-cell origin and helps to identify H/RS cells. (PMID:12609061)
• Retrovirally expressed human Pax-5 protein activates endogenous early B-cell-specific mb-1 genes in mouse plasmacytoma cells, but only when the promoter is hypomethylated. (PMID:12612069)
• Pax-5 is a key regulator of the B-cell-restricted expression of the CD23a isoform. (PMID:12731041)
• Isoform expression is modulated by specific signaling pathways in B lymphocytes. (PMID:15385562)
• Results indicate that PAX5 is a more specific marker than CD79a for B-cell ALL diagnosis. (PMID:15492262)
• Expression of mRNA for a newly identified Pax5 exon is reduced in multiple myeloma (PMID:16518692)
• In both Richter’s transformation and prolymphocytic transformation, high-levels of AID mRNA expression and high-frequency mutations of Pax-5 protein genes were detected. (PMID:16541139)
• These findings indicate a direct activating function for Pax5 in RAG-mediated immunoglobulin V(H)-to-DJ(H) recombination. (PMID:16680144)
• Results confirm that Pax-5 is expressed regularly in poorly differentiated neuroendocrine tumors. (PMID:17050077)
• Pax5 maintains cellular identity by repressing gene expression throughout B cell differentiation [review] (PMID:17102626)
• BSAP can probably contribute to T-cell lymphomagenesis not only in vitro, but also in vivo. It is rarely expressed in peripheral T-cell lymphoma, thus its detection on lymphoid malignancies cannot be considered definitively lineage specific. (PMID:17431414)
• PAX5 mutation is associated with splenic and nodal marginal zone B-cell lymphomas (PMID:17476282)
• PAX5 is a useful immunohistologic marker for the interrogation of undifferentiated neoplasms. It is an extremely specific marker of the B lineage. (PMID:17529924)
• PAX5 was identified as a useful tumor marker for the diagnosis of pediatric large cell lymphoma. (PMID:17535098)
• EBV ensures the B-cell specificity of its growth-transforming function by exploiting BSAP/Pax5 as a lineage-specific activator of the transforming program. (PMID:17626071)
• Simultaneous nuclear expression of the transcription factor gene PAX5 suggested that this major driver of B-cell differentiation did not preclude expression of CD3epsilon (PMID:17635241)
• Repression of PRDM1 by BSAP reveals an autoregulatory negative-feedback loop that could play a relevant role in controlling human PC differentiation. (PMID:17682124)
• stimulation of neoplastic growth by Pax5 occurs through B cell receptor and is sensitive to genetic and pharmacological inhibitors of this pathway (PMID:17717600)
• that transcription factors Xbp-1, Blimp-1, and PAX-5-encoded BSAP play important roles in the regulation of plasmacytic differentiation and exert their effects on differentiation induced by low 2ME2 concentrations (PMID:18192112)
• PAX-5 is a useful marker for the discrimination of low- to intermediate-grade pulmonary neuroendocrine neoplasms from high-grade ones. (PMID:18343782)
• Pax5 transgene may not interfere with their differentiation (PMID:18415655)
• Pax-5 protein expression is infrequent in bladder cancer (PMID:18604731)
• Pax-5B suppression led to an increase of CD19 mRNA and cell surface protein expression. (PMID:18617575)
• PAX-5 is the most sensitive and reliable immunohistochemical marker for B-cell malignancies (PMID:18643853)
• pax5 plays an important role in late differentiation of B cells, and may participate in signal transduction of lymphoma cells. (PMID:18718064)
• I.v. injection of an anti-PAX5 CTL clone into immunodeficient mice bearing s.c. human tumors resulted in specific growth inhibition of PAX5-expressing tumors. (PMID:18829564)
• deletion and mutation of the homologous PAX5 allele, providing further support for the key role of PAX5 in unbalanced translocations in cancer (PMID:18957548)
• several novel PAX5 partner genes not only comprise transcription factors but also structural proteins and genes involved in signal transduction, which at least in part have not been implicated in tumorigenesis. (PMID:19020546)
• PAX 5 expression was evaluated in small cell lung cancer and other cancers; determined that PAX5 could regulate the transcription of c-Met; PAX5 protein expression was relatively strong in small-cell lung cancer; expression was not detected in non-SCLC (PMID:19139719)
• PAX-5 immunoreactivity identifies alveolar rhabdomyosarcoma. (PMID:19145202)
• The role of PAX5 gene methylation in the pathogenesis of rare lymphoid neoplasms coexpressing B- and T-cell antigens is reported. (PMID:19368954)
• SWI/SNF and Mi-2/NuRD function in opposition to enable or limit the reprogramming of genes by EBF and Pax5 during B-cell development. (PMID:19549820)
• Data show that sequences 3’ of PAX5 disrupting ASXL1, and ZCCHC7 disrupted by sequences 3’ of FRG1B and LOC1499503. (PMID:19586940)
• PAX5 is mutated in 34% of adult B-cell progenitor acute lymphoblastic leukemia (PMID:19587702)
• The authors report that Pax5 assembles the ternary complexes with DNA via highly cooperative interactions that overcome the autoinhibition of Ets-1. (PMID:19616560)
• It is tempting to speculate, therefore, that PAX5 expression in alveolar rhabdomyosarcoma may identify a more aggressive subset of tumors (PMID:19641453)
• PAX5 has the greatest diagnostic usefulness and lineage determination in B-acute lympho- blastic leukemia, especially in cases with an inadequate specimen for flow cytometric analysis. (PMID:20023257)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pax5	ENSDARG00000037383
mus_musculus	Pax5	ENSMUSG00000014030
rattus_norvegicus	Pax5	ENSRNOG00000024729

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), 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)

Protein

Protein identifiers

Paired box protein Pax-5 — Q02548 (reviewed: Q02548)

Alternative names: B-cell-specific transcription factor

All UniProt accessions (7): C0KTE2, E7EQT0, E7ERK2, E7ERW5, E7ES87, Q02548, H0YB47

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that plays an essential role in commitment of lymphoid progenitors to the B-lymphocyte lineage. Fulfills a dual role by repressing B-lineage inappropriate genes and simultaneously activating B-lineage-specific genes. In turn, regulates cell adhesion and migration, induces V(H)-to-D(H)J(H) recombination, facilitates pre-B-cell receptor signaling and promotes development to the mature B-cell stage. Repression of the cohesin-release factor WAPL causes global changes of the chromosomal architecture in pro-B cells to facilitate the generation of a diverse antibody repertoire. (Microbial infection) Plays an essential role in the maintenance of Epstein-Barr virus genome copy number within the host cell by promoting EBNA1/oriP-dependent binding and transcription. Also participates in the inhibition of lytic EBV reactivation by modulating viral BZLF1 activity.

Subunit / interactions. Interacts with ETS1; this interaction alters PAX5 DNA-binding properties. Binds DNA as a monomer. Interacts with TBP; this interaction allows PAX5 to interact with the basal transcription machinery. Interacts with RB1. Interacts with TLE4. Interacts with DAXX. (Microbial infection) Interacts (via N-terminus) with Epstein-Barr virus protein BZLF1 (via C-terminus); this interaction inhibits BZLF1-mediated lytic viral reactivation. Interacts also with EBNA1; this interaction promotes EBNA1-dependent transcription.

Subcellular location. Nucleus.

Post-translational modifications. O-glycosylated. Phosphorylated by SYK. This phosphorylation plays an important role in the abolition of BLIMP1 repression by PAX5 in order to trigger plasma cell differentiation.

Disease relevance. A chromosomal aberration involving PAX5 is a cause of acute lymphoblastic leukemia. Translocation t(9;18)(p13;q11.2) with ZNF521. Translocation t(9;3)(p13;p14.1) with FOXP1. Translocation t(9;12)(p13;p13) with ETV6. Leukemia, acute lymphoblastic, 3 (ALL3) [MIM:613065] A subtype of acute leukemia, a cancer of the white blood cells. Acute lymphoblastic anemia is a malignant disease of bone marrow and the most common malignancy diagnosed in children. The malignant cells are lymphoid precursor cells (lymphoblasts) that are arrested in an early stage of development. The lymphoblasts replace the normal marrow elements, resulting in a marked decrease in the production of normal blood cells. Consequently, anemia, thrombocytopenia, and neutropenia occur to varying degrees. The lymphoblasts also proliferate in organs other than the marrow, particularly the liver, spleen, and lymphnodes. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Isoforms (11)

UniProt ID	Names	Canonical?
Q02548-1	1	yes
Q02548-2	2, delta9
Q02548-3	3, delta78
Q02548-4	4, delta789
Q02548-5	5, delta8
Q02548-6	6, delta7
Q02548-7	7
Q02548-8	8
Q02548-9	9
Q02548-10	10
Q02548-11	11

RefSeq proteins (11): NP_001267476, NP_001267477, NP_001267478, NP_001267479, NP_001267480, NP_001267481, NP_001267482, NP_001267483, NP_001267484, NP_001267485, NP_057953* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001523	Paired_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR022130	Pax2_C	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR043182	PAIRED_DNA-bd_site	Conserved_site
IPR043565	PAX_fam	Family

Pfam: PF00292, PF12403

UniProt features (48 total): sequence variant 16, splice variant 13, helix 6, region of interest 4, site 3, sequence conflict 2, chain 1, DNA-binding region 1, strand 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1K78	X-RAY DIFFRACTION	2.25
1MDM	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02548-F1	63.89	0.30

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 158–159 (breakpoint for translocation to form pax5-etv6); 260–261 (breakpoint for translocation to form pax5-foxp1); 303–304 (breakpoint for translocation to form pax5-znf521)

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8939245	RUNX1 regulates transcription of genes involved in BCR signaling

MSigDB gene sets: 306 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, MCLACHLAN_DENTAL_CARIES_UP, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_B_CELL_ACTIVATION, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_ADULT_BEHAVIOR, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, SCHLESINGER_METHYLATED_DE_NOVO_IN_CANCER, GOBP_MALE_GAMETE_GENERATION, GOBP_VENTRICULAR_SYSTEM_DEVELOPMENT, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (15): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), spermatogenesis (GO:0007283), nervous system development (GO:0007399), sensory organ development (GO:0007423), lateral ventricle development (GO:0021670), cerebral cortex development (GO:0021987), B cell differentiation (GO:0030183), adult behavior (GO:0030534), skeletal muscle cell differentiation (GO:0035914), embryonic cranial skeleton morphogenesis (GO:0048701), regulation of DNA-templated transcription (GO:0006355), cell differentiation (GO:0030154), positive regulation of transcription by RNA polymerase II (GO:0045944)

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 transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

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

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transcriptional regulation by RUNX1	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
DNA-templated transcription	2
anatomical structure development	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
developmental process involved in reproduction	1
male gamete generation	1
system development	1
animal organ development	1
telencephalon development	1
ventricular system development	1
pallium development	1
lymphocyte differentiation	1
B cell activation	1
behavior	1
skeletal muscle tissue development	1
cell differentiation	1
embryonic skeletal system morphogenesis	1
cranial skeletal system development	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cellular developmental process	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
chromosome	1
nuclear lumen	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2494 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAX5	EBF1	Q9UH73	983
PAX5	ETS1	P14921	958
PAX5	IKZF1	Q13422	949
PAX5	IRF4	Q15306	945
PAX5	BCL6	P41182	931
PAX5	PRDM1	O75626	908
PAX5	CD79A	P11912	907
PAX5	IGHV4-38-2	P0DP08	887
PAX5	IKZF3	Q9UKT9	880
PAX5	TLE4	Q04727	876
PAX5	CD19	P15391	857
PAX5	TCF3	P15883	856
PAX5	AICDA	Q9GZX7	851
PAX5	RHOH	Q15669	847
PAX5	MME	P08473	843

IntAct

146 interactions, top by confidence:

A	B	Type	Score
PAX5	ZMYM5	psi-mi:“MI:0915”(physical association)	0.560
PAX5	AIRIM	psi-mi:“MI:0915”(physical association)	0.560
MAPK9	PAX5	psi-mi:“MI:0915”(physical association)	0.560
PAX5	GNG13	psi-mi:“MI:0915”(physical association)	0.560
UBXN7	PAX5	psi-mi:“MI:0915”(physical association)	0.560
PAX5	KLHL38	psi-mi:“MI:0915”(physical association)	0.560
PAX5	SAE1	psi-mi:“MI:0915”(physical association)	0.560
PAX5	NGLY1	psi-mi:“MI:0915”(physical association)	0.560
PAX5	ACOT12	psi-mi:“MI:0915”(physical association)	0.560
HMGB3	PAX5	psi-mi:“MI:0915”(physical association)	0.560
PAX5	CIB3	psi-mi:“MI:0915”(physical association)	0.560
PAX5	DTX2	psi-mi:“MI:0915”(physical association)	0.560
CCNC	PAX5	psi-mi:“MI:0915”(physical association)	0.560
PAX5	STAC	psi-mi:“MI:0915”(physical association)	0.560
BCAS2	PAX5	psi-mi:“MI:0915”(physical association)	0.560
PAX5	LDLRAP1	psi-mi:“MI:0915”(physical association)	0.560
PAX5	LONRF1	psi-mi:“MI:0915”(physical association)	0.560
OSGIN1	PAX5	psi-mi:“MI:0915”(physical association)	0.560
HGS	PAX5	psi-mi:“MI:0915”(physical association)	0.560
HOXC8	PAX5	psi-mi:“MI:0915”(physical association)	0.560
PAX5	NEIL2	psi-mi:“MI:0915”(physical association)	0.560
PAX5	LARP4	psi-mi:“MI:0915”(physical association)	0.560
PAX5	TLK2	psi-mi:“MI:0915”(physical association)	0.560
CSNK2A1	PAX5	psi-mi:“MI:0915”(physical association)	0.560
CDK3	PAX5	psi-mi:“MI:0915”(physical association)	0.560
FBLN1	PAX5	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	PAX5	psi-mi:“MI:0915”(physical association)	0.560
PAX5	HMBOX1	psi-mi:“MI:0915”(physical association)	0.560
PAX5	GRHL2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (112): TLE4 (Two-hybrid), PAX5 (Biochemical Activity), KAT2B (Affinity Capture-Western), CDKN1B (Affinity Capture-Western), PAX5 (Two-hybrid), PAX5 (Two-hybrid), PAX5 (Two-hybrid), PAX5 (Two-hybrid), PAX5 (Two-hybrid), PAX5 (Two-hybrid), PAX5 (Two-hybrid), PAX5 (Two-hybrid), PAX5 (Two-hybrid), PAX5 (Two-hybrid), PAX5 (Two-hybrid)

ESM2 similar proteins: A0JMA6, O08656, O57682, O57685, P06601, P09022, P23759, P23760, P24610, P32114, P47239, P47240, P47242, P49639, P51974, P55166, P55771, P70056, Q00288, Q02548, Q02650, Q02962, Q06710, Q0IH87, Q28D67, Q28DP6, Q2L4T2, Q2VL50, Q2VL51, Q2VL52, Q2VL53, Q2VL54, Q2VL57, Q2VL58, Q2VL59, Q2VL60, Q2VL62, Q32NP8, Q5R9M8, Q645N4

Diamond homologs: A0JMA6, G5ED14, G5ED66, G5EDS1, O18381, O43316, O57682, O57685, O73917, O88436, P06601, P09082, P09083, P09084, P15863, P23757, P23758, P23759, P23760, P24610, P26367, P26630, P32114, P32115, P47236, P47238, P47239, P47240, P47242, P51974, P55166, P55771, P55864, P63015, P63016, Q00288, Q02548, Q02650, Q02962, Q06710

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
IL21	“up-regulates quantity by expression”	PAX5	“transcriptional regulation”
PAX5	“down-regulates activity”	BZLF1	binding
PAX5	“down-regulates activity”	TLE4	binding
SYK	“down-regulates activity”	PAX5	phosphorylation
MAPK3	“down-regulates activity”	PAX5	phosphorylation
MAPK1	“down-regulates activity”	PAX5	phosphorylation
ERK1/2	“down-regulates activity”	PAX5	phosphorylation
PRDM1	“down-regulates quantity by repression”	PAX5	“transcriptional regulation”
PAX5	“down-regulates quantity”	PRDM1	“transcriptional regulation”
PRDM1	“down-regulates quantity”	PAX5	“transcriptional regulation”

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — DLBCLNOS, PRAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	13
Uncertain significance	218
Likely benign	215
Benign	32

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1210156	NM_016734.3(PAX5):c.157G>C (p.Asp53His)	Pathogenic
1210158	NM_016734.3(PAX5):c.661C>T (p.Arg221Trp)	Pathogenic
2580248	NM_016734.3(PAX5):c.77T>G (p.Val26Gly)	Likely pathogenic
2580249	NM_016734.3(PAX5):c.401C>G (p.Ser134Cys)	Likely pathogenic
2580251	NM_016734.3(PAX5):c.1074del (p.Ser357_Trp358insTer)	Likely pathogenic
2580252	NM_016734.3(PAX5):c.613G>T (p.Glu205Ter)	Likely pathogenic
2580257	NM_016734.3(PAX5):c.46+1G>A	Likely pathogenic
2580264	NM_016734.3(PAX5):c.1073G>A (p.Trp358Ter)	Likely pathogenic
2580271	NM_016734.3(PAX5):c.388C>A (p.Pro130Thr)	Likely pathogenic
2580272	NM_016734.3(PAX5):c.967G>T (p.Gly323Ter)	Likely pathogenic
2580273	NM_016734.3(PAX5):c.134_147del (p.Ala45fs)	Likely pathogenic
2580274	NM_016734.3(PAX5):c.963dup (p.Ala322fs)	Likely pathogenic
2580275	NM_016734.3(PAX5):c.263dup (p.Val90fs)	Likely pathogenic
2637935	NM_016734.3(PAX5):c.963del (p.Ala322fs)	Likely pathogenic
624590	NM_016734.3(PAX5):c.239C>G (p.Pro80Arg)	Likely pathogenic

SpliceAI

2855 predictions. Top by Δscore:

Variant	Effect	Δscore
9:36923349:CCTCA:C	donor_loss	1.0000
9:36923350:CTCAC:C	donor_loss	1.0000
9:36923351:TCAC:T	donor_loss	1.0000
9:36923352:CA:C	donor_loss	1.0000
9:36923354:C:CT	donor_loss	1.0000
9:36923354:CCTG:C	donor_gain	1.0000
9:36923482:GGTC:G	acceptor_loss	1.0000
9:36923485:C:CC	acceptor_gain	1.0000
9:36923486:T:C	acceptor_loss	1.0000
9:36966543:GCGTA:G	donor_loss	1.0000
9:36966544:CGTA:C	donor_loss	1.0000
9:36966545:GTAC:G	donor_loss	1.0000
9:36966546:TACC:T	donor_loss	1.0000
9:36966547:ACCT:A	donor_loss	1.0000
9:36966548:C:CT	donor_loss	1.0000
9:36966548:CCTG:C	donor_gain	1.0000
9:36966722:TAC:T	acceptor_gain	1.0000
9:36966724:CCTT:C	acceptor_gain	1.0000
9:36966727:T:C	acceptor_gain	1.0000
9:36966727:T:TC	acceptor_gain	1.0000
9:36966730:A:AC	acceptor_gain	1.0000
9:36966735:C:CT	acceptor_gain	1.0000
9:36966736:A:T	acceptor_gain	1.0000
9:37002642:TCTTA:T	donor_loss	1.0000
9:37002643:CTTA:C	donor_loss	1.0000
9:37002644:TTAC:T	donor_loss	1.0000
9:37002645:TA:T	donor_loss	1.0000
9:37002646:A:AC	donor_gain	1.0000
9:37002647:C:A	donor_loss	1.0000
9:37002647:C:CC	donor_gain	1.0000

AlphaMissense

2528 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:37002698:A:T	L185Q	1.000
9:37002701:A:C	I184S	1.000
9:37002701:A:G	I184T	1.000
9:37002710:A:T	I181N	1.000
9:37006529:C:G	R140P	1.000
9:37006530:G:A	R140W	1.000
9:37006530:G:C	R140G	1.000
9:37006532:A:C	I139S	1.000
9:37006532:A:G	I139T	1.000
9:37006532:A:T	I139N	1.000
9:37006535:A:C	I138S	1.000
9:37006535:A:G	I138T	1.000
9:37006535:A:T	I138N	1.000
9:37006537:C:A	R137S	1.000
9:37006537:C:G	R137S	1.000
9:37014997:C:A	R137M	1.000
9:37014997:C:G	R137T	1.000
9:37014998:T:A	R137W	1.000
9:37014998:T:C	R137G	1.000
9:37014999:G:C	N136K	1.000
9:37014999:G:T	N136K	1.000
9:37015000:T:A	N136I	1.000
9:37015001:T:C	N136D	1.000
9:37015003:A:C	I135S	1.000
9:37015003:A:G	I135T	1.000
9:37015003:A:T	I135N	1.000
9:37015004:T:A	I135F	1.000
9:37015006:G:A	S134F	1.000
9:37015006:G:C	S134C	1.000
9:37015006:G:T	S134Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000018963 (9:37025442 G>A,T), RS1000034871 (9:37030171 G>A), RS1000094846 (9:36863281 A>G), RS1000105042 (9:36833921 C>T), RS1000111496 (9:36984657 T>C), RS1000133330 (9:36991649 G>A), RS1000139571 (9:36978468 C>T), RS1000144419 (9:36952938 C>T), RS1000145206 (9:36924924 T>G), RS1000181358 (9:36926015 G>A), RS1000198331 (9:36886040 T>G), RS1000198741 (9:37020123 T>C), RS1000202012 (9:36858197 G>C), RS1000211641 (9:37013335 A>T), RS1000221175 (9:36908749 C>T)

Disease associations

OMIM: gene MIM:167414 | disease phenotypes: MIM:615545

GenCC curated gene-disease

Disease	Classification	Inheritance
leukemia, acute lymphoblastic, susceptibility to, 3	Definitive	Autosomal dominant
neurodevelopmental disorder	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
PAX5-related B lymphopenia and autism spectrum disorder	Moderate	AR
leukemia, acute lymphoblastic, susceptibility to, 3	Definitive	AD

Mondo (3): leukemia, acute lymphoblastic, susceptibility to, 3 (MONDO:0014241), neurodevelopmental disorder (MONDO:0700092), acute lymphoblastic leukemia (MONDO:0004967)

Orphanet (1): Acute lymphoblastic leukemia (Orphanet:513)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0006721	Acute lymphoblastic leukemia

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001288_1	Obesity-related traits	9.000000e-09
GCST001288_3	Obesity-related traits	5.000000e-06
GCST001428_4	Intelligence	4.000000e-08
GCST002818_5	HIV-1 susceptibility	4.000000e-07
GCST002818_7	HIV-1 susceptibility	5.000000e-07
GCST006041_10	Major depressive disorder	1.000000e-08
GCST006097_8	Moderate to vigorous physical activity levels	4.000000e-09
GCST006281_10	Coronary artery disease in type 1 diabetes	6.000000e-07
GCST007565_167	Morning person	2.000000e-16
GCST007600_75	Alzheimer’s disease	4.000000e-06
GCST008573_6	Composite immunoglobulin trait (IgA/IgM)	4.000000e-08
GCST010988_396	Adult body size	1.000000e-08
GCST011767_1	Bipolar disorder	3.000000e-09
GCST012316_10	ghrelin levels	8.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004337	intelligence
EFO:0000180	HIV-1 infection
EFO:0008002	physical activity measurement
EFO:0008328	chronotype measurement
EFO:0600001	ghrelin measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, increases expression	2
entinostat	increases expression, affects cotreatment	2
Fulvestrant	affects cotreatment, increases methylation, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Aflatoxin B1	affects methylation, decreases methylation	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
triphenyl phosphate	affects expression	1
arsenite	increases methylation	1
sodium arsenite	increases expression	1
aflatoxin B2	affects methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
GW 7604	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	affects binding, decreases reaction, decreases expression	1
SGI-1027	increases expression, increases reaction, decreases methylation	1
Capecitabine	decreases expression	1
Irinotecan	decreases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Cadmium	increases abundance, decreases expression	1
Coal	increases abundance, increases expression	1
Cyclophosphamide	decreases methylation, affects reaction, decreases expression, increases cleavage, increases expression (+1 more)	1
Dexamethasone	affects expression	1
Estradiol	affects cotreatment, increases expression	1
Lipopolysaccharides	increases expression, decreases reaction	1
Progesterone	affects cotreatment, increases expression	1
Smoke	increases abundance, increases expression	1

Cellosaurus cell lines

14 cell lines: 10 cancer cell line, 3 embryonic stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_3039	NALL-1	Cancer cell line	Male
CVCL_A5D8	SEES3-1V human PAX5, clone1	Embryonic stem cell	Male
CVCL_A5D9	SEES3-1V human PAX5, clone2	Embryonic stem cell	Male
CVCL_A5E0	SEES3-1V human PAX5, clone3	Embryonic stem cell	Male
CVCL_B8M1	Abcam HCT 116 PAX5 KO	Cancer cell line	Male
CVCL_B8ZY	Abcam MCF-7 PAX5 KO	Cancer cell line	Female
CVCL_B9P8	Abcam A-549 PAX5 KO	Cancer cell line	Male
CVCL_C7Y1	HAP1 PAX5 (-) 1	Cancer cell line	Male
CVCL_C7Y2	HAP1 PAX5 (-) 2	Cancer cell line	Male
CVCL_D3Z2	KOPN-75	Cancer cell line	Sex unspecified

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice