HMGXB4

Summary

HMGXB4 (HMG-box containing 4, HGNC:5003) is a protein-coding gene on chromosome 22q12.3, encoding HMG domain-containing protein 4 (Q9UGU5). Negatively regulates Wnt/beta-catenin signaling during development.

High mobility group (HMG) proteins are nonhistone chromosomal proteins. See HMG2 (MIM 163906) for additional information on HMG proteins.

Source: NCBI Gene 10042 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 68 total
• MANE Select transcript: NM_001003681

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5003
Approved symbol	HMGXB4
Name	HMG-box containing 4
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Aliases	THC211630, P53N
Ensembl gene	ENSG00000100281
Ensembl biotype	protein_coding
OMIM	604702
Entrez	10042

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000216106, ENST00000418170, ENST00000420166, ENST00000455359, ENST00000464480, ENST00000466438, ENST00000498212, ENST00000498325, ENST00000912955, ENST00000912956, ENST00000943161

RefSeq mRNA: 2 — MANE Select: NM_001003681 NM_001003681, NM_001362972

CCDS: CCDS33641

Canonical transcript exons

ENST00000216106 — 11 exons

Exon	Start	End
ENSE00001909264	35293607	35295807
ENSE00001956559	35257493	35257557
ENSE00003479331	35283962	35284043
ENSE00003494950	35292992	35293114
ENSE00003505055	35288238	35288407
ENSE00003567715	35264648	35265603
ENSE00003579783	35263078	35263226
ENSE00003582875	35263796	35263874
ENSE00003628260	35287347	35287452
ENSE00003644539	35285997	35286061
ENSE00003651363	35262323	35262421

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 95.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.0337 / max 484.7332, expressed in 1801 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191955	25.0337	1801

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	95.57	gold quality
secondary oocyte	CL:0000655	95.23	gold quality
buccal mucosa cell	CL:0002336	93.20	gold quality
sperm	CL:0000019	91.78	gold quality
sural nerve	UBERON:0015488	91.43	gold quality
male germ cell	CL:0000015	90.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.60	gold quality
adrenal tissue	UBERON:0018303	88.41	gold quality
ventricular zone	UBERON:0003053	88.12	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.20	gold quality
placenta	UBERON:0001987	86.67	gold quality
tibia	UBERON:0000979	86.62	gold quality
bone marrow	UBERON:0002371	86.56	gold quality
urethra	UBERON:0000057	86.50	gold quality
nipple	UBERON:0002030	86.26	gold quality
embryo	UBERON:0000922	86.09	gold quality
synovial joint	UBERON:0002217	86.08	gold quality
cartilage tissue	UBERON:0002418	85.66	gold quality
cranial nerve II	UBERON:0000941	85.58	gold quality
trabecular bone tissue	UBERON:0002483	85.34	gold quality
islet of Langerhans	UBERON:0000006	85.31	gold quality
cortical plate	UBERON:0005343	85.30	gold quality
penis	UBERON:0000989	85.27	gold quality
bone marrow cell	CL:0002092	85.26	gold quality
calcaneal tendon	UBERON:0003701	85.18	gold quality
germinal epithelium of ovary	UBERON:0001304	85.10	gold quality
ganglionic eminence	UBERON:0004023	85.04	gold quality
adult organism	UBERON:0007023	84.98	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.95	gold quality
stromal cell of endometrium	CL:0002255	84.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.24

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
ACTA2	Repression
CNN1	Repression
MYH11	Repression
TAGLN	Repression

Upstream regulators (CollecTRI, top): APOE, SRF

Literature-anchored findings (GeneRIF, showing 4)

• high-mobility group protein 2-like 1 and SNP mapping of a psychotic bipolar affective disorder linkage region on 22q12.3 (PMID:17671966)
• the first evidence of this novel HMG2L1 molecule playing an important role in attenuating smooth muscle differentiation (PMID:20511232)
• These results highlight a previously un-reported role of HMGXB4 in the hematopoietic system and transcriptional imbalances of HMGXB4 could contribute to the aberrant expansion of the megakaryocytic lineage in primary myelofibrosis patients (PMID:26547506)
• Analysis of the P(53N) a Novel Protein Encoded on Chromosome 22q12.1-12.3 in Glioblastomas and Ependymomas Specimens. (PMID:33595778)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hmgxb4a	ENSDARG00000075783
mus_musculus	Hmgxb4	ENSMUSG00000034518
rattus_norvegicus	Hmgxb4	ENSRNOG00000013878
caenorhabditis_elegans	hmg-3	WBGENE00001973
caenorhabditis_elegans		WBGENE00001974

Paralogs (20): HMGB3 (ENSG00000029993), HMG20B (ENSG00000064961), SP100 (ENSG00000067066), SMARCE1 (ENSG00000073584), SP140 (ENSG00000079263), TOX4 (ENSG00000092203), TOX3 (ENSG00000103460), TFAM (ENSG00000108064), UBTF (ENSG00000108312), HMGB1P1 (ENSG00000124097), TOX2 (ENSG00000124191), SP110 (ENSG00000135899), HMG20A (ENSG00000140382), SSRP1 (ENSG00000149136), HMGB2 (ENSG00000164104), HMGB4 (ENSG00000176256), SP140L (ENSG00000185404), HMGB1 (ENSG00000189403), TOX (ENSG00000198846), UBTFL1 (ENSG00000255009)

Protein

Protein identifiers

HMG domain-containing protein 4 — Q9UGU5 (reviewed: Q9UGU5)

Alternative names: HMG box-containing protein 4, High mobility group protein 2-like 1, Protein HMGBCG

All UniProt accessions (4): Q9UGU5, B0QXZ8, B0QXZ9, F8WDU7

UniProt curated annotations — full annotation on UniProt →

Function. Negatively regulates Wnt/beta-catenin signaling during development.

Subcellular location. Nucleus.

RefSeq proteins (2): NP_001003681, NP_001349901 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR025228	DUF4171	Domain
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR042477	HMGXB4	Family
IPR048016	HMGXB4_HMG-box	Domain

Pfam: PF00505, PF13775

UniProt features (18 total): modified residue 5, compositionally biased region 5, cross-link 2, region of interest 2, chain 1, DNA-binding region 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UGU5-F1	56.15	0.09

Functional residue map

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

Post-translational modifications (7): 197, 497, 502, 512, 8, 191, 102

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 201 (showing top): E2F_Q4, TAATAAT_MIR126, GOBP_LYSOSOMAL_TRANSPORT, E2F4DP1_01, GOBP_ENDOSOME_TO_LYSOSOME_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_VACUOLAR_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, YY1_Q6, E2F1DP1_01, E2F1DP2_01, YY1_02, BLALOCK_ALZHEIMERS_DISEASE_UP

GO Biological Process (3): endosome to lysosome transport (GO:0008333), Wnt signaling pathway (GO:0016055), negative regulation of Wnt signaling pathway (GO:0030178)

GO Molecular Function (3): DNA binding (GO:0003677), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (2): NURF complex (GO:0016589), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lysosomal transport	1
intercellular transport	1
vesicle-mediated transport	1
cell surface receptor signaling pathway	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
nucleic acid binding	1
protein binding	1
binding	1
ISWI-type complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

978 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HMGXB4	TOM1	O60784	924
HMGXB4	MCM5	P33992	862
HMGXB4	HMOX2	P30519	547
HMGXB4	CCDC30	Q5VVM6	535
HMGXB4	FOXRED2	Q8IWF2	490
HMGXB4	AHSP	Q9NZD4	480
HMGXB4	BPGM	P07738	475
HMGXB4	TENT5C	Q5VWP2	468
HMGXB4	WDR64	B1ANS9	458
HMGXB4	IFIT1B	Q5T764	440
HMGXB4	ZFYVE16	Q7Z3T8	438
HMGXB4	GYPB	P06028	436
HMGXB4	CELSR3	Q9NYQ7	429
HMGXB4	HGS	O14964	428
HMGXB4	HMOX1	P09601	425

IntAct

91 interactions, top by confidence:

A	B	Type	Score
KIFAP3	KIF3B	psi-mi:“MI:0914”(association)	0.900
RBBP4	CDK2AP1	psi-mi:“MI:0914”(association)	0.790
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640
DPY30	AKAP8	psi-mi:“MI:0914”(association)	0.610
ENKD1	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
CCHCR1	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
STAC3	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
ZCCHC10	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
TSPYL2	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
INO80B	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
AKAP17A	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
HMGXB4	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
LENG8	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
NKAPD1	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
PIAS2	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
STRBP	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
UBL5	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
UBE2I	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
TENT5B	HMGXB4	psi-mi:“MI:0915”(physical association)	0.560
SMARCA5	RBBP4	psi-mi:“MI:0914”(association)	0.530
RBBP4	TNRC18	psi-mi:“MI:0914”(association)	0.530
BACC1	SMARCA1	psi-mi:“MI:0914”(association)	0.530
BACC1	SMARCA5	psi-mi:“MI:0914”(association)	0.530
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
HMGXB4	HSP90B1	psi-mi:“MI:0915”(physical association)	0.400
HMGXB4	NR1H2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (136): HMGXB4 (Protein-peptide), HMGXB4 (Affinity Capture-MS), HMGXB4 (Two-hybrid), HMGXB4 (Biochemical Activity), RAD51 (Affinity Capture-MS), RRAS (Affinity Capture-MS), TBCA (Affinity Capture-MS), RABGAP1L (Affinity Capture-MS), HMGXB4 (Affinity Capture-MS), HMGXB4 (Affinity Capture-MS), HMGXB4 (Affinity Capture-MS), HMGXB4 (Affinity Capture-MS), HMGXB4 (Affinity Capture-MS), HMGXB4 (Affinity Capture-MS), ARAP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A087WPF7, A0A0R4IBL7, O09000, O54972, O70305, O75081, O75376, P15806, P15881, P15884, P15923, P21677, P30985, P51514, P98180, Q05AQ8, Q14157, Q14687, Q1LY51, Q2VPM4, Q3U3C9, Q4KKX4, Q4VCS5, Q566L4, Q5F3B1, Q5SFM8, Q5T6F2, Q60722, Q60974, Q61286, Q62655, Q6DIH5, Q7ZWN6, Q7ZXS3, Q80X50, Q86YP4, Q8BZ47, Q8CHY6, Q8IXK0, Q8VHG2

Diamond homologs: A9RA84, B0CM99, B1MTB0, B2RPK0, O01683, O04235, O15347, O15405, O49595, O49596, O49597, O54879, O64702, O94842, O94900, P07156, P07746, P09429, P0CO24, P0CO25, P10103, P11632, P11633, P11873, P12682, P17741, P23497, P26583, P26584, P26585, P26586, P27347, P30681, P40618, P40619, P40620, P40621, P40622, P40623, P40632

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
NuRD complex assembly	5	14.7×	2e-03
Activation of anterior HOX genes in hindbrain development during early embryogenesis	6	11.4×	2e-03
CHD1 and CHD2 subfamily	5	11.3×	5e-03
mRNA Polyadenylation	5	9.2×	9e-03
mRNA Splicing - Major Pathway	6	6.8×	9e-03
Dengue Virus-Host Interactions	7	6.7×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
nucleosome assembly	6	12.4×	1e-03
mRNA processing	8	9.3×	9e-04
RNA splicing	7	9.1×	1e-03
chromatin remodeling	8	8.6×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	57
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1586 predictions. Top by Δscore:

Variant	Effect	Δscore
22:35257741:G:GT	donor_gain	1.0000
22:35263057:A:AG	acceptor_gain	1.0000
22:35263058:A:G	acceptor_gain	1.0000
22:35263060:T:G	acceptor_gain	1.0000
22:35263061:A:AG	acceptor_gain	1.0000
22:35263062:A:G	acceptor_gain	1.0000
22:35263062:AACCT:A	acceptor_gain	1.0000
22:35263063:A:AG	acceptor_gain	1.0000
22:35263063:ACCT:A	acceptor_gain	1.0000
22:35263064:C:G	acceptor_gain	1.0000
22:35263066:T:A	acceptor_gain	1.0000
22:35263068:T:TA	acceptor_gain	1.0000
22:35263073:CTCA:C	acceptor_loss	1.0000
22:35263074:TCA:T	acceptor_loss	1.0000
22:35263075:CAGA:C	acceptor_loss	1.0000
22:35263076:A:AG	acceptor_gain	1.0000
22:35263076:A:C	acceptor_loss	1.0000
22:35263077:G:GG	acceptor_gain	1.0000
22:35263077:G:GT	acceptor_loss	1.0000
22:35263223:GAAG:G	donor_gain	1.0000
22:35263227:G:GG	donor_gain	1.0000
22:35263228:T:A	donor_loss	1.0000
22:35263788:A:AG	acceptor_gain	1.0000
22:35263789:A:G	acceptor_gain	1.0000
22:35263791:TATA:T	acceptor_loss	1.0000
22:35263792:ATAG:A	acceptor_gain	1.0000
22:35263793:TA:T	acceptor_loss	1.0000
22:35263794:A:AG	acceptor_gain	1.0000
22:35263794:AG:A	acceptor_gain	1.0000
22:35263795:G:A	acceptor_loss	1.0000

AlphaMissense

3899 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:35283986:T:A	Y414N	1.000
22:35283986:T:C	Y414H	1.000
22:35283986:T:G	Y414D	1.000
22:35283987:A:G	Y414C	1.000
22:35283995:T:C	F417L	1.000
22:35283996:T:C	F417S	1.000
22:35283996:T:G	F417C	1.000
22:35283997:C:A	F417L	1.000
22:35283997:C:G	F417L	1.000
22:35284010:C:A	R422S	1.000
22:35285999:T:C	F434L	1.000
22:35286000:T:G	F434C	1.000
22:35286001:T:A	F434L	1.000
22:35286001:T:G	F434L	1.000
22:35286009:T:C	L437P	1.000
22:35286021:T:A	L441Q	1.000
22:35286021:T:C	L441P	1.000
22:35286024:C:A	A442D	1.000
22:35286032:T:A	W445R	1.000
22:35286032:T:C	W445R	1.000
22:35286033:G:C	W445S	1.000
22:35286034:G:C	W445C	1.000
22:35286034:G:T	W445C	1.000
22:35286058:A:C	K453N	1.000
22:35286058:A:T	K453N	1.000
22:35287350:T:A	W456R	1.000
22:35287350:T:C	W456R	1.000
22:35287351:G:C	W456S	1.000
22:35287352:G:C	W456C	1.000
22:35287352:G:T	W456C	1.000

dbSNP variants (sampled 300 via entrez): RS1000008720 (22:35241667 T>A), RS1000050365 (22:35253788 G>A), RS1000117191 (22:35282452 C>G), RS1000184578 (22:35283895 G>T), RS1000205825 (22:35288781 G>A), RS1000365778 (22:35259816 T>G), RS1000403889 (22:35244355 G>A), RS1000456865 (22:35250798 CCTCT>C,CCT), RS1000493889 (22:35261371 G>A), RS1000545773 (22:35261682 TTGG>T), RS1000643095 (22:35258334 C>G,T), RS1000716029 (22:35259537 G>A), RS1000725789 (22:35257067 C>T), RS1000775006 (22:35294245 C>T), RS1000787231 (22:35248644 A>G)

Disease associations

OMIM: gene MIM:604702 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002782_43	Waist-to-hip ratio adjusted for body mass index	5.000000e-06
GCST002782_44	Waist-to-hip ratio adjusted for body mass index	8.000000e-06
GCST004067_204	Hip circumference adjusted for BMI	2.000000e-09
GCST004067_7	Hip circumference adjusted for BMI	4.000000e-08
GCST005956_75	Waist-to-hip ratio adjusted for BMI	1.000000e-07
GCST005958_13	Waist-to-hip ratio adjusted for BMI (age >50)	1.000000e-06
GCST005962_33	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	6.000000e-06
GCST012490_136	Femur bone mineral density x serum urate levels interaction	2.000000e-08
GCST012490_351	Femur bone mineral density x serum urate levels interaction	2.000000e-13
GCST90002402_645	Platelet count	4.000000e-10
GCST90020026_215	Hip index	4.000000e-09
GCST90020028_1547	Hip circumference adjusted for BMI	2.000000e-13

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004531	urate measurement
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases expression, decreases methylation, affects cotreatment	5
Air Pollutants	affects cotreatment, decreases expression, increases abundance	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
geraniol	decreases expression	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
Leflunomide	increases expression	1
Acrolein	increases abundance, affects cotreatment, decreases expression	1
Amiodarone	increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Ozone	affects cotreatment, decreases expression, increases abundance	1
Selenium	affects cotreatment, decreases expression	1
Thiram	increases expression	1
Tretinoin	decreases expression	1
Vitamin E	affects cotreatment, decreases expression	1
Cyclosporine	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_A2S0	SEES3-1V human HMG2L1, clone1	Embryonic stem cell	Male
CVCL_A2S1	SEES3-1V human HMG2L1, clone2	Embryonic stem cell	Male
CVCL_A2S2	SEES3-1V human HMG2L1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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