HMGA2

Summary

HMGA2 (high mobility group AT-hook 2, HGNC:5009) is a protein-coding gene on chromosome 12q14.3, encoding High mobility group protein HMGI-C (P52926). Functions as a transcriptional regulator.

This gene encodes a protein that belongs to the non-histone chromosomal high mobility group (HMG) protein family. HMG proteins function as architectural factors and are essential components of the enhancesome. This protein contains structural DNA-binding domains and may act as a transcriptional regulating factor. Identification of the deletion, amplification, and rearrangement of this gene that are associated with myxoid liposarcoma suggests a role in adipogenesis and mesenchymal differentiation. A gene knock out study of the mouse counterpart demonstrated that this gene is involved in diet-induced obesity. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 8091 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Silver-Russell syndrome 5 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 92
• Clinical variants (ClinVar): 58 total — 8 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 71
• Transcription factor: yes — 49 downstream targets (CollecTRI)
• MANE Select transcript: NM_003483

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5009
Approved symbol	HMGA2
Name	high mobility group AT-hook 2
Location	12q14.3
Locus type	gene with protein product
Status	Approved
Aliases	BABL, LIPO
Ensembl gene	ENSG00000149948
Ensembl biotype	protein_coding
OMIM	600698
Entrez	8091

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000354636, ENST00000393577, ENST00000393578, ENST00000403681, ENST00000425208, ENST00000536545, ENST00000537275, ENST00000537429, ENST00000539662, ENST00000541363, ENST00000545998, ENST00000913613

RefSeq mRNA: 5 — MANE Select: NM_003483 NM_001300918, NM_001300919, NM_001330190, NM_003483, NM_003484

CCDS: CCDS31854, CCDS44936, CCDS73491, CCDS73492, CCDS81709

Canonical transcript exons

ENST00000403681 — 5 exons

Exon	Start	End
ENSE00001208078	65828001	65828087
ENSE00001362889	65838519	65838569
ENSE00001559325	65963245	65966291
ENSE00002247030	65824483	65825381
ENSE00003528080	65951383	65951415

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 88.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 100.3362 / max 1878.4181, expressed in 1234 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126521	33.0450	1153
126520	22.7861	1094
126513	15.3343	992
126511	7.5735	934
126512	5.1084	834
126514	2.9078	809
126519	2.6961	764
126517	1.8108	669
126508	1.5665	503
126510	1.4668	499

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	88.67	gold quality
embryo	UBERON:0000922	87.09	gold quality
stromal cell of endometrium	CL:0002255	85.55	gold quality
ventricular zone	UBERON:0003053	85.11	gold quality
cartilage tissue	UBERON:0002418	84.54	gold quality
ganglionic eminence	UBERON:0004023	80.30	gold quality
adrenal tissue	UBERON:0018303	80.30	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.25	gold quality
pigmented layer of retina	UBERON:0001782	75.50	gold quality
buccal mucosa cell	CL:0002336	72.65	gold quality
amniotic fluid	UBERON:0000173	71.78	silver quality
colonic mucosa	UBERON:0000317	70.92	gold quality
mucosa of sigmoid colon	UBERON:0004993	70.21	gold quality
mucosa of transverse colon	UBERON:0004991	70.15	gold quality
rectum	UBERON:0001052	69.89	gold quality
cortical plate	UBERON:0005343	67.81	gold quality
pancreatic ductal cell	CL:0002079	67.14	silver quality
colonic epithelium	UBERON:0000397	65.77	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	64.82	silver quality
lower lobe of lung	UBERON:0008949	64.27	silver quality
transverse colon	UBERON:0001157	63.86	gold quality
left testis	UBERON:0004533	62.65	gold quality
testis	UBERON:0000473	62.49	gold quality
right uterine tube	UBERON:0001302	62.08	gold quality
bone marrow	UBERON:0002371	61.95	gold quality
tibial nerve	UBERON:0001323	61.68	gold quality
pericardium	UBERON:0002407	61.66	silver quality
bronchial epithelial cell	CL:0002328	61.37	gold quality
ileal mucosa	UBERON:0000331	61.31	gold quality
epithelium of bronchus	UBERON:0002031	60.95	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	1385.11
E-MTAB-10855	yes	1082.44
E-GEOD-124858	yes	494.68
E-MTAB-6819	yes	492.07
E-HCAD-56	yes	417.03
E-HCAD-10	yes	36.19
E-CURD-112	yes	8.79
E-ANND-3	yes	6.89
E-CURD-11	no	522.11
E-GEOD-124472	no	485.33

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

49 targets.

Target	Regulation
ACTG2
AKT1
AQP5
CCNA2	Activation
CCNB2	Activation
CCNG1
CDC73
CDH1	Activation
CDH17
CDKN2A	Repression
COL11A2	Activation
DBI
ERCC1
FOSL1	Activation
FZD2
H19
HLA-DRA
HMGA2
IFNB1
IGF1
IGF2
IGF2BP2	Unknown
IGFBP4
IL11	Activation
JUN
JUNB	Activation
KLF5
KRAS
LIN28A
LOX

Upstream regulators (CollecTRI, top): BRCA1, HMGA2, MYCN, NKX2-1, SP1, SP3, STAT3, TTF1, ZNF350, ZNF382

miRNA regulators (miRDB)

246 targeting HMGA2, 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-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-511-3P	99.99	68.85	1467
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-103A-3P	99.98	69.14	1595

Literature-anchored findings (GeneRIF, showing 40)

• findings suggest that amplification and overexpression of HMGIC and possibly MDM2 might be important genetic events that may contribute to malignant transformation of benign pleomorphic adenoma (PMID:11839563)
• Overexpression of HMG1C does not depend on chromosomal rearrangements in radiation associated pleomorphic adenomas (PMID:11894114)
• Based on sequence analysis of the entire intron 3 of HMGA2, a possible new exon of HMGA2 is described, the expression of which in a transcript may have more striking effects than wild-type HMGA2 in terms of tumorigenesis. (PMID:11921278)
• HMGIC alterations in smooth muscle tumors of soft tissues and other sites (PMID:12419585)
• Expression of the HMGA2-LPP fusion transcript in only 1 of 61 karyotypically normal pulmonary chondroid hamartomas. (PMID:12505264)
• HMGA2 promoter is coregulated by a polymorphic dinucleotide (TC)-repeat (PMID:12569368)
• Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine leiomyomata with rearrangements in 12q15. (PMID:12649198)
• Expression of this protein’s mRNA in the peripheral blood is an independent poor prognostic indicator for survival in metastatic breast cancer. (PMID:12778070)
• Results support a model in which the expression of the wild-type HMGA allele is critical for the pathogenesis of mesenchymal tumors and in which rearrangements of HMGA do not lead to a gain of function in the chimeric HMGA protein (PMID:12781451)
• Histone deacetylase inhibition is associated with transcriptional repression of the Hmga2 gene. (PMID:12799440)
• HMGA2 expression is required in normal adult myometrial physiology. (PMID:12874787)
• Dysregulation and overexpression of HMGA2 in myeloid progenitors contribute to the pathogenesis of myelofibrosis with myeloid metaplasia. (PMID:14603445)
• HMGA2 was expressed in 4 of six soft tissue chondromas, all displaying 12q-rearrangements at cytogenetic analysis. (PMID:14614053)
• HMGA2 associates with the E1A-regulated transcriptional repressor p120(E4F), interfering with p120(E4F) binding to the cyclin A promoter. (PMID:14645522)
• we propose that an increased expression level of the HMGA2 protein is closely associated with the malignant phenotype in the pancreatic exocrine system. (PMID:14647145)
• HMGA2 overexpression is associated with aggressiveness of oral carcinoma (PMID:15026339)
• Geme ay be involved in growtwh of tumors. (PMID:15618962)
• Abnormalities of HMGA2 play an important and previously unsuspected role in myelodysplasia. (PMID:15618963)
• HMGA2-dependent tumorigenesis is caused by a disturbed equilibrium in the co-expression of the HMGA2 splice variants leading to aberrant cell proliferation and/or malignant transformation of cells. (PMID:15882911)
• Enhanced cytotoxicity by double-strand breaks in HMGA2-expressing cells is mediated, at least in part, through the signaling pathway of which the physiologic function is to maintain genome integrity. (PMID:16061642)
• HMGA2, although obviously contributes to invasion, is not a specific marker for the detection of circulating tumor cells in breast cancer. (PMID:16077985)
• Active expression of HMGA2 found in serous carcinoma of ovarian epithelial cells. (PMID:16222997)
• Translocation in chromosome 3 and 12 involves fusion of this protein with LPP protein in pulmonary chondroid hamartoma. (PMID:16271958)
• Pathogenetically significant event is fusion, truncation or transcriptional activation of HMGA2 contributes to lipoma development. (PMID:16276091)
• HMGA2 gene is overexpressed in pituitary adenomas and thus plays a role in pituitary oncogenesis (PMID:16322327)
• HMGA2-LPP fusion promotes chondrogenesis by upregulating cartilage-specific collagen gene expression through the N-terminal DNA binding domains. (PMID:16375854)
• Endogenous HMGA2 mediates Epithelial-mesenchymal transition (EMT) by TGF-beta, whereas ectopic HMGA2 causes irreversible EMT characterized by severe E-cadherin suppression. (PMID:16831886)
• expression of HMGA2 RNA is repressed in human cytomegalovirus infected cells; findings suggest that IE2 86 is involved in the inhibition of HMGA2 (PMID:17005673)
• The three novel transcripts, A15, B6 and D12 are located within the HMGA2 gene itself and are transcribed from the opposite strand. (PMID:17045619)
• HMGA2 interacts with nucleosomes in a way that imposes a global effect on the state of ES cell chromatin, which may contribute to the establishment of both ES cell identity and the initiation of specific differentiation programs. (PMID:17078040)
• These studies validate the observation that HMGA2 plays a prominent role in governing genotoxic responses. (PMID:17222355)
• it is reported that chromosomal translocations previously associated with human tumors disrupt repression of Hmga2 by let-7 miRNA (PMID:17322030)
• HMGA2 plays a central role in the pathogenesis of Lymphangiomyomatosis. (PMID:17332316)
• We provide evidence that there is a strong and statistically significant correlation between HMGA2 and IMP2 gene expression in human liposarcomas. (PMID:17426251)
• Ectopic expression of let-7 miRNA reduced HMGA2 and cell proliferation in a lung cancer cell. (PMID:17437991)
• HMGA2 overexpression is associated with non-small cell lung cancer (PMID:17477356)
• establish HMGA2 as a regulator of human genes linked to mesenchymal cell differentiation, adipogenesis, and human embryonic stem cell growth (PMID:17624332)
• The diagnostic usefulness of HMGA2 rearrangements to differentiate between AAM and other tumors of the lower genital tract may be limited due to the their low frequency (PMID:17654722)
• variant of HMGA2 is associated with adult and childhood height in the general population (PMID:17767157)
• HMGA2 overexpression is associated with polycythemia vera (PMID:17854665)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hmga2	ENSDARG00000069912
mus_musculus	Hmga2	ENSMUSG00000056758
rattus_norvegicus	Hmga2	ENSRNOG00000042460

Protein

Protein identifiers

High mobility group protein HMGI-C — P52926 (reviewed: P52926)

Alternative names: High mobility group AT-hook protein 2

All UniProt accessions (5): P52926, F5H2A4, F5H2U8, F5H6H0, H0YFY4

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a transcriptional regulator. Functions in cell cycle regulation through CCNA2. Plays an important role in chromosome condensation during the meiotic G2/M transition of spermatocytes. Plays a role in postnatal myogenesis, is involved in satellite cell activation. Positively regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner.

Subunit / interactions. Interacts with E4F1. Interacts with NEK2.

Subcellular location. Nucleus.

Post-translational modifications. Regulated by cell cycle-dependent phosphorylation which alters its DNA binding affinity. Phosphorylated by NEK2.

Disease relevance. Silver-Russell syndrome 5 (SRS5) [MIM:618908] A form of Silver-Russell syndrome, a clinically heterogeneous condition characterized by severe intrauterine growth retardation, poor postnatal growth, craniofacial features such as a triangular shaped face and a broad forehead, body asymmetry, and a variety of minor malformations. The phenotypic expression changes during childhood and adolescence, with the facial features and asymmetry usually becoming more subtle with age. SRS5 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving HMGA2 is associated with a subclass of benign mesenchymal tumors known as lipomas. Translocation t(3;12)(q27-q28;q13-q15) with LPP is shown in lipomas. HMGA2 is also fused with a number of other genes in lipomas. A chromosomal aberration involving HMGA2 is associated with pulmonary chondroid hamartomas. Translocation t(3;12)(q27-q28;q14-q15) with LPP is detected in pulmonary chondroid hamartomas. A chromosomal aberration involving HMGA2 is associated with parosteal lipomas. Translocation t(3;12)(q28;q14) with LPP is also shown in one parosteal lipoma. A chromosomal aberration involving HMGA2 is found in uterine leiomyoma. Translocation t(12;14)(q15;q23-24) with RAD51B. Chromosomal rearrangements involving HMGA2 do not seem to be the principle pathobiological mechanism in uterine leiomyoma.

Polymorphism. Genetic variations in HMGA2 define the stature quantitative trait locus 9 (STQTL9) [MIM:611547]. Human height is a classic, highly heritable quantitative trait.

Similarity. Belongs to the HMGA family.

Isoforms (6)

UniProt ID	Names	Canonical?
P52926-1	1, HMGA2a	yes
P52926-2	2, HMGA2f
P52926-3	3, HMGA2d'
P52926-4	4, HMGA2d
P52926-5	5, HMGA2c'
P52926-6	6, HMGA2c

RefSeq proteins (5): NP_001287847, NP_001287848, NP_001317119, NP_003474, NP_003475 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000116	HMGA	Family
IPR000637	HMGI/Y_DNA-bd_CS	Conserved_site
IPR017956	AT_hook_DNA-bd_motif	Conserved_site

Pfam: PF02178

UniProt features (22 total): modified residue 5, splice variant 5, compositionally biased region 4, DNA-binding region 3, region of interest 2, initiator methionine 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52926-F1	65.46	0.00

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 (5): 2, 40, 44, 101, 105

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2559584	Formation of Senescence-Associated Heterochromatin Foci (SAHF)

MSigDB gene sets: 822 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_CHROMOSOME_ORGANIZATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EPITHELIUM_DEVELOPMENT, HORIUCHI_WTAP_TARGETS_DN, GOMF_ENDONUCLEASE_ACTIVITY, ACTACCT_MIR196A_MIR196B, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, MYOGENIN_Q6, GOBP_CARTILAGE_DEVELOPMENT, GOBP_REGULATION_OF_PHOSPHORYLATION

GO Biological Process (62): negative regulation of transcription by RNA polymerase II (GO:0000122), epithelial to mesenchymal transition (GO:0001837), chondrocyte differentiation (GO:0002062), mesodermal-endodermal cell signaling (GO:0003131), base-excision repair (GO:0006284), chromatin organization (GO:0006325), regulation of DNA-templated transcription (GO:0006355), spermatogenesis (GO:0007283), male gonad development (GO:0008584), response to virus (GO:0009615), regulation of cell cycle process (GO:0010564), positive regulation of gene expression (GO:0010628), cell proliferation in forebrain (GO:0021846), pituitary gland development (GO:0021983), negative regulation of Wnt signaling pathway (GO:0030178), chromosome condensation (GO:0030261), adrenal gland development (GO:0030325), heterochromatin formation (GO:0031507), negative regulation of intracellular steroid hormone receptor signaling pathway (GO:0033144), somatic stem cell population maintenance (GO:0035019), multicellular organism growth (GO:0035264), intracellular signal transduction (GO:0035556), endodermal cell differentiation (GO:0035987), chondrocyte proliferation (GO:0035988), positive regulation of multicellular organism growth (GO:0040018), negative regulation of apoptotic process (GO:0043066), negative regulation of DNA binding (GO:0043392), host-mediated suppression of viral transcription (GO:0043922), fat cell differentiation (GO:0045444), positive regulation of angiogenesis (GO:0045766), negative regulation of single stranded viral RNA replication via double stranded DNA intermediate (GO:0045869), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of receptor signaling pathway via JAK-STAT (GO:0046426), fibroblast proliferation (GO:0048144), positive regulation of fibroblast proliferation (GO:0048146), mesodermal cell differentiation (GO:0048333), astrocyte differentiation (GO:0048708), negative regulation of astrocyte differentiation (GO:0048712)

GO Molecular Function (18): transcription cis-regulatory region binding (GO:0000976), nucleic acid binding (GO:0003676), minor groove of adenine-thymine-rich DNA binding (GO:0003680), transcription coregulator activity (GO:0003712), transcription corepressor activity (GO:0003714), DNA-(apurinic or apyrimidinic site) endonuclease activity (GO:0003906), DNA binding, bending (GO:0008301), enzyme binding (GO:0019899), nucleosomal DNA binding (GO:0031492), cAMP response element binding (GO:0035497), MH2 domain binding (GO:0035500), MH1 domain binding (GO:0035501), SMAD binding (GO:0046332), 5’-deoxyribose-5-phosphate lyase activity (GO:0051575), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), C2H2 zinc finger domain binding (GO:0070742), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (8): nuclear chromosome (GO:0000228), male germ cell nucleus (GO:0001673), nucleus (GO:0005634), nucleoplasm (GO:0005654), protein-DNA complex (GO:0032993), senescence-associated heterochromatin focus (GO:0035985), SMAD protein complex (GO:0071141), chromatin (GO:0000785)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
DNA Damage/Telomere Stress Induced Senescence	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein domain specific binding	3
negative regulation of DNA-templated transcription	2
regulation of gene expression	2
endocrine system development	2
gland development	2
binding	2
protein binding	2
chromosome	2
nuclear lumen	2
cellular anatomical structure	2
protein-containing complex	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
mesenchymal cell differentiation	1
cell differentiation	1
cartilage development	1
cell-cell signaling	1
DNA repair	1
cellular component organization	1
DNA-templated transcription	1
regulation of RNA biosynthetic process	1
developmental process involved in reproduction	1
male gamete generation	1
gonad development	1
development of primary male sexual characteristics	1
response to other organism	1
cell cycle process	1
regulation of cell cycle	1
gene expression	1
positive regulation of macromolecule biosynthetic process	1
forebrain development	1
neural precursor cell proliferation	1
diencephalon development	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
chromosome organization	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

38 interactions, top by confidence:

A	B	Type	Score
EGFR	NDUFA4	psi-mi:“MI:0914”(association)	0.530
RYK	PCDH7	psi-mi:“MI:0914”(association)	0.530
PRMT6	HMGA2	psi-mi:“MI:0915”(physical association)	0.520
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
DUX4	HMGA2	psi-mi:“MI:0915”(physical association)	0.400
H1-5	HMGA2	psi-mi:“MI:0915”(physical association)	0.400
HMGA2	RUNX1	psi-mi:“MI:0915”(physical association)	0.400
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
PRMT1	HMGA2	psi-mi:“MI:0915”(physical association)	0.400
CREB1	NFIX	psi-mi:“MI:0914”(association)	0.350
NFATC1	SMARCA5	psi-mi:“MI:0914”(association)	0.350
DUX4L9		psi-mi:“MI:0914”(association)	0.350
EBNA1	IGF2BP3	psi-mi:“MI:0914”(association)	0.350
DLST		psi-mi:“MI:0914”(association)	0.350
SYDE1	APBB1	psi-mi:“MI:0914”(association)	0.350
CDC7	AMY1A	psi-mi:“MI:0914”(association)	0.350
MAP2K5	HMGN1	psi-mi:“MI:0914”(association)	0.350
PDK1	LRRC37A2	psi-mi:“MI:0914”(association)	0.350
EPHA1	MYO1B	psi-mi:“MI:0914”(association)	0.350
EPHA2	MYO1C	psi-mi:“MI:0914”(association)	0.350
ROR2	NDUFA4	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
TMIGD1	LAD1	psi-mi:“MI:0914”(association)	0.350
SP2	SHTN1	psi-mi:“MI:0914”(association)	0.350
	POLR3A	psi-mi:“MI:0914”(association)	0.350
HMGA2	KPNA4	psi-mi:“MI:0914”(association)	0.350

BioGRID (181): E4F1 (Reconstituted Complex), E4F1 (Affinity Capture-Western), E4F1 (Far Western), HMGA2 (Affinity Capture-MS), HMGA2 (Proximity Label-MS), HMGA2 (Affinity Capture-MS), HMGA2 (Affinity Capture-MS), HMGA2 (Affinity Capture-MS), HMGA2 (Affinity Capture-MS), HMGA2 (Affinity Capture-MS), HMGA2 (Affinity Capture-MS), HMGA2 (Affinity Capture-MS), HMGA2 (Affinity Capture-MS), TP53 (Affinity Capture-Western), HMGA2 (Affinity Capture-Western)

ESM2 similar proteins: A0A0G2K0D3, A0A1L8GR68, A0JPP1, B5DF11, D3ZTQ1, O88878, P17095, P17096, P28667, P29536, P35566, P49006, P51608, P52926, P52927, P84798, Q00566, Q0VBZ9, Q15004, Q15054, Q3USH5, Q3UZA1, Q3ZBT0, Q5BK20, Q5EG55, Q5XG50, Q5ZK28, Q60974, Q69Z61, Q6DGQ4, Q6JBY9, Q6PGH2, Q6URC2, Q86XZ4, Q86YP4, Q8BVA4, Q8CHY6, Q8K1N4, Q8K585, Q8N228

Diamond homologs: P52926, P52927

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
HMGA2	“up-regulates quantity by expression”	CCNA2	“transcriptional regulation”
HMGA2	down-regulates	E4F1	binding
HMGA2	up-regulates	Apoptosis
SMAD2/SMAD4	“up-regulates activity”	HMGA2	binding
SMAD3/SMAD4	“up-regulates activity”	HMGA2	binding
HMGA2	“up-regulates quantity by expression”	SNAI1	“transcriptional regulation”
HMGA2	“up-regulates quantity by expression”	TWIST1	“transcriptional regulation”
CDK1	down-regulates	HMGA2	phosphorylation
HMGA2	“down-regulates quantity by repression”	SCNN1A	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 50 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
Transcriptional regulation of granulopoiesis	6	21.5×	1e-04
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	5	17.2×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
chromatin organization	5	12.1×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	4
Uncertain significance	20
Likely benign	10
Benign	3

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1679403	NM_003483.6(HMGA2):c.47dup (p.Gln18fs)	Pathogenic
253034	NM_003483.6(HMGA2):c.193C>T (p.Gln65Ter)	Pathogenic
253035	NM_003483.6(HMGA2):c.189del (p.Ala64fs)	Pathogenic
2685438	GRCh37/hg19 12q14.3(chr12:65716808-66690108)x1	Pathogenic
3234118	NM_003483.6(HMGA2):c.138_141delinsCT (p.Lys46fs)	Pathogenic
4755469	Single allele	Pathogenic
685804	GRCh37/hg19 12q14.3(chr12:66200777-66575257)x1	Pathogenic
917504	NM_003483.6(HMGA2):c.283-6_283del	Pathogenic
1705396	NM_003483.6(HMGA2):c.44_48del (p.Ala15fs)	Likely pathogenic
4294469	NM_003483.6(HMGA2):c.52_56del (p.Gln18fs)	Likely pathogenic
4531432	NM_003483.6(HMGA2):c.112-2A>G	Likely pathogenic
4688022	NM_003483.6(HMGA2):c.112-1G>A	Likely pathogenic

SpliceAI

1935 predictions. Top by Δscore:

Variant	Effect	Δscore
12:65838517:A:AG	acceptor_gain	1.0000
12:65838517:A:G	acceptor_loss	1.0000
12:65838518:G:GC	acceptor_gain	1.0000
12:65838518:GAA:G	acceptor_gain	1.0000
12:65838518:GAAA:G	acceptor_gain	1.0000
12:65838565:AATGG:A	donor_gain	1.0000
12:65838566:ATGG:A	donor_gain	1.0000
12:65838567:TGG:T	donor_gain	1.0000
12:65838568:GG:G	donor_gain	1.0000
12:65838568:GGG:G	donor_gain	1.0000
12:65838569:GG:G	donor_gain	1.0000
12:65838570:G:GG	donor_gain	1.0000
12:65838571:T:A	donor_loss	1.0000
12:65838572:GAG:G	donor_loss	1.0000
12:65951381:A:AG	acceptor_gain	1.0000
12:65951382:G:GG	acceptor_gain	1.0000
12:65951414:AGGTA:A	donor_loss	1.0000
12:65951415:GG:G	donor_loss	1.0000
12:65951416:G:GC	donor_loss	1.0000
12:65952471:A:T	donor_gain	1.0000
12:65825369:G:GT	donor_gain	0.9900
12:65825378:GCAA:G	donor_gain	0.9900
12:65825382:GTCA:G	donor_gain	0.9900
12:65825386:G:GG	donor_gain	0.9900
12:65838518:GA:G	acceptor_gain	0.9900
12:65924114:AAATT:A	donor_gain	0.9900
12:65924118:T:TA	donor_gain	0.9900
12:65948418:GAAGA:G	donor_gain	0.9900
12:65948422:A:G	donor_gain	0.9900
12:65951379:TTAGC:T	acceptor_loss	0.9900

AlphaMissense

691 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:65828038:G:A	G50E	1.000
12:65828030:A:C	R47S	0.999
12:65828030:A:T	R47S	0.999
12:65828035:G:C	R49T	0.999
12:65828035:G:T	R49M	0.999
12:65828036:G:C	R49S	0.999
12:65828036:G:T	R49S	0.999
12:65828037:G:A	G50R	0.999
12:65828037:G:C	G50R	0.999
12:65828041:G:C	R51T	0.999
12:65828042:A:C	R51S	0.999
12:65828042:A:T	R51S	0.999
12:65828043:C:T	P52S	0.999
12:65828044:C:A	P52H	0.999
12:65838551:A:C	R77S	0.999
12:65838551:A:T	R77S	0.999
12:65838553:G:A	G78D	0.999
12:65838556:G:C	R79T	0.999
12:65838557:A:C	R79S	0.999
12:65838557:A:T	R79S	0.999
12:65838562:G:C	R81T	0.999
12:65838562:G:T	R81M	0.999
12:65838563:G:C	R81S	0.999
12:65838563:G:T	R81S	0.999
12:65825359:G:A	G30D	0.998
12:65825361:C:A	R31S	0.998
12:65828043:C:A	P52T	0.998
12:65828049:G:C	G54R	0.998
12:65828052:A:C	S55R	0.998
12:65828054:C:A	S55R	0.998

dbSNP variants (sampled 300 via entrez): RS1000010497 (12:65902245 C>A,G,T), RS1000036093 (12:65861071 A>G,T), RS1000039239 (12:65944169 A>G), RS1000092139 (12:65833714 C>T), RS1000115932 (12:65954281 C>T), RS1000168536 (12:65823847 T>C), RS1000179775 (12:65917253 G>T), RS1000185497 (12:65879480 A>C,T), RS1000195652 (12:65836223 G>A), RS1000209816 (12:65946438 A>G), RS1000238082 (12:65953046 T>C), RS1000254247 (12:65926253 A>G), RS1000284825 (12:65842490 G>A), RS1000316086 (12:65829148 G>A,C), RS1000328170 (12:65853146 T>C)

Disease associations

OMIM: gene MIM:600698 | disease phenotypes: MIM:618908, MIM:180860, MIM:150699

GenCC curated gene-disease

Disease	Classification	Inheritance
Silver-Russell syndrome 5	Definitive	Autosomal dominant
uterine corpus leiomyoma	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Silver-Russell syndrome 5	Definitive	AD

Mondo (3): Silver-Russell syndrome 5 (MONDO:0020795), Silver-Russell syndrome 1 (MONDO:0020796), uterine corpus leiomyoma (MONDO:0007886)

Orphanet (1): Silver-Russell syndrome (Orphanet:813)

HPO phenotypes

71 total (30 of 71 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000045	Abnormal scrotum morphology
HP:0000047	Hypospadias
HP:0000048	Bifid scrotum
HP:0000085	Horseshoe kidney
HP:0000086	Ectopic kidney
HP:0000089	Renal hypoplasia
HP:0000175	Cleft palate
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000426	Prominent nasal bridge
HP:0000445	Wide nose
HP:0000490	Deeply set eye
HP:0000574	Thick eyebrow
HP:0000664	Synophrys
HP:0000668	Hypodontia
HP:0000750	Delayed speech and language development
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0000953	Hyperpigmentation of the skin
HP:0000957	Cafe-au-lait spot
HP:0001159	Syndactyly
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability

GWAS associations

92 associations (top):

Study	Trait	p-value
GCST000068_1	Height	6.000000e-16
GCST000174_3	Height	3.000000e-18
GCST000175_45	Height	2.000000e-16
GCST000176_9	Height	3.000000e-20
GCST000372_20	Height	5.000000e-14
GCST000442_4	Aortic root size	2.000000e-09
GCST000609_4	Primary tooth development (time to first tooth eruption)	8.000000e-06
GCST000610_2	Primary tooth development (number of teeth)	4.000000e-06
GCST000644_6	Height	4.000000e-07
GCST000712_15	Type 2 diabetes	4.000000e-09
GCST000817_120	Height	2.000000e-65
GCST000909_3	Type 2 diabetes nephropathy	4.000000e-06
GCST001221_2	Permanent tooth development	2.000000e-12
GCST001263_2	Height	7.000000e-10
GCST001290_6	Height	4.000000e-10
GCST001481_1	Brain structure	1.000000e-12
GCST001484_1	Head circumference (infant)	3.000000e-10
GCST001634_8	Polycystic ovary syndrome	2.000000e-21
GCST001758_4	Birth weight	1.000000e-19
GCST001956_2	Height	7.000000e-32
GCST002030_7	Primary tooth development (time to first tooth eruption)	6.000000e-11
GCST002031_6	Primary tooth development (number of teeth)	1.000000e-10
GCST002115_17	Axial length	2.000000e-07
GCST002352_20	Type 2 diabetes	4.000000e-08
GCST002560_11	Type 2 diabetes	9.000000e-09
GCST002560_17	Type 2 diabetes	3.000000e-12
GCST002644_3	Birth length	7.000000e-07
GCST002646_8	Infant length	3.000000e-08
GCST002647_48	Height	5.000000e-90
GCST002702_90	Height	2.000000e-07

EFO canonical traits (23, from GWAS)

EFO ID	Trait name
EFO:0004886	intracranial volume measurement
EFO:0004344	birth weight
EFO:0005318	axial length measurement
EFO:0006784	body height at birth
EFO:0006785	infant body height
EFO:1001870	late-onset Alzheimers disease
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference
EFO:0004318	smoking behavior
EFO:0009184	heart rate response to exercise
EFO:0009270	heel bone mineral density
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0009924	Drugs used in diabetes use measurement
EFO:0005939	parental genotype effect measurement
EFO:0009658	adverse effect
EFO:0008381	total cortical area measurement
EFO:0004530	triglyceride measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004980	appendicular lean mass
EFO:0004833	neutrophil count
EFO:0007985	platelet crit
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression, affects cotreatment	5
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	5
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	increases expression, affects methylation, decreases expression	3
bisphenol S	increases expression, affects cotreatment, decreases expression	3
(+)-JQ1 compound	decreases expression	3
Cadmium Chloride	increases abundance, increases expression, affects reaction, decreases expression, increases phosphorylation	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
cobaltous chloride	decreases expression	2
chromium hexavalent ion	increases reaction, increases expression, affects reaction, decreases expression	2
4-phenylbutyric acid	decreases reaction, increases expression, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Cadmium	affects reaction, decreases expression, decreases reaction, increases expression, increases abundance	2
Caffeine	decreases expression, decreases phosphorylation	2
Cisplatin	decreases expression, affects cotreatment, increases expression	2
Doxorubicin	decreases expression, affects response to substance	2
Formaldehyde	decreases expression	2
Silicon Dioxide	increases expression	2
Smoke	decreases expression, increases abundance	2
Tobacco Smoke Pollution	affects expression, decreases methylation	2
Tunicamycin	affects reaction, decreases expression, increases expression	2
1-Methyl-4-phenylpyridinium	decreases reaction, affects reaction, increases expression, decreases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression, affects localization	1
quercitrin	increases expression	1

Cellosaurus cell lines

7 cell lines: 4 cancer cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2S6	SEES3-1V human HMGA2, clone1	Embryonic stem cell	Male
CVCL_A2S7	SEES3-1V human HMGA2, clone2	Embryonic stem cell	Male
CVCL_A2S8	SEES3-1V human HMGA2, clone3	Embryonic stem cell	Male
CVCL_B8HI	Abcam HCT 116 HMGA2 KO	Cancer cell line	Male
CVCL_B8WV	Abcam MCF-7 HMGA2 KO	Cancer cell line	Female
CVCL_B9JT	Abcam A-549 HMGA2 KO	Cancer cell line	Male
CVCL_D8MG	Ubigene HCT 116 HMGA2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00159328	PHASE4	COMPLETED	Efficacy Study of Magnetic Resonance (MR) Guided Focused Ultrasound in the Treatment of Large Fibroids
NCT00180739	PHASE4	WITHDRAWN	Safety Trial of Magnetic Resonance (MR) Guided Focused Ultrasound Surgery (FUS) in Women With Uterine Fibroids Wishing to Pursue Pregnancy in the Future
NCT00628901	PHASE4	COMPLETED	A Prospective Study Comparing Contour SE™ Microspheres to Embosphere® Microspheres for Treating Symptomatic Uterine Fibroids With Uterine Fibroid Embolization (UFE)
NCT00995878	PHASE4	COMPLETED	The FIRSTT: Comparing MRgFUS(MR-guided Focused Ultrasound) Versus UAE (Uterine Artery Embolization)for Uterine Fibroids.
NCT01239641	PHASE4	UNKNOWN	High Intensity Focused Ultrasound Ablation Virus Myomectomy to Treat Uterine Fibroids
NCT01388907	PHASE4	COMPLETED	Efficacity Assessment of PREVADH® in Adhesion Prevention in Gynaecologic Surgery
NCT01555073	PHASE4	TERMINATED	Preemptive Analgesia Following Uterine Artery Embolization
NCT01738724	PHASE4	TERMINATED	Study of the Efficacy of Dienogest in the Treatment of Uterine Leiomyomas When Compared to Desogestrel and Goserelin
NCT02293447	PHASE4	COMPLETED	Intra-arterial Lidocaine for Pain Control Post Uterine Fibroid Embolization
NCT02440750	PHASE4	UNKNOWN	Endometrial Preparation Before Operative Hysteroscopy in Premenopausal Women
NCT02470741	PHASE4	COMPLETED	Pilot of Letrozole for Uterine Myomas
NCT03210324	PHASE4	TERMINATED	A Study on the Mifepristone Tablets in the Treatment of Symptomatic Uterine Fibroids With Safety and Efficacy
NCT03317795	PHASE4	COMPLETED	Treatment of Heavy Menstrual Bleeding in Women With Uterine Fibroids
NCT03500367	PHASE4	UNKNOWN	Efficacy and Safety of Rapamycin (Sirolimus) in the Treatment of Symptomatic Uterine Fibroids and Leiomyomatosis
NCT03886220	PHASE4	COMPLETED	A Study to Evaluate the Safety and Efficacy of Elagolix for the Management of Heavy Menstrual Bleeding Associated With Uterine Fibroids in Premenopausal Women
NCT04132349	PHASE4	TERMINATED	Ulipristal Acetate in Symptomatic Uterine Fibroid
NCT04832906	PHASE4	COMPLETED	UA Versus UAE in Treatment of Fibroids
NCT06143631	PHASE4	RECRUITING	Prescription of Letrozole for Uterine Myoma
NCT00152256	PHASE3	COMPLETED	A Study to Evaluate of the Safety and Effectiveness of Asoprisnil in Treating Women With Uterine Fibroids
NCT00156156	PHASE3	COMPLETED	Study of Asoprisnil in the Treatment of Uterine Fibroids.
NCT00156208	PHASE3	COMPLETED	Safety of Treatment of Uterine Fibroids With Asoprisnil
NCT00295217	PHASE3	COMPLETED	MR Guided Focused Ultrasound Surgery in the Treatment of Uterine Fibroids: Software V4.2 Validation
NCT00365989	PHASE3	COMPLETED	MR Guided Focused Ultrasound Treatment of Uterine Fibroids With Enhanced Sonication
NCT00702702	PHASE3	TERMINATED	Safety and Efficacy of Proellex in Pre-menopausal Anemic Women With Symptomatic Uterine Fibroids
NCT00735553	PHASE3	TERMINATED	Evaluating the Safety and Efficacy of Proellex® (CDB-4124) in Premenopausal Women With Symptomatic Uterine Fibroids
NCT00737282	PHASE3	TERMINATED	Multicenter Study Evaluating the Safety of Proellex® in Premenopausal Women With Uterine Fibroids
NCT00785356	PHASE3	TERMINATED	Safety and Efficacy of Proellex in Pre-Menopausal Anemic Women With Symptomatic Uterine Fibroids
NCT00853567	PHASE3	TERMINATED	Evaluating the Safety and Efficacy of Proellex® in Premenopausal Women With Symptomatic Uterine Fibroids
NCT00874302	PHASE3	WITHDRAWN	Safety and Efficacy of 25 and 50 mg Doses of Proellex® in Treating the Recurrence of Uterine Fibroid Symptoms
NCT01064960	PHASE3	COMPLETED	Therapeutic MRI-HIFU Ablation of Uterine Fibroids in a 3T MRI Scanner
NCT01069120	PHASE3	TERMINATED	Safety of 25 and 50 mg Proellex® in the Treatment of Women With Symptomatic Uterine Fibroids
NCT01141062	PHASE3	COMPLETED	Therapeutic MRI Guided High Intensity Focused Ultrasound Ablation of Uterine Fibroids
NCT01156857	PHASE3	COMPLETED	PGL4001 Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata
NCT01252069	PHASE3	COMPLETED	PGL4001 Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata (PEARLIII-extension Study)
NCT01629563	PHASE3	COMPLETED	PGL4001 Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata
NCT01642472	PHASE3	COMPLETED	PGL4001 Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata
NCT01715597	PHASE3	COMPLETED	Study on the Effect of Intravenous Ascorbic Acid on Intraoperative Blood Loss in Women With Uterine Myoma
NCT02425878	PHASE3	TERMINATED	Ulipristal Acetate 10 mg and Asisted Reproduction
NCT02654054	PHASE3	COMPLETED	Efficacy and Safety of Elagolix in Combination With Estradiol/Norethindrone Acetate for the Management of Heavy Menstrual Bleeding Associated With Uterine Fibroids in Premenopausal Women
NCT02655224	PHASE3	COMPLETED	A Placebo-Controlled, Phase 3 Study of Relugolix (TAK-385) 40 mg in the Treatment of Pain Symptoms Associated With Uterine Fibroids