HMGA1

Chr 6AD

high mobility group AT-hook 1

Also known as: HMG-R, HMGA1A, HMGIY

NCBI Gene: 3159ENSG00000137309UniProt: P17096

This gene encodes a chromatin-associated protein involved in the regulation of gene transcription, integration of retroviruses into chromosomes, and the metastatic progression of cancer cells. The encoded protein preferentially binds to the minor groove of AT-rich regions in double-stranded DNA. Multiple transcript variants encoding different isoforms have been found for this gene. Pseudogenes of this gene have been identified on multiple chromosomes. [provided by RefSeq, Jan 2016]

Primary Disease Associations & Inheritance

{Type 2 diabetes mellitus, susceptibility to}MIM #125853
AD
16
ClinVar variants
4
Pathogenic / LP
0.83
pLI score
1
Active trials
Clinical Summary— HMGA1
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.83) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
4 Pathogenic / Likely Pathogenic· 9 VUS of 16 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.51LOEUF
pLI 0.832
Z-score 2.25
OE 0.00 (0.00–0.51)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.81Z-score
OE missense 0.38 (0.27–0.53)
25 obs / 66.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.51)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.38 (0.27–0.53)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 0 / 5.9Missense obs/exp: 25 / 66.5Syn Z: 0.04

ClinVar Variant Classifications

16 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
VUS9
Likely Benign1
Benign2
4
Pathogenic
9
VUS
1
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
4
0
4
Likely Pathogenic
0
0
0
0
0
VUS
0
7
2
0
9
Likely Benign
0
0
0
1
1
Benign
0
0
1
1
2
Total077216

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

HMGA1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Type 2 diabetes mellitus, susceptibility to}

MIM #125853

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mediterranean Diet Nutrients to Turn the Tide against Insulin Resistance and Related Diseases.
Mirabelli M et al.·Nutrients
2020Review
NAT10 Promotes Prostate Cancer Growth and Metastasis by Acetylating mRNAs of HMGA1 and KRT8.
Li KJ et al.·Adv Sci (Weinh)
2024
High Mobility Group A1 (HMGA1): Structure, Biological Function, and Therapeutic Potential.
Wang L et al.·Int J Biol Sci
2022Review
Exosome-transmitted LUCAT1 promotes stemness transformation and chemoresistance in bladder cancer by binding to IGF2BP2.
Zhan Y et al.·J Exp Clin Cancer Res
2025
HMGA1 orchestrates chromatin compartmentalization and sequesters genes into 3D networks coordinating senescence heterogeneity.
Olan I et al.·Nat Commun
2024
HMGA1 deficiency: a pathogenic link between tau pathology and insulin resistance.
Mirabelli M et al.·EBioMedicine
2025
HMGA1 in cancer: Cancer classification by location.
Wang Y et al.·J Cell Mol Med
2019Review
Clinical Implications of Extracellular HMGA1 in Breast Cancer.
Méndez O et al.·Int J Mol Sci
2019Review
HMGA1 variant IVS5-13insC is associated with insulin resistance and type 2 diabetes: an updated meta-analysis.
Liu Y et al.·Afr Health Sci
2018Meta-analysis
"Best friends" sharing the HMGA1 gene: comparison of the human and canine HMGA1 to orthologous other species.
Murua Escobar H et al.·J Hered
2005Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
The role of HMGA1 in genome stability: Implications in human cancer.
Lei XY et al.·Cell Mol Life Sci
2026🔓 Open Access
Promoter Hypomethylation Unleashes HMGA1 to Orchestrate Immune Evasion and Therapy Resistance Across Cancers.
Shahzadi I et al.·Biology (Basel)
2025🔓 Open Access
HMGA1 drives EMT in obliterative bronchiolitis through epigenetic regulation of chromatin accessibility in pulmonary epithelial cells.
Xia T et al.·Clin Epigenetics
2025🔓 Open Access
Sequestration and suppressed synthesis of oncogenic HMGA1 using engineered adenoviruses decreases human pancreatic and breast cancer cell characteristics.
Hasan MS et al.·PLoS One
2025🔓 Open Access
HMGA1/SMAD3 Promoter Complex Mediates PD-L1-Dependent Transcriptional Regulation of GAS6, EGR1 and PD-L1.
Guo H et al.·Front Biosci (Landmark Ed)
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Obesity and Obesity-related Medical ConditionsCardiovascular RiskGenetics

Cardiometabolic Risk of Obese Subjects: Cross-sectional Study

RECRUITING
NCT06714058IRCCS Azienda Ospedaliero-Universitaria di BolognaStarted 2024-11-30

External Resources

Links to major genomics databases and tools