HMGB3

Chr XX-linked

high mobility group box 3

Also known as: HMG-2a, HMG-4, HMG2A, HMG4

NCBI Gene: 3149ENSG00000029993UniProt: O15347

This gene encodes a member of a family of proteins containing one or more high mobility group DNA-binding motifs. The encoded protein plays an important role in maintaining stem cell populations, and may be aberrantly expressed in tumor cells. A mutation in this gene was associated with microphthalmia, syndromic 13. There are numerous pseudogenes of this gene on multiple chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

Primary Disease Associations & Inheritance

?Microphthalmia, syndromic 13MIM #300915
X-linked
116
ClinVar variants
88
Pathogenic / LP
0.80
pLI score
0
Active trials
Clinical Summary— HMGB3
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.80) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
88 Pathogenic / Likely Pathogenic· 18 VUS of 116 total submissions

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.
0.57LOEUF
pLI 0.798
Z-score 2.13
OE 0.00 (0.00–0.57)
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.
1.78Z-score
OE missense 0.42 (0.32–0.57)
32 obs / 75.4 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 (0.00–0.57)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.42 (0.32–0.57)
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.1.46
0≤1.21.6
LoF obs/exp: 0 / 5.3Missense obs/exp: 32 / 75.4Syn Z: -1.86

ClinVar Variant Classifications

116 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic87
Likely Pathogenic1
VUS18
Likely Benign7
Benign2
Conflicting1
87
Pathogenic
1
Likely Pathogenic
18
VUS
7
Likely Benign
2
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
87
0
87
Likely Pathogenic
0
0
1
0
1
VUS
1
12
5
0
18
Likely Benign
0
0
4
3
7
Benign
0
0
1
1
2
Conflicting
—1
Total112984116

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

View in ClinVar →

Protein Context — Lollipop Plot

HMGB3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

HMGB3-related colobomatous microphthalmia, microcephaly, intellectual disability, and short stature

limited
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Microphthalmia, syndromic 13

MIM #300915

Molecular basis of disorder known

X-linked
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Proteogenomic characterization of small cell lung cancer identifies biological insights and subtype-specific therapeutic strategies.
Liu Q et al.·Cell
2024
Overview of high mobility group box 3 (HMGB3] protein.
Mirzaee F et al.·Mol Genet Genomics
2025Review
HMGB3 promotes brain metastasis of lung adenocarcinoma by recruiting SSBP1 for nuclear translocation to remodel mitochondrial metabolism.
Cui H et al.·Cancer Commun (Lond)
2025Functional
Malignant epithelial cell marker-driven risk signature enables precise stratification in esophageal cancer.
Zhang H et al.·Front Immunol
2025
Targeting HMGB3/hTERT axis for radioresistance in cervical cancer.
Li Z et al.·J Exp Clin Cancer Res
2020
Nuclear exosome HMGB3 secreted by nasopharyngeal carcinoma cells promotes tumour metastasis by inducing angiogenesis.
Zhang K et al.·Cell Death Dis
2021
Hsa_circ_0004662 Accelerates the Progression of Ulcerative Colitis via the microRNA-532/HMGB3 Signalling Axis.
Qiu C et al.·J Cell Mol Med
2025
ELAVL1 regulates glycolysis in nasopharyngeal carcinoma cells through the HMGB3/β-catenin axis.
Cui Y et al.·Mol Med
2024
Prognostic value of HMGB3 expression in patients with non-small cell lung cancer.
Song N et al.·Tumour Biol
2013Cohort
LncRNA SNHG5 promotes nasopharyngeal carcinoma progression by regulating miR-1179/HMGB3 axis.
Liu D et al.·BMC Cancer
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools