HMGB1

Chr 13

high mobility group box 1

Also known as: HMG-1, HMG1, HMG3, SBP-1

NCBI Gene: 3146 ENSG00000189403 UniProt: P09429 OMIM: 163905

The encoded protein is a multifunctional chromatin-associated non-histone protein that acts as a DNA chaperone involved in transcription, replication, chromatin remodeling, and DNA repair, and also functions as a danger-associated molecular pattern molecule in immune responses. This gene is associated with neurodevelopmental disorders and intellectual disability, with an autosomal dominant inheritance pattern. The gene shows high constraint against loss-of-function variants (pLI 0.82, LOEUF 0.47), indicating that haploinsufficiency is likely not well tolerated.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein that belongs to the High Mobility Group-box superfamily. The encoded non-histone, nuclear DNA-binding protein regulates transcription, and is involved in organization of DNA. This protein plays a role in several cellular processes, including inflammation, cell differentiation and tumor cell migration. Multiple pseudogenes of this gene have been identified. Alternative splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Sep 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · HMGB1-related brachyphalangy, polydactyly and tibial aplasia syndrome · AD · ClinGen 2026

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

1774

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.47

LOEUF

—

Mechanism

📖

GeneReview available — HMGB1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.820

Z-score 2.64

OE 0.10 (0.03–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.69Z-score

OE missense 0.27 (0.20–0.37)

30 obs / 109.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.10 (0.03–0.47)

0≤0.351.4

Missense OE?0.27 (0.20–0.37)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 1 / 10.0Missense obs/exp: 30 / 109.2Syn Z: -0.62

Background carrier burden — how many people carry a rare variant somewhere in HMGB1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 420

92 rare PASS variants

Rare truncating (LoF)

1 in 720,000

1 rare PASS variants

Rare synonymous (reference)

1 in 510

97 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HMGB1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 400	none seen
South Asian	~43k	1 in 520	none seen
Remaining (unassigned)	~30k	1 in 450	none seen
European (Finnish)	~27k	1 in 530	≈ 1 in 26,000
Admixed American	~22k	1 in 570	none seen
African / African American	~21k	1 in 340	none seen
East Asian	~20k	1 in 390	none seen
Ashkenazi Jewish	~13k	1 in 2,000	none seen
Middle Eastern	~2,882	≈ 1 in 1,200	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 3 of 4 coding exons well covered in gnomAD exomes; exon 2 marginal. Genomes: all 4.? see exons ↓