H3-3A

Chr 1AD

H3.3 histone A

Also known as: BRYLIB1, H3.3A, H3F3, H3F3A

NCBI Gene: 3020ENSG00000163041UniProt: P84243

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene contains introns and its mRNA is polyadenylated, unlike most histone genes. The protein encoded is a replication-independent member of the histone H3 family. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Bryant-Li-Bhoj neurodevelopmental syndrome 1MIM #619720
AD
Bryant-Li-Bhoj neurodevelopmental syndrome 1MIM #619720
AD
Bryant-Li-Bhoj neurodevelopmental syndrome 2MIM #619721
AD
UniProtGlioma
90
ClinVar variants
52
Pathogenic / LP
0.12
pLI score
0
Active trials
Clinical Summary— H3-3A
🧬
Gene-Disease Validity (ClinGen)
Bryant-Li-Bhoj neurodevelopmental syndrome 1 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.12) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
52 Pathogenic / Likely Pathogenic· 29 VUS of 90 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
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.
1.16LOEUF
pLI 0.123
Z-score 1.36
OE 0.37 (0.15–1.16)
Tolerant

Highly tolerant — LoF variants common in population

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.
3.16Z-score
OE missense 0.06 (0.03–0.12)
5 obs / 88.6 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.37 (0.15–1.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.06 (0.03–0.12)
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.1.08
0≤1.21.6
LoF obs/exp: 2 / 5.4Missense obs/exp: 5 / 88.6Syn Z: -0.33

ClinVar Variant Classifications

90 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36
Likely Pathogenic16
VUS29
Likely Benign6
Conflicting3
36
Pathogenic
16
Likely Pathogenic
29
VUS
6
Likely Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
5
31
0
36
Likely Pathogenic
0
15
1
0
16
VUS
2
23
4
0
29
Likely Benign
1
1
2
2
6
Benign
0
0
0
0
0
Conflicting
—3
Total34438290

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

View in ClinVar →

Protein Context — Lollipop Plot

H3-3A · protein map & ClinVar variants

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

Gene2Phenotype Curations

H3-3A-related Bryant-Li-Bhoj neurodevelopmental syndrome

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

3 OMIM entries

OMIM

Bryant-Li-Bhoj neurodevelopmental syndrome 1

MIM #619720

Molecular basis of disorder known

Autosomal dominant

Bryant-Li-Bhoj neurodevelopmental syndrome 1

MIM #619720

Molecular basis of disorder known

Autosomal dominant

Bryant-Li-Bhoj neurodevelopmental syndrome 2

MIM #619721

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — H3-3A
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Antisense oligonucleotide therapy for H3.3K27M diffuse midline glioma.
Zhang Q et al.·Sci Transl Med
2023
A new subtype of diffuse midline glioma, H3 K27 and BRAF/FGFR1 co-altered: a clinico-radiological and histomolecular characterisation.
Auffret L et al.·Acta Neuropathol
2023
Divergent molecular pathways drive monomorphic epitheliotropic and enteropathy-associated intestinal T-cell lymphoma.
Vallois D et al.·Leukemia
2026
Expanded phenotypic spectrum of neurodevelopmental and neurodegenerative disorder Bryant-Li-Bhoj syndrome with 38 additional individuals.
Layo-Carris DE et al.·Eur J Hum Genet
2024
Tectal glioma: clinical, radiological, and pathological features, and the importance of molecular analysis.
Imoto R et al.·Brain Tumor Pathol
2025
Methylation Analysis Reveals Epigenetic Congruence Between Bone Sarcomas With H3-3A Mutations and Malignant Giant Cell Tumors of Bone.
Saoud C et al.·Mod Pathol
2025
Pan-tumor landscape of fibroblast growth factor receptor 1-4 genomic alterations.
Murugesan K et al.·ESMO Open
2022
Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma.
Mellid S et al.·Front Endocrinol (Lausanne)
2023
Genomic Insights Into High-Grade Infarct-Associated Bone Sarcomas.
Tvrdik T et al.·Mod Pathol
2024
Drivers underpinning the malignant transformation of giant cell tumour of bone.
Fittall MW et al.·J Pathol
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