TUBB4A

Chr 19AD

tubulin beta 4A class IVa

Also known as: DYT4, TUBB4, beta-5

NCBI Gene: 10382ENSG00000104833UniProt: P04350

This gene encodes a member of the beta tubulin family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. Mutations in this gene cause hypomyelinating leukodystrophy-6 and autosomal dominant torsion dystonia-4. Alternate splicing results in multiple transcript variants encoding different isoforms. A pseudogene of this gene is found on chromosome X. [provided by RefSeq, Jan 2014]

Primary Disease Associations & Inheritance

Dystonia 4, torsion, autosomal dominantMIM #128101
AD
Leukodystrophy, hypomyelinating, 6MIM #612438
AD
386
ClinVar variants
54
Pathogenic / LP
0.11
pLI score
1
Active trials
Clinical Summary— TUBB4A
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.
📋
ClinVar Variants
54 Pathogenic / Likely Pathogenic· 144 VUS of 386 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
0.67LOEUF
pLI 0.109
Z-score 2.41
OE 0.29 (0.14–0.67)
Tolerant

Typical tolerance to LoF variation

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.
4.26Z-score
OE missense 0.31 (0.26–0.37)
93 obs / 301.1 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.0.29 (0.14–0.67)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.31 (0.26–0.37)
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.1.16
0≤1.21.6
LoF obs/exp: 4 / 13.6Missense obs/exp: 93 / 301.1Syn Z: -1.48

ClinVar Variant Classifications

386 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic35
VUS144
Likely Benign131
Benign31
Conflicting15
19
Pathogenic
35
Likely Pathogenic
144
VUS
131
Likely Benign
31
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
10
9
0
19
Likely Pathogenic
0
35
0
0
35
VUS
5
111
23
5
144
Likely Benign
0
4
21
106
131
Benign
0
2
23
6
31
Conflicting
—15
Total516276117375

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

View in ClinVar →

Protein Context — Lollipop Plot

TUBB4A · protein map & ClinVar variants

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

Gene2Phenotype Curations

TUBB4A-related hypomyelination with atrophy of the basal ganglia and cerebellum

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
TUBULIN, BETA-4A; TUBB4A
MIM #602662 · *

Dystonia 4, torsion, autosomal dominant

MIM #128101

Molecular basis of disorder known

Autosomal dominant

Leukodystrophy, hypomyelinating, 6

MIM #612438

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
H-ABC- and dystonia-causing TUBB4A mutations show distinct pathogenic effects.
Krajka V et al.·Sci Adv
2022
In-silico phenotype prediction by normal mode variant analysis in TUBB4A-related disease.
Fellner A et al.·Sci Rep
2022
Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants.
Vulinovic F et al.·Hum Mutat
2018
Gross Motor Function in Pediatric Onset TUBB4A-Related Leukodystrophy: GMFM-88 Performance and Validation of GMFC-MLD in TUBB4A.
Gavazzi F et al.·J Child Neurol
2023
DYT-TUBB4A (DYT4 Dystonia): New Clinical and Genetic Observations.
Bally JF et al.·Neurology
2021
Update on the Genetics of Dystonia.
Lohmann K et al.·Curr Neurol Neurosci Rep
2017Review
Novel TUBB4A mutations and expansion of the neuroimaging phenotype of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC).
Ferreira C et al.·Am J Med Genet A
2014Review
Recent advances in the genetics of dystonia.
Xiao J et al.·Curr Neurol Neurosci Rep
2014Review
[A report of atypical hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum caused by a de novo mutation in tubulin beta 4A (TUBB4A) gene and literature review].
Du Y et al.·Zhonghua Nei Ke Za Zhi
2017Review
The natural history of variable subtypes in pediatric-onset TUBB4A-related leukodystrophy.
Gavazzi F et al.·Mol Genet Metab
2025Natural history
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
LeukodystrophyWhite Matter DiseaseLeukoencephalopathies

The Myelin Disorders Biorepository Project

RECRUITING
NCT03047369Children's Hospital of PhiladelphiaStarted 2016-12-08

External Resources

Links to major genomics databases and tools