TUBB4A

Chr 19AD

tubulin beta 4A class IVa

Also known as: DYT4, TUBB4, beta-5

NCBI Gene: 10382 ENSG00000104833 UniProt: P04350 OMIM: 602662

This gene encodes a beta tubulin protein that heterodimerizes with alpha tubulin to form microtubules, which are essential components of the cellular cytoskeleton. Mutations cause autosomal dominant dystonia-4 (torsion dystonia) and hypomyelinating leukodystrophy-6 through a dominant-negative mechanism where mutant proteins disrupt normal microtubule function. Both conditions follow autosomal dominant inheritance with the dystonia typically presenting with focal onset and the leukodystrophy causing developmental delays and motor dysfunction.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.672 OMIM phenotypes

VCEP Guidelines: LeukodystrophyPilot

ClinGen Panel

Clinical Summary— TUBB4A

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Gene-Disease Validity (ClinGen)

TUBB4A-related neurologic disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

22 unique Pathogenic / Likely Pathogenic· 129 VUS of 292 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TUBB4A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.67LOEUF

pLI 0.109

Z-score 2.41

OE 0.29 (0.14–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

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?

LoF OE?0.29 (0.14–0.67)

0≤0.351.4

Missense OE?0.31 (0.26–0.37)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 4 / 13.6Missense obs/exp: 93 / 301.1Syn Z: -1.48

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTUBB4A-related hypomyelination with atrophy of the basal ganglia and cerebellumGOFAD

This gene — mechanism propensity

0.74top 25%

GOF

0.5465th %ile

LOF

0.3646th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNTUBB4A is highly expressed in neurons, and Simons et al. (2013) suggested that the mutation may result in a dominant-negative effect on tubulin dimerization, microtubule polymerization, or microtubule stability in neurons with a secondary involvement of glial cells.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 23582646 ↗

ClinVar Variant Classifications

292 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic19

VUS129

Likely Benign120

Benign10

Conflicting9

Pathogenic

Likely Pathogenic

129

VUS

120

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	0	0	3
Likely Pathogenic	0	19	0	0	19
VUS	7	104	13	5	129
Likely Benign	0	2	20	98	120
Benign	0	1	9	0	10
Conflicting	—				9
Total	7	129	42	103	290

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

View in ClinVar →

2 pathogenic / likely-pathogenic (of 8) ClinVar copy-number / structural variants overlap TUBB4A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →