TUBB4A

Chr 19AD

tubulin beta 4A class IVa

Also known as: DYT4, TUBB4, beta-5

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]

GeneReviewsOMIMResearchGenerating clinical summary…
GOFmechanismADLOEUF 0.672 OMIM phenotypes
VCEP Guidelines: LeukodystrophyPilot
ClinGen Panel
Clinical SummaryTUBB4A
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Gene-Disease Validity (ClinGen)
TUBB4A-related neurologic disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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
48 unique Pathogenic / Likely Pathogenic· 140 VUS of 378 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
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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

Missense constrained — critical functional residues
LoF Constraint?
0.67LOEUF
pLI 0.109
Z-score 2.41
OE 0.29 (0.140.67)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?
4.26Z-score
OE missense 0.31 (0.260.37)
93 obs / 301.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?
LoF OE?0.29 (0.140.67)
00.351.4
Missense OE?0.31 (0.260.37)
00.61.4
Synonymous OE?1.16
01.21.6
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

DN
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. 1.PMID 23582646

ClinVar Variant Classifications

378 submitted variants in ClinVar

Classification Summary

Pathogenic10
Likely Pathogenic38
VUS140
Likely Benign135
Benign29
Conflicting15
10
Pathogenic
38
Likely Pathogenic
140
VUS
135
Likely Benign
29
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
9
1
0
10
Likely Pathogenic
0
38
0
0
38
VUS
7
114
14
5
140
Likely Benign
0
5
21
109
135
Benign
0
1
23
5
29
Conflicting
15
Total716759119367

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 15) 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 →

Protein Context — Lollipop Plot

TUBB4A · protein map & ClinVar variants

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