TUBA4A

Chr 2ADAR

tubulin alpha 4a

Also known as: ALS22, CMYO26, FTDALS9, H2-ALPHA, OZEMA23, SPAX11, TUBA1

NCBI Gene: 7277 ENSG00000127824 UniProt: P68366 OMIM: 191110

This gene encodes an alpha tubulin protein that forms heterodimers with beta tubulin to constitute microtubules, the major structural components of the cellular cytoskeleton. Mutations cause autosomal dominant spastic ataxia, frontotemporal dementia with or without amyotrophic lateral sclerosis, and autosomal recessive congenital myopathy, affecting the nervous system and skeletal muscle. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.62), and inheritance patterns vary by phenotype with both dominant and recessive forms described.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Microtubules of the eukaryotic cytoskeleton perform essential and diverse functions and are composed of a heterodimer of alpha and beta tubulin. The genes encoding these microtubule constituents are part of the tubulin superfamily, which is composed of six distinct families. Genes from the alpha, beta and gamma tubulin families are found in all eukaryotes. The alpha and beta tubulins represent the major components of microtubules, while gamma tubulin plays a critical role in the nucleation of microtubule assembly. There are multiple alpha and beta tubulin genes and they are highly conserved among and between species. This gene encodes an alpha tubulin that is a highly conserved homolog of a rat testis-specific alpha tubulin. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2013]

OMIM ResearchGenerating clinical summary…

DNmechanismAD/ARLOEUF 0.624 OMIM phenotypes

Clinical Summary— TUBA4A

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Gene-Disease Validity (ClinGen)

amyotrophic lateral sclerosis type 22 · ADModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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ClinVar Variants

24 unique Pathogenic / Likely Pathogenic· 34 VUS of 123 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.62LOEUF

pLI 0.160

Z-score 2.60

OE 0.27 (0.13–0.62)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

3.30Z-score

OE missense 0.44 (0.38–0.51)

120 obs / 273.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.27 (0.13–0.62)

0≤0.351.4

Missense OE?0.44 (0.38–0.51)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 4 / 14.8Missense obs/exp: 120 / 273.8Syn Z: 0.07

This gene — mechanism propensity

0.78top 25%

GOF

0.4875th %ile

LOF

0.3746th %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

DNTUBA4A mutants act as dominant negatives to alter microtubule dynamics and stability1

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

References

1.PMID 25374358 ↗

ClinVar Variant Classifications

123 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic7

VUS34

Likely Benign45

Benign16

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	10	5	0	17
Likely Pathogenic	4	3	0	0	7
VUS	3	29	1	1	34
Likely Benign	0	1	9	35	45
Benign	0	0	12	4	16
Conflicting	—				1
Total	9	43	27	40	120

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap TUBA4A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →