TUBA4A

Chr 2

tubulin alpha 4a

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

NCBI Gene: 7277 ENSG00000127824 UniProt: P68366

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.

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]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtFrontotemporal dementia and/or amyotrophic lateral sclerosis 9

UniProtCongenital myopathy 26

UniProtSpastic ataxia 11, autosomal dominant

UniProtOocyte/zygote/embryo maturation arrest 23

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.62

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in TUBA4A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 460

316 rare PASS variants

Rare truncating (LoF)

1 in 3,000

55 rare PASS variants

Rare synonymous (reference)

1 in 200

243 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TUBA4A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 560	1 in 2,900
South Asian	~43k	1 in 360	1 in 1,600
Remaining (unassigned)	~30k	1 in 450	≈ 1 in 7,900
European (Finnish)	~27k	1 in 520	1 in 4,800
Admixed American	~22k	1 in 380	1 in 2,700
African / African American	~21k	1 in 640	1 in 2,200
East Asian	~20k	1 in 200	1 in 2,600
Ashkenazi Jewish	~13k	1 in 540	≈ 1 in 3,400
Middle Eastern	~2,884	1 in 480	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 3 of 4 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 4.? see exons ↓