TUBA1A

Chr 12

tubulin alpha 1a

Also known as: B-ALPHA-1, LIS3, TUBA3

NCBI Gene: 7846 ENSG00000167552 UniProt: Q71U36

This gene encodes alpha tubulin, a major component of microtubules that is predominantly expressed in differentiated neurologic cells and essential for proper neuronal migration during brain development. Heterozygous loss-of-function mutations cause autosomal dominant lissencephaly type 3 (LIS3), characterized by microcephaly, intellectual disability, and early-onset epilepsy. The pathogenic mechanism involves disrupted microtubule function leading to defective neuronal migration and abnormal cortical development.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Microtubules of the eukaryotic cytoskeleton perform essential and diverse functions and are composed of a heterodimer of alpha and beta tubulins. The genes encoding these microtubule constituents belong to 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, which are highly conserved among species. This gene encodes alpha tubulin and is highly similar to the mouse and rat Tuba1 genes. Northern blot studies have shown that the gene expression is predominantly found in morphologically differentiated neurologic cells. This gene is one of three alpha-tubulin genes in a cluster on chromosome 12q. Mutations in this gene cause lissencephaly type 3 (LIS3) - a neurological condition characterized by microcephaly, intellectual disability, and early-onset epilepsy caused by defective neuronal migration. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.32

VCEP Guidelines: Brain MalformationsReleased

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Clinical Summary— TUBA1A

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Gene-Disease Validity (ClinGen)

tubulinopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

200 unique Pathogenic / Likely Pathogenic· 92 VUS of 441 total submissions

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GeneReview available — TUBA1A

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.32LOEUF

pLI 0.967

Z-score 3.34

OE 0.07 (0.02–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

5.58Z-score

OE missense 0.03 (0.01–0.05)

7 obs / 260.7 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.07 (0.02–0.32)

0≤0.351.4

Missense OE?0.03 (0.01–0.05)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 1 / 15.0Missense obs/exp: 7 / 260.7Syn Z: -0.77

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTUBA1A-related tubulinopathyOTHERAD

This gene — mechanism propensity

0.4983th %ile

GOF

0.3689th %ile

LOF

0.69top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.32

DN1 literature citation

Literature Evidence

DNOur data suggest that the TUBA1A mutations disrupting lateral interactions have pronounced dominant-negative effects on microtubule dynamics that are associated with the severe end of the lissencephaly spectrum.1

LOFThe diminished production of TUBA1A tubulin in R264C individuals is consistent with haploinsufficiency as a cause of the disease phenotype.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

441 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic63

Likely Pathogenic137

VUS92

Likely Benign98

Benign14

Conflicting32

Pathogenic

137

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	1	62	0	0	63
Likely Pathogenic	1	135	1	0	137
VUS	4	84	4	0	92
Likely Benign	0	1	27	70	98
Benign	0	0	6	8	14
Conflicting	—				32
Total	6	282	38	78	436

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap TUBA1A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →