TUBB2A

Chr 6AD

tubulin beta 2A class IIa

Also known as: CDCBM5, TUBB, TUBB2

NCBI Gene: 7280 ENSG00000137267 UniProt: Q13885 OMIM: 615101

This gene encodes a beta-tubulin protein that forms heterodimers with alpha-tubulin to create microtubules, which are essential cytoskeletal structures that facilitate mitosis and intracellular transport. Mutations cause complex cortical dysplasia with other brain malformations-5, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (pLI 0.93, LOEUF 0.36), reflecting its critical role in normal brain development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Microtubules, key participants in processes such as mitosis and intracellular transport, are composed of heterodimers of alpha- and beta-tubulins. The protein encoded by this gene is a beta-tubulin. Defects in this gene are associated with complex cortical dysplasia with other brain malformations-5. Two transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.361 OMIM phenotype

Clinical Summary— TUBB2A

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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 0.93). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.36LOEUF

pLI 0.935

Z-score 3.10

OE 0.08 (0.03–0.36)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

5.26Z-score

OE missense 0.11 (0.08–0.15)

31 obs / 277.9 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.36)

0≤0.351.4

Missense OE?0.11 (0.08–0.15)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 1 / 13.1Missense obs/exp: 31 / 277.9Syn Z: -0.06

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTUBB2A-related cortical dysplasia, complex, with other brain malformationsOTHERAD

This gene — mechanism propensity

0.5869th %ile

GOF

0.4578th %ile

LOF

0.60top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOF1 literature citation · LOEUF 0.36

Literature Evidence

LOFThus, confirming that these specific developmental brain malformations are due to TUBB2A and TUBB2B haploinsufficiency.1

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

References