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.

GeneReviews 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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Cortical dysplasia, complex, with other brain malformations 5MIM #615763

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · tubulinopathy · AD · ClinGen 2023

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.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.36

LOEUF

LOF

Mechanism· predicted

📖

GeneReview available — TUBB2A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in TUBB2A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 410

91 rare PASS variants

Rare truncating (LoF)

1 in 26,000

11 rare PASS variants

Rare synonymous (reference)

1 in 120

205 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TUBB2A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 8 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 2,200	1 in 79,000
South Asian	~43k	1 in 600	1 in 2,300
Remaining (unassigned)	~30k	1 in 2,100	none seen
European (Finnish)	~27k	1 in 3,100	none seen
Admixed American	~22k	1 in 550	≈ 1 in 22,000
African / African American	~21k	1 in 1,300	≈ 1 in 21,000
East Asian	~20k	1 in 2,500	none seen
Ashkenazi Jewish	~13k	1 in 1,300	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 4 marginal. Genomes: 3 of 4 (exon 4 below).? see exons ↓