TUBB2B

Chr 6AD

tubulin beta 2B class IIb

Also known as: CDCBM7, PMGYSA, bA506K6.1

The encoded protein is a beta-tubulin isoform that binds GTP and serves as a major component of microtubules in the cytoskeleton. Mutations cause autosomal dominant asymmetric polymicrogyria and complex cortical dysplasia with other brain malformations. The high pLI score (0.99) indicates the gene is extremely intolerant to loss-of-function mutations, suggesting haploinsufficiency as the likely pathogenic mechanism.

OMIMResearchSummary from RefSeq, OMIM, UniProt
DNmechanismADLOEUF 0.221 OMIM phenotype
VCEP Guidelines: Brain MalformationsReleased
View SpecificationsClinGen Panel
Clinical SummaryTUBB2B
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Gene-Disease Validity (ClinGen)
complex cortical dysplasia with other brain malformations · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Dual constrained — LoF & missense intolerant
LoF Constraint
0.22LOEUF
pLI 0.988
Z-score 3.40
OE 0.00 (0.000.22)
Highly constrained

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

Missense Constraint
5.12Z-score
OE missense 0.11 (0.080.15)
30 obs / 264.1 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios
LoF OE0.00 (0.000.22)
00.351.4
Missense OE0.11 (0.080.15)
00.61.4
Synonymous OE0.82
01.21.6
LoF obs/exp: 0 / 13.4Missense obs/exp: 30 / 264.1Syn Z: 1.53
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveTUBB2B-related polymicrogyria asymmetricDNAD
DN
0.5477th %ile
GOF
0.4382th %ile
LOF
0.64top 25%

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.

LOF1 literature citation · LOEUF 0.22
DN1 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

DNTUBB2B codes for one of the isotypes of beta-tubulin and dominant negative variants in this gene result in distinctive malformations of cortical development (MCD), including dysgyria, dysmorphic basal ganglia and cerebellar anomalies.PMID:34592644
LOFThus, confirming that these specific developmental brain malformations are due to TUBB2A and TUBB2B haploinsufficiency.PMID:31634935

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

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

TUBB2B · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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