TUBB3

Chr 16AD

tubulin beta 3 class III

Also known as: CDCBM, CDCBM1, CFEOM3, CFEOM3A, FEOM3, TUBB4, beta-4

NCBI Gene: 10381ENSG00000258947UniProt: Q13509OMIM: 602661

This gene encodes beta-tubulin III, a neuron-specific microtubule component that heterodimerizes with alpha-tubulin to form microtubules essential for neurogenesis, axon guidance, and axon maintenance. Autosomal dominant mutations cause congenital fibrosis of extraocular muscles type 3A and cortical dysplasia with other brain malformations. The pathogenic mechanism involves disruption of microtubule assembly and function, leading to abnormal neuronal development and axonal pathfinding.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
DNmechanismADLOEUF 1.112 OMIM phenotypes
VCEP Guidelines: Brain MalformationsReleased
View SpecificationsClinGen Panel
Clinical Summary— TUBB3
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Gene-Disease Validity (ClinGen)
TUBB3-related tubulinopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
92 unique Pathogenic / Likely Pathogenic· 181 VUS of 445 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — TUBB3
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.11LOEUF
pLI 0.000
Z-score 1.13
OE 0.75 (0.52–1.11)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
1.78Z-score
OE missense 0.78 (0.72–0.85)
400 obs / 513.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.75 (0.52–1.11)
0≤0.351.4
Missense OE0.78 (0.72–0.85)
0≤0.61.4
Synonymous OE1.30
0≤1.21.6
LoF obs/exp: 18 / 24.0Missense obs/exp: 400 / 513.8Syn Z: -3.73
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongTUBB3-related cortical dysplasia, complex, with other brain malformationsOTHERAD
strongTUBB3-related fibrosis of extraocular muscles, congenitalOTHERAD
DN
0.6453th %ile
GOF
0.5072th %ile
LOF
0.56top 25%

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median · 1 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

DNTUBB3(E410K) or TUBB3(D417H) is co-assembled with normal tubulins and dominant negatively inhibit KIF-dependent axonal transport.PMID:23503589

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

445 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47
Likely Pathogenic45
VUS181
Likely Benign111
Benign30
Conflicting25
47
Pathogenic
45
Likely Pathogenic
181
VUS
111
Likely Benign
30
Benign
25
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
15
32
0
47
Likely Pathogenic
0
39
6
0
45
VUS
5
144
27
5
181
Likely Benign
0
6
21
84
111
Benign
0
3
22
5
30
Conflicting
—25
Total520710894439

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

View in ClinVar →

Protein Context — Lollipop Plot

TUBB3 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients