TUBB3

Chr 16AD

tubulin beta 3 class III

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

NCBI Gene: 10381ENSG00000258947UniProt: Q13509

This gene encodes a class III member of the beta tubulin protein family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. This protein is primarily expressed in neurons and may be involved in neurogenesis and axon guidance and maintenance. Mutations in this gene are the cause of congenital fibrosis of the extraocular muscles type 3. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Oct 2010]

Primary Disease Associations & Inheritance

Cortical dysplasia, complex, with other brain malformations 1MIM #614039
AD
Fibrosis of extraocular muscles, congenital, 3AMIM #600638
AD
436
ClinVar variants
92
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— TUBB3
🧬
Gene-Disease Validity (ClinGen)
TUBB3-related tubulinopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
92 Pathogenic / Likely Pathogenic· 180 VUS of 436 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.78Z-score
OE missense 0.78 (0.72–0.85)
400 obs / 513.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.75 (0.52–1.11)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.78 (0.72–0.85)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.30
0≤1.21.6
LoF obs/exp: 18 / 24.0Missense obs/exp: 400 / 513.8Syn Z: -3.73

ClinVar Variant Classifications

436 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47
Likely Pathogenic45
VUS180
Likely Benign109
Benign30
Conflicting25
47
Pathogenic
45
Likely Pathogenic
180
VUS
109
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
1
143
31
5
180
Likely Benign
0
6
21
82
109
Benign
0
3
22
5
30
Conflicting
—25
Total120611292436

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.

Gene2Phenotype Curations

TUBB3-related cortical dysplasia, complex, with other brain malformations

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

TUBB3-related fibrosis of extraocular muscles, congenital

strong
ADUndeterminedAltered Gene Product Structure
Eye
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
TUBULIN, BETA-3; TUBB3
MIM #602661 · *

Cortical dysplasia, complex, with other brain malformations 1

MIM #614039

Molecular basis of disorder known

Autosomal dominant

Fibrosis of extraocular muscles, congenital, 3A

MIM #600638

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — TUBB3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
NF1 mutation and TUBB3 amplification in gastric histiocytic sarcoma: a case report and literature review.
Yang Y et al.·Med Mol Morphol
2024Review
TUBB3 M323V Syndrome Presents with Infantile Nystagmus.
Jin S et al.·Genes (Basel)
2021Review
Prenatal phenotyping of fetal tubulinopathies: A multicenter retrospective case series.
Brar BK et al.·Prenat Diagn
2022Review
Clinical and genetic characteristics of Chinese patients with congenital fibrosis of the extraocular muscles.
Wu J et al.·Orphanet J Rare Dis
2024Cohort
Insights on the Role of α- and β-Tubulin Isotypes in Early Brain Development.
Tantry MSA et al.·Mol Neurobiol
2023Review
Attenuated Clinical Forms of Tubulinopathies in Children and Adults: A Series of 24 Individuals.
Durizot M et al.·Pediatr Neurol
2025Cohort
Looking at drug resistance mechanisms for microtubule interacting drugs: does TUBB3 work?
Ferlini C et al.·Curr Cancer Drug Targets
2007Review
Epilepsy in Tubulinopathy: Personal Series and Literature Review.
Romaniello R et al.·Cells
2019Review
Identification of TUBB3 as an immunotherapy target in lung cancer by genome wide in vivo CRISPR screening.
Zhao D et al.·Neoplasia
2025
Evaluating the clinical utility and strategy of whole-exome sequencing testing for fetuses with increased nuchal translucency.
Zhou F et al.·Am J Obstet Gynecol
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Breast Cancer

First-line Gemcitabine Plus Cisplatin in Locally Advanced (IIIC Stage) Breast Cancer Patients

ACTIVE NOT RECRUITING
NCT06531447Phase PHASE2The National Center of Oncology, AzerbaijanStarted 2014-05
CisplatinGemcitabineDoxorubicin
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07

External Resources

Links to major genomics databases and tools