TUBB3

Chr 16AD

tubulin beta 3 class III

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

NCBI Gene: 10381 ENSG00000258947 UniProt: Q13509 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 1.112 OMIM phenotypes

VCEP Guidelines: Brain MalformationsReleased

View Specifications ClinGen 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

55 unique Pathogenic / Likely Pathogenic· 159 VUS of 386 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 OE?0.75 (0.52–1.11)

0≤0.351.4

Missense OE?0.78 (0.72–0.85)

0≤0.61.4

Synonymous OE?1.30

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

This gene — mechanism propensity

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.1

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

References

1.PMID 23503589 ↗

ClinVar Variant Classifications

386 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic40

VUS159

Likely Benign112

Benign30

Conflicting25

Pathogenic

Likely Pathogenic

159

VUS

112

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	14	1	0	15
Likely Pathogenic	0	40	0	0	40
VUS	5	144	5	5	159
Likely Benign	0	7	21	84	112
Benign	0	3	22	5	30
Conflicting	—				25
Total	5	208	49	94	381

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

View in ClinVar →

38 pathogenic / likely-pathogenic (of 63) ClinVar copy-number / structural variants overlap TUBB3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →