TUBB4B

Chr 9AD

tubulin beta 4B class IVb

Also known as: Beta2, LCAEOD, TUBB2, TUBB2C

NCBI Gene: 10383ENSG00000188229UniProt: P68371

Enables double-stranded RNA binding activity. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Located in axonemal microtubule; intercellular bridge; and mitotic spindle. Implicated in Leber congenital amaurosis with early-onset deafness. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

Leber congenital amaurosis with early-onset deafnessMIM #617879
AD
277
ClinVar variants
102
Pathogenic / LP
0.81
pLI score
0
Active trials
Clinical Summary— TUBB4B
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.81) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
102 Pathogenic / Likely Pathogenic· 36 VUS of 277 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
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.
0.44LOEUF
pLI 0.809
Z-score 3.00
OE 0.14 (0.06–0.44)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
4.50Z-score
OE missense 0.24 (0.20–0.29)
66 obs / 276.4 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.14 (0.06–0.44)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.24 (0.20–0.29)
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.2.06
0≤1.21.6
LoF obs/exp: 2 / 14.2Missense obs/exp: 66 / 276.4Syn Z: -9.11

ClinVar Variant Classifications

277 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic92
Likely Pathogenic10
VUS36
Likely Benign110
Benign19
Conflicting5
92
Pathogenic
10
Likely Pathogenic
36
VUS
110
Likely Benign
19
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
90
0
92
Likely Pathogenic
0
3
7
0
10
VUS
1
21
13
1
36
Likely Benign
0
0
18
92
110
Benign
0
0
9
10
19
Conflicting
—5
Total126137103272

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

View in ClinVar →

Protein Context — Lollipop Plot

TUBB4B · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
TUBULIN, BETA-4B; TUBB4B
MIM #602660 · *

Leber congenital amaurosis with early-onset deafness

MIM #617879

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A novel missense TUBB4B variant outside of the canonical hotspot is associated with cone-rod dystrophy and sensorineural hearing loss.
Cao LY et al.·Ophthalmic Genet
2025
Primary ciliary dyskinesia phenotypes and correlation with genotype.
Horani A et al.·Curr Opin Pulm Med
2025Review
Whole genome sequencing enhances molecular diagnosis of primary ciliary dyskinesia.
Black HA et al.·Pediatr Pulmonol
2024
Mutation of beta-tubulin 4B gene (TUBB4B) causes autosomal dominant retinitis pigmentosa with sensorineural hearing loss in a multigenerational family.
Gregory-Evans CY et al.·Mol Vis
2025
Comprehensive analysis of two hotspot codons in the TUBB4B gene and associated phenotypes.
Bodenbender JP et al.·Sci Rep
2024
TUBB4B Downregulation Is Critical for Increasing Migration of Metastatic Colon Cancer Cells.
Sobierajska K et al.·Cells
2019
A Novel Variant in TUBB4B Causes Progressive Cone-Rod Dystrophy and Early Onset Sensorineural Hearing Loss.
Scarpato M et al.·Mol Genet Genomic Med
2025Case report
R391 human dominant mutation does not affect TubB4b localization and sensory hair cells structure in zebrafish inner ear and lateral line.
Smaili W et al.·Dev Biol
2025Functional
TUBB4B gene mutation in Leber phenotype of congenital amaurosis syndrome associated with early-onset deafness.
Maasz A et al.·Eur J Med Genet
2022
Exploring the diverse clinical and variant spectrum of CEP78-associated syndrome: Novel pathogenic variants identified in a case series.
Zhai Y et al.·Am J Med Genet A
2024Cohort
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools