TUBG1

Chr 17

tubulin gamma 1

Also known as: CDCBM4, GCP-1, TUBG, TUBGCP1

NCBI Gene: 7283 ENSG00000131462 UniProt: P23258

The protein is gamma-tubulin, a key component of the gamma-tubulin ring complex that mediates microtubule nucleation at the centrosome, which is critical for centrosome duplication and spindle formation during cell division. Mutations cause cortical dysplasia with complex brain malformations and follow an autosomal dominant inheritance pattern. The gene is moderately constrained against loss-of-function variants (LOEUF 0.52), reflecting its essential role in cellular division and brain development.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the tubulin superfamily. The encoded protein localizes to the centrosome where it binds to microtubules as part of a complex referred to as the gamma-tubulin ring complex. The protein mediates microtubule nucleation and is required for microtubule formation and progression of the cell cycle. A pseudogene of this gene is found on chromosome 7. [provided by RefSeq, Jan 2009]

GeneReviews ResearchGenerating clinical summary…

DNmechanismLOEUF 0.52

VCEP Guidelines: Brain MalformationsReleased

View Specifications ClinGen Panel

Clinical Summary— TUBG1

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Gene-Disease Validity (ClinGen)

lissencephaly spectrum disorders · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 71 VUS of 227 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TUBG1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.52LOEUF

pLI 0.129

Z-score 3.27

OE 0.26 (0.14–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

4.16Z-score

OE missense 0.30 (0.25–0.36)

82 obs / 276.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.26 (0.14–0.52)

0≤0.351.4

Missense OE?0.30 (0.25–0.36)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 6 / 22.9Missense obs/exp: 82 / 276.4Syn Z: 0.07

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongTUBG1-related posteriorly predominant pachygyria and severe microcephalyOTHERAD

This gene — mechanism propensity

0.7327th %ile

GOF

0.5464th %ile

LOF

0.3065th %ile

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

DNIn view of the fact that both KIF2A alleles are expressed in patient fibroblasts (Supplementary Fig. 4b) and the KIF2A molecule functions as a dimer22, our in vitro and in vivo data are consistent with a dominant-negative effect of these mutations.1

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

References

1.PMID 23603762 ↗

ClinVar Variant Classifications

227 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic12

VUS71

Likely Benign101

Benign26

Conflicting4

Pathogenic

Likely Pathogenic

VUS

101

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	0	2
Likely Pathogenic	1	11	0	0	12
VUS	5	53	11	2	71
Likely Benign	1	1	44	55	101
Benign	0	2	17	7	26
Conflicting	—				4
Total	7	69	72	64	216

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap TUBG1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →